Science.gov

Sample records for key structural analogues

  1. Synthesis of prostaglandin analogues, latanoprost and bimatoprost, using organocatalysis via a key bicyclic enal intermediate.

    PubMed

    Prvost, Sbastien; Thai, Karen; Schtzenmeister, Nina; Coulthard, Graeme; Erb, William; Aggarwal, Varinder K

    2015-02-01

    Two antiglaucoma drugs, bimatoprost and latanoprost, which are analogues of the prostaglandin, PGF2?, have been synthesized in just 7 and 8 steps, respectively. The syntheses employ an organocatalytic aldol reaction that converts succinaldehyde into a key bicyclic enal intermediate, which is primed for attachment of the required lower and upper side chains. By utilizing the crystalline lactone, the drug molecules were prepared in >99% ee. PMID:25582321

  2. Component-based syntheses of trioxacarcin A, DC-45-A1 and structural analogues

    NASA Astrophysics Data System (ADS)

    Magauer, Thomas; Smaltz, Daniel J.; Myers, Andrew G.

    2013-10-01

    The trioxacarcins are polyoxygenated, structurally complex natural products that potently inhibit the growth of cultured human cancer cells. Here we describe syntheses of trioxacarcin A, DC-45-A1 and structural analogues by late-stage stereoselective glycosylation reactions of fully functionalized, differentially protected aglycon substrates. Key issues addressed in this work include the identification of an appropriate means to activate and protect each of the two 2-deoxysugar components, trioxacarcinose A and trioxacarcinose B, as well as a viable sequencing of the glycosidic couplings. The convergent, component-based sequence we present allows for rapid construction of structurally diverse, synthetic analogues that would be inaccessible by any other means, in amounts required to support biological evaluation. Analogues that arise from the modification of four of five modular components are assembled in 11 steps or fewer. The majority of these are found to be active in antiproliferative assays using cultured human cancer cells.

  3. Dirac structures for higher analogues of Courant algebroids

    NASA Astrophysics Data System (ADS)

    Bi, Yanhui; Sheng, Yunhe

    2015-11-01

    In this paper, we introduce the notion of a (p, k)-Dirac structure in TM ? ?pT*M, where 0 ? k ? p - 1. The (p, 0)-Dirac structures are exactly the higher analogues of Dirac structures of order p introduced by Zambon in [L?-algebras and higher analogues of Dirac structures and Courant algebroids, J. Symplectic Geom.10(4) (2012) 563-599]. The (p, p - 1)-Dirac structures are exactly the Nambu-Dirac structures introduced by Hagiwara in [Nambu-Dirac manifolds, J. Phys. A35(5) (2002) 1263-1281]. In the regular case, such a (p, k)-Dirac structure is characterized by a characteristic pair.

  4. The International Space Analogue Rock Store (ISAR): A key tool for future planetary exploration.

    NASA Astrophysics Data System (ADS)

    Bost, N.; Westall, F.; Ramboz, C.; Foucher, F.

    2012-04-01

    In order to prepare the next in situ space missions we have created a « lithothèque » of analogue rocks for calibrating and testing future (and existing) space flight instruments. This rock collection is called the International Space Analogue Rockstore (ISAR) and is hosted in the CNRS and the Observatoire des Sciences de l'Univers en Region Centre (OSUC) in Orléans. For maximum science return, all instruments on a single mission should ideally be tested with the same suite of relevant analogue materials. The ISAR lithothéque aims to fulfill this role by providing suitable materials to instrument teams [1]. The lithothèque is accompanied by an online database of all relevant structural, textural, and geochemical data (www.isar.cnrs-orleans.fr).The data base will also be available during missions to aid interpretation of data obtained in situ. Mars is the immediate goal for MSL-2011 and the new international Mars 2018 mission. The lithothèque thus presently contains relevant Mars-analogue rock and mineral samples, a preliminary range of which is now available to the scientific community for instrument testing [2]. The preliminary group of samples covers a range of lithologies to be found on Mars, especially those in Noachain/Hesperian terrains where MSL will land (Gale Crater) and where the 2018 landing site will most likely be located. It includes a variety of basalts (tephrite, primitive basalt, silicified basalt; plus cumulates), komatiites, artificially synthesized martian basalts [3], volcanic sands, a banded iron formation, carbonates associated with volcanic lithologies and hydrothermalism, the clay Nontronite, and hydrothermal cherts. Some of the silicified volcanic sands contain traces of early life that are good analogues for potential martian life [4]. [1] Westall F. et al., LPI contribution 1608, 1346, 42nd LPSC, 2011; [2] Bost N. et al., in review (Icarus); [3] Bost N. et al., in review (Meteoritics); [4] Westall et al., 2011, Planetary and Space Science 59. ISAR Team: N. Bost, F. Westall, C; Ramboz, F. Foucher, D. Pullan, T. Zegers, B. Hoffman, F. Rull, J. Bridges, A; Steele, H. Amundsen, R. Barbieri, A. Hubert, B. Cavalazzi, J. Bridges, M. Viso, J. Vago, S. Petit, A. Meunier, I. Fleischer, G. Klingelhöfer, N. Arndt…

  5. Polychlorinated biphenyls as hormonally active structural analogues

    SciTech Connect

    McKinney, J.D. ); Waller, C.L. )

    1994-03-01

    Among the environmental chemicals that may be able to disrupt the endocrine systems of animals and humans, the polychlorinated biphenyls (PCBs) are a chemical class of considerable concern. One possible mechanism by which PCBs may interfere with endocrine function is their ability to mimic natural hormones. These actions reflect a close relationship between the physicochemical properties encoded in the PCB molecular structure and the responses they evoke in biological systems. These physiocochemical properties determine the molecular reactivities of PCBs and are responsible for their recognition as biological acceptors and receptors, as well as for triggering molecular mechanisms that lead to tissue response. [open quotes]Coplanarity[close quotes] of PCB phenyl rings and [open quotes]laterality[close quotes] of chlorine atoms are important structural features determining specific binding behavior with proteins and certain toxic responses in biological systems. We compare qualitative structure-activity relationships for PCBs with the limited information on the related non-coplanar chlorinated diphenyl ethers, providing further insights into the nature of the molecular recognition processes and support for the structural relationship of PCBs to thyroid hormones. Steriodlike activity requires conformational restriction and possibility hydroxylation. We offer some simple molecular recognition models to account for the importance of these different structural features in the structure-activity relationships that permit one to express PCB reactivities in terms of dioxin, thyroxine, and estradiol equivalents. The available data support the involvement of PCBs as mimics of thyroid and other steroidal hormones. The potential for reproductive and developmental toxicity associated with human exposure to PCBs is of particular concern. 53 refs., 6 figs.

  6. Novel ynamide structural analogues and their synthetic transformations

    PubMed Central

    Lu, Ting; Hsung, Richard P.

    2015-01-01

    This Highlight accounts for a recent phenomenon in which a series of novel ynamide structural analogues have emerged and caught the attention of the synthetic community. Preparations and reactions of these de novo ynamide variants are delineated here to demonstrate their accessibility as well as their reactivity. This Highlight should help reveal that these unique N-containing alkynes can become highly versatile building blocks in organic syntheses. PMID:26280027

  7. Resveratrol and resveratrol analogues--structure-activity relationship.

    PubMed

    Szekeres, Thomas; Fritzer-Szekeres, Monika; Saiko, Philipp; Jger, Walter

    2010-06-01

    Resveratrol (3,4',5-trihydroxy-trans-stilbene) is a compound found in wine and is held responsible for a number of beneficial effects of red wine. Besides the prevention of heart disease and significant anti-inflammatory effects, resveratrol might inhibit tumor cell growth and even play a role in the aging process. We here describe the structure-activity relationship of resveratrol and analogues of resveratrol regarding the free radical scavenging and antitumor effects of this exciting natural compound. In addition, we have synthesized a number of analogues of resveratrol with the aim to further improve the beneficial effects of resveratrol. Our studies were based on the analysis of structural properties, which were responsible for the most important effects of this compound. Striking in vivo effects can be observed with hexahydroxystilbene (M8), the most effective synthetic analogue of resveratrol. We could show that M8 inhibits tumor as well as metastasis growth of human melanoma in two different animal models, alone and in combination with dacarbacine. PMID:20232118

  8. Structural apelin analogues: mitochondrial ROS inhibition and cardiometabolic protection in myocardial ischaemia reperfusion injury

    PubMed Central

    Pisarenko, Oleg; Shulzhenko, Valentin; Studneva, Irina; Pelogeykina, Yulia; Timoshin, Alexander; Anesia, Rodica; Valet, Philippe; Parini, Angelo; Kunduzova, Oksana

    2015-01-01

    Background and Purpose Mitochondria-derived oxidative stress is believed to be crucially involved in cardiac ischaemia reperfusion (I/R) injury, although currently no therapies exist that specifically target mitochondrial reactive oxygen species (ROS) production. The present study was designed to evaluate the potential effects of the structural analogues of apelin-12, an adipocyte-derived peptide, on mitochondrial ROS generation, cardiomyocyte apoptosis, and metabolic and functional recovery to myocardial I/R injury. Experimental Approach In cultured H9C2 cardiomyoblasts and adult cardiomyocytes, oxidative stress was induced by hypoxia reoxygenation. Isolated rat hearts were subjected to 35?min of global ischaemia and 30?min of reperfusion. Apelin-12, apelin-13 and structural apelin-12 analogues, AI and AII, were infused during 5?min prior to ischaemia. Key Results In cardiac cells, mitochondrial ROS production was inhibited by the structural analogues of apelin, AI and AII, in comparison with the natural peptides, apelin-12 and apelin-13. Treatment of cardiomyocytes with AI and AII decreased cell apoptosis concentration-dependently. In a rat model of I/R injury, pre-ischaemic infusion of AI and AII markedly reduced ROS formation in the myocardial effluent and attenuated cell membrane damage. Prevention of oxidative damage by AI and AII was associated with the improvement of functional and metabolic recovery after I/R in the heart. Conclusions and Implications These data provide the evidence for the potential of the structural apelin analogues in selective reduction of mitochondrial ROS generation and myocardial apoptosis and form the basis for a promising therapeutic strategy in the treatment of oxidative stress-related heart disease. PMID:25521429

  9. Solution structures of purine base analogues 9-deazaguanine and 9-deazahypoxanthine.

    PubMed

    Karnawat, Vishakha; Puranik, Mrinalini

    2016-03-01

    Deaza analogues of nucleobases are potential drugs against infectious diseases caused by parasites. A caveat is that apart from binding their target parasite enzymes, they also bind and inhibit enzymes of the host. In order to design derivatives of deaza analogues which specifically bind target enzymes, knowledge of their molecular structure, protonation state, and predominant tautomers at physiological conditions is essential. We have employed resonance Raman spectroscopy at an excitation wavelength of 260nm, to decipher solution structure of 9-deazaguanine (9DAG) and 9-deazahypoxanthine (9DAH). These are analogues of guanine and hypoxanthine, respectively, and have been exploited to study static complexes of nucleobase binding enzymes. Such enzymes are known to perturb pKa of their ligands, and thus, we also determined solution structures of these analogues at two, acidic and alkaline, pH. Structure of each possible protonation state and tautomer was computed using density functional theoretical calculations. Species at various pHs were identified based on isotopic shifts in experimental wavenumbers and by comparing these shifts with corresponding computed isotopic shifts. Our results show that at physiological pH, N1 of pyrimidine ring in 9DAG and 9DAH bears a proton. At lower pH, N3 is place of protonation, and at higher pH, deprotonation occurs at N1 position. The proton at N7 of purine ring remains intact even at pH 12.5. We have further compared these results with naturally occurring nucleotides. Our results identify key vibrational modes which can report on hydrogen bonding interactions, protonation and deprotonation in purine rings upon binding to the active site of enzymes. PMID:25894214

  10. [Insulin analogues: modifications in the structure, molecular and metabolic consequences].

    PubMed

    de Luis, D A; Romero, E

    2013-01-01

    Recombinant DNA technology has provided insulin analogues for the treatment of diabetes mellitus, with an efficacy and safety that has improved the treatment of this disease. We briefly review the principal characteristics of the insulin analogues currently available. Both rapid-acting (lispro, aspart and glulisine) and long acting (glargine and determir) insulin analogues are included in this review. We describe the pharmacology of each insulin analogue, their differences with the human insulin, the administration, indication, efficacy and safety. In addition we discussed the main controversies of the use of these insulin analogues. In particular, those related with the risk of cancer and retinopathy, and their use in pregnant women. PMID:23517895

  11. Structural analogues inhibit the sensitizing capacity of carvone.

    PubMed

    Karlberg, A T; Nilsson, A M; Luthman, K; Nilsson, J L

    2001-01-01

    The aim of the study was to investigate the effect of non-allergenic structural analogues on the sensitizing potential of carvone, a fragrance allergen. The possibility that one molecule might inhibit the allergenic activity of another molecule has been debated for 25 years. The Research Institute for Fragrance Materials states that the sensitizing activity from certain fragrance aldehydes is "quenched" by the addition of other specific chemicals. However, other studies do not confirm the results, although several attempts have been made. We used a guinea pig method designed to study the sensitizing capacity of fragrance allergens. Induction was performed with either carvone alone or with a mixture of carvone and one of two analogues. A significant difference in the response rates (p < 0.001) was observed between the animals induced with carvone alone and those induced with any of the mixtures. Our investigation shows that by using selected molecules it is possible to significantly reduce the sensitizing effect of a fragrance allergen. PMID:11859940

  12. Improved synthesis of structural analogues of (-)-epicatechin gallate for modulation of staphylococcal ?-lactam resistance.

    PubMed

    Anderson, James C; Grounds, Helen; Reeves, Suzanna; Taylor, Peter W

    2014-05-27

    The high-yielding synthesis of enantiomerically pure epicatechin gallate analogues where the A and/or B-ring hydroxylation is reduced or altered has been achieved by optimising routes to the catechin stereochemistry. The B-ring analogues were synthesised by using an electrophilic ring closure onto an enantiomerically enriched epoxide as a key step. The A and B-ring hydroxyl-deleted analogues were synthesised through a Mitsunobu cyclisation. For the B-ring analogues, the anti- (catechin) stereochemistry was converted to the syn- (epicatechin) stereochemistry by a known oxidation/reduction protocol. Absolute stereochemistry was derived from either a Sharpless epoxidation or asymmetric dihydroxylation. PMID:24876661

  13. Capsaicin and its analogues: structure-activity relationship study.

    PubMed

    Huang, X-F; Xue, J-Y; Jiang, A-Q; Zhu, H-L

    2013-01-01

    Capsaicin, the main ingredient responsible for the hot pungent taste of chilli peppers, is an alkaloid found in the Capsicum family. Capsaicin was traditionally used for muscular pain, headaches, to improve circulation and for its gastrointestinal protective effects. It was also commonly added to herbal formulations because it acts as a catalyst for other herbs and aids in their absorption. In addition, capsaicin and other capsaicinoid compounds showed strong evidence of having promising potential in the fight against many types of cancer. The mechanism of action of capsaicin has been extensively studied over the past decade. It has been established that capsaicin binds to the transient receptor potential vanilloid 1 receptor which was expressed predominantly by sensory neurons. And many analogues of capsaicin have been synthesized and evaluated for diverse bioactivities. In this review, we will attempt to summarize the biology and structure-activity relationship of capsaicinoids. PMID:23627937

  14. Modern freshwater microbialite analogues for ancient dendritic reef structures

    NASA Technical Reports Server (NTRS)

    Laval, B.; Cady, S. L.; Pollack, J. C.; McKay, C. P.; Bird, J. S.; Grotzinger, J. P.; Ford, D. C.; Bohm, H. R.

    2000-01-01

    Microbialites are organosedimentary structures that can be constructed by a variety of metabolically distinct taxa. Consequently, microbialite structures abound in the fossil record, although the exact nature of the biogeochemical processes that produced them is often unknown. One such class of ancient calcareous structures, Epiphyton and Girvanella, appear in great abundance during the Early Cambrian. Together with Archeocyathids, stromatolites and thrombolites, they formed major Cambrian reef belts. To a large extent, Middle to Late Cambrian reefs are similar to Precambrian reefs, with the exception that the latter, including terminal Proterozoic reefs, do not contain Epiphyton or Girvanella. Here we report the discovery in Pavilion Lake, British Columbia, Canada, of a distinctive assemblage of freshwater calcite microbialites, some of which display microstructures similar to the fabrics displayed by Epiphyton and Girvanella. The morphologies of the modern microbialites vary with depth, and dendritic microstructures of the deep water (> 30 m) mounds indicate that they may be modern analogues for the ancient calcareous structures. These microbialites thus provide an opportunity to study the biogeochemical interactions that produce fabrics similar to those of some enigmatic Early Cambrian reef structures.

  15. Antithyroid drugs and their analogues: synthesis, structure, and mechanism of action.

    PubMed

    Manna, Debasish; Roy, Gouriprasanna; Mugesh, Govindasamy

    2013-11-19

    Thyroid hormones are essential for the development and differentiation of all cells of the human body. They regulate protein, fat, and carbohydrate metabolism. In this Account, we discuss the synthesis, structure, and mechanism of action of thyroid hormones and their analogues. The prohormone thyroxine (T4) is synthesized on thyroglobulin by thyroid peroxidase (TPO), a heme enzyme that uses iodide and hydrogen peroxide to perform iodination and phenolic coupling reactions. The monodeiodination of T4 to 3,3',5-triiodothyronine (T3) by selenium-containing deiodinases (ID-1, ID-2) is a key step in the activation of thyroid hormones. The type 3 deiodinase (ID-3) catalyzes the deactivation of thyroid hormone in a process that removes iodine selectively from the tyrosyl ring of T4 to produce 3,3',5'-triiodothyronine (rT3). Several physiological and pathological stimuli influence thyroid hormone synthesis. The overproduction of thyroid hormones leads to hyperthyroidism, which is treated by antithyroid drugs that either inhibit the thyroid hormone biosynthesis and/or decrease the conversion of T4 to T3. Antithyroid drugs are thiourea-based compounds, which include propylthiouracil (PTU), methimazole (MMI), and carbimazole (CBZ). The thyroid gland actively concentrates these heterocyclic compounds against a concentration gradient. Recently, the selenium analogues of PTU, MMI, and CBZ attracted significant attention because the selenium moiety in these compounds has a higher nucleophilicity than that of the sulfur moiety. Researchers have developed new methods for the synthesis of the selenium compounds. Several experimental and theoretical investigations revealed that the selone (C?Se) in the selenium analogues is more polarized than the thione (C?S) in the sulfur compounds, and the selones exist predominantly in their zwitterionic forms. Although the thionamide-based antithyroid drugs have been used for almost 70 years, the mechanism of their action is not completely understood. Most investigations have revealed that MMI and PTU irreversibly inhibit TPO. PTU, MTU, and their selenium analogues also inhibit ID-1, most likely by reacting with the selenenyl iodide intermediate. The good ID-1 inhibitory activity of PTU and its analogues can be ascribed to the presence of the -N(H)-C(?O)- functionality that can form hydrogen bonds with nearby amino acid residues in the selenenyl sulfide state. In addition to the TPO and ID-1 inhibition, the selenium analogues are very good antioxidants. In the presence of cellular reducing agents such as GSH, these compounds catalytically reduce hydrogen peroxide. They can also efficiently scavenge peroxynitrite, a potent biological oxidant and nitrating agent. PMID:23883148

  16. Total synthesis, stereochemical assignment, and biological activity of chamuvarinin and structural analogues.

    PubMed

    Florence, Gordon J; Morris, Joanne C; Murray, Ross G; Vanga, Raghava R; Osler, Jonathan D; Smith, Terry K

    2013-06-17

    A highly stereocontrolled synthesis of (+)-chamuvarinin has been completed in 1.5% overall yield over 20 steps. The key fragment coupling reactions were the addition of alkyne 8 to aldehyde 7 (under Felkin-Anh control), followed by the two step activation/cyclization to close the C20-C23 2,5-cis-substituted tetrahydrofuran ring and a Julia-Kocienski olefination at C8-C9 to introduce the terminal butenolide. The inherent flexibility of our coupling strategy led to a streamlined synthesis with 17 steps in the longest sequence (2.2% overall yield), in which the key bond couplings are reversed. In addition, a series of structural analogues of chamuvarinin have been prepared and screened for activity against HeLa cancer cell lines and both the bloodstream and insect forms of Trypanosoma brucei, the parasitic agent responsible for African sleeping sickness. PMID:23630031

  17. DNA information: from digital code to analogue structure.

    PubMed

    Travers, A A; Muskhelishvili, G; Thompson, J M T

    2012-06-28

    The digital linear coding carried by the base pairs in the DNA double helix is now known to have an important component that acts by altering, along its length, the natural shape and stiffness of the molecule. In this way, one region of DNA is structurally distinguished from another, constituting an additional form of encoded information manifest in three-dimensional space. These shape and stiffness variations help in guiding and facilitating the DNA during its three-dimensional spatial interactions. Such interactions with itself allow communication between genes and enhanced wrapping and histone-octamer binding within the nucleosome core particle. Meanwhile, interactions with proteins can have a reduced entropic binding penalty owing to advantageous sequence-dependent bending anisotropy. Sequence periodicity within the DNA, giving a corresponding structural periodicity of shape and stiffness, also influences the supercoiling of the molecule, which, in turn, plays an important facilitating role. In effect, the super-helical density acts as an analogue regulatory mode in contrast to the more commonly acknowledged purely digital mode. Many of these ideas are still poorly understood, and represent a fundamental and outstanding biological question. This review gives an overview of very recent developments, and hopefully identifies promising future lines of enquiry. PMID:22615471

  18. In Vitro Structure-Activity Relationship of Re-cyclized Octreotide Analogues

    PubMed Central

    Dannoon, Shorouk F.; Bigott-Hennkens, Heather M.; Ma, Lixin; Gallazzi, Fabio; Lewis, Michael R.; Jurisson, Silvia S.

    2010-01-01

    Introduction Development of radiolabeled octreotide analogues is of interest for targeting somatostatin receptor-positive tumors for diagnostic and therapeutic purposes. We are investigating a direct labeling approach for incorporation of a Re ion into octreotide analogues, where the peptide sequences are cyclized via coordination to Re rather than through a disulfide bridge. Methods Various octreotide analogue sequences and coordination systems (e.g., S2N2 and S3N) were synthesized and cyclized with non-radioactive Re. In vitro competitive binding assays with 111In-DOTA-Tyr3-octreotide in AR42J rat pancreatic tumor cells yielded IC50 values as a measure of somatostatin receptor affinity of the Re-cyclized analogues. Three-dimensional structures of Re-cyclized Tyr3-octreotate and its disulfide-bridged analogue were calculated from two-dimensional NMR experiments to visualize the effect of metal cyclization on the analogues pharmacophore. Results Only two of the eleven Re-cyclized analogues investigated showed moderate in vitro binding affinity toward somatostatin subtype 2 receptors. Three-dimensional molecular structures of Re- and disulfide-cyclized Tyr3-octreotate were calculated, and both of their pharmacophore turns appear to be very similar with minor differences due to metal coordination to the amide nitrogen of one of the pharmacophore amino acids. Conclusions Various Re-cyclized analogues were developed and analogue 4 had moderate affinity toward somatostatin subtype 2 receptors. In vitro stable studies that are in progress showed stable radiometal-cyclization of octreotide analogues via NS3 and N2S2 coordination forming 5- and 6- membered chelate rings. In vivo biodistribution studies are underway of 99m Tc- cyclized analogue 4. PMID:20610157

  19. A comparative study on the crystal structure of bicycle analogues to the natural phytotoxin helminthosporins

    NASA Astrophysics Data System (ADS)

    Barbosa, Luiz Cláudio de Almeida; Teixeira, Robson Ricardo; Nogueira, Leonardo Brandão; Maltha, Celia Regina Alvares; Doriguetto, Antônio Carlos; Martins, Felipe Terra

    2016-02-01

    Herein we described structural insights of a series of analogues to helminthosporin phytotoxins. The key reaction used to prepare the compounds corresponded to the [3 + 4] cycloaddition between the oxyallyl cation generated from 2,4-dibromopentan-3-one and different furans. Their structures were confirmed upon IR, NMR and X-ray diffraction analyses. While bicycles 7, 8 and 9 crystallize in the centrosymmetric monoclinic space group P21/c, compound 10 was solved in the noncentrosymmetric orthorhombic space group P212121. The solid materials obtained were shown to be racemic crystals (7, 8, 9) or racemic conglomerate (10). In all compounds, there is formation of a bicycle featured by fused tetrahydropyranone and 2,5-dihydrofuran rings. They adopt chair and envelope conformations, respectively. Crystal packing of all compounds is stabilized through C-H•••O contacts. Conformational aspects as well as similarities and differences among the crystal structures of the synthesized analogues are discussed.

  20. Isoxazole analogues bind the System xc? Transporter: Structure-activity Relationship and Pharmacophore Model

    PubMed Central

    Patel, Sarjubhai A.; Rajale, Trideep; OBrien, Erin; Burkhart, David J.; Nelson, Jared K.; Twamley, Brendan; Blumenfeld, Alex; Szabon-Watola, Monika I.; Gerdes, John M.; Bridges, Richard J.; Natale, Nicholas R.

    2009-01-01

    Analogues of amino methylisoxazole propionic acid (AMPA), were prepared from a common intermediate 12, including lipophilic analogues using lateral metalation and electrophilic quenching, and were evaluated at System xc?. Both the 5-naphthylethyl-(16) and 5-naphthylmethoxymethyl-(17) analogues adopt an E-conformation in the solid state, yet while the former has robust binding at System xc?, the latter is virtually devoid of activity. The most potent analogues were amino acid naphthyl-ACPA 7g, and hydrazone carboxylic acid, 11e Y=Y?=3,5-(CF3)2, which both inhibited glutamate up-take by the System xc? transporter with comparable potency to the endogenous substrate cystine, whereas in contrast the closed isoxazolo[3,4-d] pyridazinones 13 have significantly lower activity. A preliminary pharmacophore model has been constructed to provide insight into the analogue structure-activity relationships. PMID:19932968

  1. Synthesis and structure/antioxidant activity relationship of novel catecholic antioxidant structural analogues to hydroxytyrosol and its lipophilic esters.

    PubMed

    Bernini, Roberta; Crisante, Fernanda; Barontini, Maurizio; Tofani, Daniela; Balducci, Valentina; Gambacorta, Augusto

    2012-08-01

    A large panel of novel catecholic antioxidants and their fatty acid or methyl carbonate esters has been synthesized in satisfactory to good yields through a 2-iodoxybenzoic acid (IBX)-mediated aromatic hydroxylation as the key step. The new catechols are structural analogues of naturally occurring hydroxytyrosol (3,4-DHE). To evaluate structure/activity relationships, the antioxidant properties of all catecholic compounds were evaluated in vitro by ABTS assay and on whole cells by DCF fluorometric assay and compared with that of the corresponding already known hydroxytyrosyl derivatives. Results outline that all of the new catechols show antioxidant capacity in vitro higher than that of the corresponding hydroxytyrosyl derivatives. Less evident positive effects have been detected in whole cells experiments. Cytotoxicity experiments, using MTT assay, on a representative set of compounds evidenced no influence in cell survival. PMID:22780104

  2. Preparing to return to the Moon: Lessons from science-driven analogue missions to the Mistastin Lake impact structure, Canada, a unique lunar analogue site

    NASA Astrophysics Data System (ADS)

    Osinski, G. R.; Barfoot, T.; Chanou, A.; Daly, M. G.; Francis, R.; Hodges, K. V.; Jolliff, B. L.; Mader, M. M.; McCullough, E. M.; Moores, J. E.; Pickersgill, A.; Pontefract, A.; Preston, L.; Shankar, B.; Singleton, A.; Sylvester, P.; Tornabene, L. L.; Young, K. E.

    2013-12-01

    Impact cratering is the dominant geological process on the Moon, Near Earth Asteroids (NEAs) and the moons of Mars - the objectives for the new Solar System Exploration Research Virtual Institute (SSERVI). Led by members of the Canadian Lunar Research Network (CLRN), funded by the Canadian Space Agency, and with participants from the U.S., we carried out a series of analogue missions on Earth in order to prepare and train for future potential robotic and human sample return missions. Critically, these analogue missions were driven by the paradigm that operational and technical objectives are conducted while conducting new science and addressing real overarching scientific objectives. An overarching operational goal was to assess the utility of a robotic field reconnaissance mission as a precursor to a human sortie sample return mission. Here, we focus on the results and lessons learned from a robotic precursor mission and follow on human-robotic mission to the Mistastin Lake impact structure in Labrador, northern Canada (5553'N; 6318'W). The Mistastin structure was chosen because it represents an exceptional analogue for lunar craters. This site includes both an anorthositic target, a central uplift, well-preserved impact melt rocks - mostly derived from melting anorthosite - and is (or was) relatively unexplored. This crater formed ~36 million years ago and has a diameter of ~28 km. The scientific goals for these analogue missions were to further our understanding of impact chronology, shock processes, impact ejecta and potential resources within impact craters. By combining these goals in an analogue mission campaign key scientific requirements for a robotic precursor were determined. From the outset, these analogue missions were formulated and executed like an actual space mission. Sites of interest were chosen using remote sensing imagery without a priori knowledge of the site through a rigorous site selection process. The first deployment occurred in August and September 2010 and involved simulated robotic surveying of selected 'landing sites' at the Mistastin structure. The second deployment took place at the same location in 2011, which included simulated astronaut surface operations with, and without, the aid of a robotic assistant. A mission control team, based at the University of Western Ontario, London, Ontario, 1,900 km from the field site, oversaw operations. Our study showed the value of precursor reconnaissance missions in providing surface geology visualization at resolutions and from viewpoints not achievable from orbit, including high-resolution surface imagery on the scale of 10s of metres to kilometres. Indeed, data collected during the robotic precursor mission led to the formulation of a hypothesis that a large impact melt outcrop - named Discovery Hill - represents an impact melt pond in the terraced region of the crater, analogous to similar ponds of melt documented around the rim of well-preserved lunar craters such as Tycho. Further discoveries, that will be highlight here, include documentation of ejecta deposits for the first time at Mistastin, quantification of shock in anorthosites, and refined age estimates for the Mistastin impact event.

  3. Photosensitising potency of structural analogues of benzoporphyrin derivative (BPD) in a mouse tumour model.

    PubMed Central

    Richter, A. M.; Waterfield, E.; Jain, A. K.; Allison, B.; Sternberg, E. D.; Dolphin, D.; Levy, J. G.

    1991-01-01

    The in vivo characteristics of four analogues of benzoporphyrin derivative (BPD) have been investigated. Biodistribution data obtained in DBA/2J mice with BPD-MA (monoacid ring A analogue) which had been tritiated or internally labelled with 14C showed that both labelled materials acted in an essentially identical manner during the period of study. Biodistribution and clearance studies showed that relative distribution in a variety of mouse tissues was similar for all BPD analogues. M1 tumour cells (rhabdomyosarcoma in DBA/2J mice) taken from tumours excised from animals treated 3 h earlier with BPD, and tested in vitro for photosensitivity provided evidence that significant levels of photosensitiser detected in tumour was both active and associated with tumour cells. The monoacid forms of BPD were found to be much more photodynamically active in this test than were the diacid analogues. The ability of the analogues to ablate tumours in mice by photodynamic therapy was also tested. Again, BPD-MA and BPD-MB proved to be measurably better than the diacid analogues. These findings are discussed in reference to structural and physical differences between the analogues. PMID:1989669

  4. Synthesis and Biopharmaceutical Evaluation of Imatinib Analogues Featuring Unusual Structural Motifs.

    PubMed

    Nicolaou, Kyriacos C; Vourloumis, Dionisios; Totokotsopoulos, Sotirios; Papakyriakou, Athanasios; Karsunky, Holger; Fernando, Hanan; Gavrilyuk, Julia; Webb, Damien; Stepan, Antonia F

    2016-01-01

    A convenient synthesis of imatinib, a potent inhibitor of ABL1 kinase and widely prescribed drug for the treatment of a variety of leukemias, was devised and applied to the construction of a series of novel imatinib analogues featuring a number of non-aromatic structural motifs in place of the parent molecule's phenyl moiety. These analogues were subsequently evaluated for their biopharmaceutical properties (e.g., ABL1 kinase inhibitory activity, cytotoxicity). The bicyclo[1.1.1]pentane- and cubane-containing analogues were found to possess higher themodynamic solubility, whereas cubane- and cyclohexyl-containing analogues exhibited the highest inhibitory activity against ABL1 kinase and the most potent cytotoxicity values against cancer cell lines K562 and SUP-B15. Molecular modeling was employed to rationalize the weak activity of the compounds against ABL1 kinase, and it is likely that the observed cytotoxicity of these agents arises through off-target effects. PMID:26585829

  5. Lead structures for new antibacterials: stereocontrolled synthesis of a bioactive muraymycin analogue.

    PubMed

    Spork, Anatol P; Bschleb, Martin; Ries, Oliver; Wiegmann, Daniel; Boettcher, Stefan; Mihalyi, Agnes; Bugg, Timothy D H; Ducho, Christian

    2014-11-17

    Naturally occurring muraymycin nucleoside antibiotics represent a promising class of novel antibacterial agents. The structural complexity suggests the investigation of simplified analogues as potential lead structures, which can then be further optimized towards highly potent antimicrobials. Herein we report studies on muraymycin-derived potential lead structures lacking an aminoribose motif found in most naturally occurring muraymycins. We have identified a 5'-defunctionalized motif to be ideal in terms of stability and chemical accessibility and have synthesized a full-length muraymycin analogue based on this structure using a novel fully stereocontrolled route. The obtained 5'-deoxy analogue of the natural product muraymycin C4 showed good inhibitory properties towards the bacterial target protein MraY, sufficient pharmacokinetic stability and no cytotoxicity against human cells, thus making it a promising lead for antibacterial drug development. PMID:25318977

  6. The Clar Structure in Inorganic BN Analogues of Polybenzenoid Hydrocarbons: Does it Exist or Not?

    PubMed

    Wu, Jingjing; Zhu, Jun

    2015-12-01

    The Clar structure of polybenzenoid hydrocarbons (PBHs) have attracted considerable interest of both theoretical and experimental chemists since it was proposed in the 1950s. However, it remains unclear whether the Clar structure could exist in inorganic PBHs, the boron nitride (BN) analogues where the alternate boron and nitrogen atoms are used to replace the carbon atoms of PBHs. Here, we carry out thorough density functional theory (DFT) calculations to probe the possibility of Clar structures in BN analogues of PBHs. A strong correlation (r(2) =0.975) between the ring number (n=3-10) of BN analogues of [n]acenes and energy differences between the most and least stable isomers is identified, suggesting the existence of Clar structures in inorganic PBHs. In addition, the slightly weaker correlations in comparison to that (r(2) =0.989) of the organic PBHs is rationalized by the reduced aromaticity, which is revealed by two aromatic indices: ELF? and SCI. PMID:26467786

  7. Total Synthesis of Viridicatumtoxin B and Analogues Thereof: Strategy Evolution, Structural Revision, and Biological Evaluation

    PubMed Central

    2015-01-01

    The details of the total synthesis of viridicatumtoxin B (1) are described. Initial synthetic strategies toward this intriguing tetracycline antibiotic resulted in the development of key alkylation and Lewis acid-mediated spirocyclization reactions to form the hindered EF spirojunction, as well as MichaelDieckmann reactions to set the A and C rings. The use of an aromatic A-ring substrate, however, was found to be unsuitable for the introduction of the requisite hydroxyl groups at carbons 4a and 12a. Applying these previous tactics, we developed stepwise approaches to oxidize carbons 12a and 4a based on enol- and enolate-based oxidations, respectively, the latter of which was accomplished after systematic investigations that revealed critical reactivity patterns. The herein described synthetic strategy resulted in the total synthesis of viridicatumtoxin B (1), which, in turn, formed the basis for the revision of its originally assigned structure. The developed chemistry facilitated the synthesis of a series of viridicatumtoxin analogues, which were evaluated against Gram-positive and Gram-negative bacterial strains, including drug-resistant pathogens, revealing the first structureactivity relationships within this structural type. PMID:25317739

  8. Total synthesis of viridicatumtoxin B and analogues thereof: strategy evolution, structural revision, and biological evaluation.

    PubMed

    Nicolaou, K C; Hale, Christopher R H; Nilewski, Christian; Ioannidou, Heraklidia A; ElMarrouni, Abdelatif; Nilewski, Lizanne G; Beabout, Kathryn; Wang, Tim T; Shamoo, Yousif

    2014-08-27

    The details of the total synthesis of viridicatumtoxin B (1) are described. Initial synthetic strategies toward this intriguing tetracycline antibiotic resulted in the development of key alkylation and Lewis acid-mediated spirocyclization reactions to form the hindered EF spirojunction, as well as Michael-Dieckmann reactions to set the A and C rings. The use of an aromatic A-ring substrate, however, was found to be unsuitable for the introduction of the requisite hydroxyl groups at carbons 4a and 12a. Applying these previous tactics, we developed stepwise approaches to oxidize carbons 12a and 4a based on enol- and enolate-based oxidations, respectively, the latter of which was accomplished after systematic investigations that revealed critical reactivity patterns. The herein described synthetic strategy resulted in the total synthesis of viridicatumtoxin B (1), which, in turn, formed the basis for the revision of its originally assigned structure. The developed chemistry facilitated the synthesis of a series of viridicatumtoxin analogues, which were evaluated against Gram-positive and Gram-negative bacterial strains, including drug-resistant pathogens, revealing the first structure-activity relationships within this structural type. PMID:25317739

  9. Dipolar Quinoidal Acene Analogues as Stable Isoelectronic Structures of Pentacene and Nonacene.

    PubMed

    Shi, Xueliang; Kueh, Weixiang; Zheng, Bin; Huang, Kuo-Wei; Chi, Chunyan

    2015-11-23

    Quinoidal thia-acene analogues, as the respective isoelectronic structures of pentacene and nonacene, were synthesized and an unusual 1,2-sulfur migration was observed during the Friedel-Crafts alkylation reaction. The analogues display a closed-shell quinoidal structure in the ground state with a distinctive dipolar character. In contrast to their acene isoelectronic structures, both compounds are stable because of the existence of more aromatic sextet rings, a dipolar character, and kinetic blocking. They exhibit unique packing in single crystals resulting from balanced dipole-dipole and [C?H????]/[C?H???S] interactions. PMID:26447720

  10. Structure and UV absorption of QCCs: carbonaceous dust analogues.

    PubMed

    Wada, S; Kaito, C; Kimura, S; Tokunaga, A T

    1999-01-01

    "Quenched Carbonaceous Composites (QCCs)" are carbonaceous interstellar dust analogues synthesized in the laboratory from a hydrocarbon plasma. We produced new types of carbonaceous condensates from the ejecta of plasma with mixtures of methane and hydrogen as source gases. We find that QCC with an absorbance peak at 220 nm is composed of onion-like spherules, and QCCs with an absorbance peak at 230-240 nm are composed of polyhedral particles. The onion-like QCC contains aromatic hydrogen bonds, and it shows the 3.3 and 11.4 micrometers absorption bands. The QCC with an absorbance peak at 230-240 nm is composed of ribbons with bent graphitic layers. This suggests that the carrier of the interstellar 220 nm extinction band might also be an emitter of the interstellar diffuse emission bands. PMID:11543341

  11. Design and X-ray crystal structures of human thrombin with synthetic cyanopeptide-analogues.

    PubMed

    Radau, G; Fokkens, J

    2007-02-01

    Based on the X-ray crystals of cocrystallized cyanopeptide-trypsin and cyanopeptide-thrombin-com-plexes, a rational drug design succeeded in the establishment of suitable lead structures for the development of new potential inhibitors of thrombin. This report deals with the design and X-ray crystallography data of new synthetic, low-molecular weight cyanopeptide-analogues, RA-1008 and RA-1014, complexed with human alpha-thrombin at 1.85 A resolution. The crystal structures of the complexes reveal, by analogy with modeling studies, that the salt bridge of Asp189 to this type of synthetic thrombin inhibitors leads to an almost identically binding into the S1 specificity pocket in comparison to the complex of the natural products, whereas in the overall binding modes the P2-P4 substructures differ from those of the leads. The strongest member of the second series of described thrombin inhibitors, RA-1014, shows in the crystal complex with thrombin a slightly higher affinity towards the enzyme than RA-1008 as confirmed by inhibition tests. This result and other key informations will be helpful to design a more potent series of inhibitors. PMID:17341023

  12. Magnetic-Directed Assembly from Janus Building Blocks to Multiplex Molecular-Analogue Photonic Crystal Structures.

    PubMed

    Yin, Su-Na; Yang, Shengyang; Wang, Cai-Feng; Chen, Su

    2016-01-20

    The predictable assembly of colloidal particles into a programmable superstructure is a challenging and vital task in chemistry and materials science. In this work, we develop an available magnetic-directed assembly strategy to construct a series of molecular-analogue photonic crystal cluster particles involving dot, line, triangle, tetrahedron, and triangular bipyramid configurations from solid-liquid Janus building blocks. These versatile multiplex molecular-analogue structural clusters containing photonic band gap, fluorescent, and magnetic information can open a new promising access to a variety of robust hierarchical microstructural particle materials. PMID:26708560

  13. Structural and Spectroscopic Characterizations of Amide-AlCl3-Based Ionic Liquid Analogues.

    PubMed

    Hu, Pengcheng; Zhang, Rui; Meng, Xianghai; Liu, Haiyan; Xu, Chunming; Liu, Zhichang

    2016-03-01

    Several amide-AlCl3-based ionic liquid (IL) analogues were synthesized through a one-step method using three different structure amides as donor molecules. The effects of the steric and inductive effects of the methyl group substituted on the N atom on the asymmetric splitting of AlCl3 and the coordination site of the amide were investigated by (27)Al NMR, Raman, in situ IR, and UV-vis spectra for these IL analogues. Bidentate coordination through both the O and N atoms was dominant in the N-methylacetamide-AlCl3- and N,N-dimethylacetamide-AlCl3-based IL analogues because of the inductive effect of the methyl group. By contrast, the acetamide-AlCl3-based IL analogue presented mainly in the form of monodentate coordination via the O atom. Compared with monodentate coordination, bidentate coordination was favorable to the asymmetric splitting of AlCl3 with the same amide-AlCl3 molar ratio. Under the influence of the steric and inductive effects of the methyl group, the ionic species percentages in these IL analogues ranked in the following order: N-methylacetamide > N,N-dimethylacetamide > acetamide. PMID:26848508

  14. The development of structures in analogue and natural debris avalanches

    NASA Astrophysics Data System (ADS)

    Paguican, Engielle Mae; van Wyk de Vries, Benjamin; Mahar Francisco Lagmay, Alfredo; Grosse, Pablo

    2010-05-01

    All types of rockslide-debris avalanches present a plethora of internal structures that are also well observed on the surface. Many of these are seen as faults and folds that can be used to determine deformation history and kinematics. We present two sets of simple and well-constrained experiments of reduced basal friction laboratory rockslides, equivalent to a highly deformed simple shear layer, with plug-flow. These follow the original ramp-slide work of Shea and van Wyk de Vries (Geosphere, 2008). The experiments used a curved ramp where materials accelerate until reaching a gently-sloped depositional surface and a constantly inclined ramp with a more regular slope and longer slides. A detailed description of deposit structures, their sequential formation and morphology is then used to investigate the transport type and deformation chronology from slide initiation to runout stopping of avalanches. Results using a curved ramp show accumulation and thickening at where the slope decreases. The thickened mass then further remobilises and advances by secondary collapse of the mass. Such a stop-start process may be important in many mountainous avalanches where there are rapid changes in slope. The constantly inclined ramp shows shearing and extensional structures at the levees and a set of compression and extension structures in the middle. We noted that frontal accumulation during flow occurs as materials at the front move slower relative to those in the medial and proximal zones. This also leads to secondary frontal collapse, and helps to maintain a thicker mass that can flow further. Descriptions and analyses of these structures are then applied to the kinematics and dynamics of natural examples. We study the 2006 Guinsaugon Rockslide event in the Philippines and find that frontal accumulation and secondary avalanching had also occurred and were important in determining the distribution and runout of the mass. Frontal bulking and collapse may also have occurred at the Tacna Avalanche, Peru and the Pajonales-Aracar event in Argentina.

  15. Structure of mandelate racemase with bound intermediate analogues benzohydroxamate and cupferron.

    PubMed

    Lietzan, Adam D; Nagar, Mitesh; Pellmann, Elise A; Bourque, Jennifer R; Bearne, Stephen L; St Maurice, Martin

    2012-02-14

    Mandelate racemase (MR, EC 5.1.2.2) from Pseudomonas putida catalyzes the Mg(2+)-dependent interconversion of the enantiomers of mandelate, stabilizing the altered substrate in the transition state by 26 kcal/mol relative to the substrate in the ground state. To understand the origins of this binding discrimination, we determined the X-ray crystal structures of wild-type MR complexed with two analogues of the putative aci-carboxylate intermediate, benzohydroxamate and Cupferron, to 2.2-Å resolution. Benzohydroxamate is shown to be a reasonable mimic of the transition state and/or intermediate because its binding affinity for 21 MR variants correlates well with changes in the free energy of transition state stabilization afforded by these variants. Both benzohydroxamate and Cupferron chelate the active site divalent metal ion and are bound in a conformation with the phenyl ring coplanar with the hydroxamate and diazeniumdiolate moieties, respectively. Structural overlays of MR complexed with benzohydroxamate, Cupferron, and the ground state analogue (S)-atrolactate reveal that the para carbon of the substrate phenyl ring moves by 0.8-1.2 Å between the ground state and intermediate state, consistent with the proposal that the phenyl ring moves during MR catalysis while the polar groups remain relatively fixed. Although the overall protein structure of MR with bound intermediate analogues is very similar to that of MR with bound (S)-atrolactate, the intermediate-Mg(2+) distance becomes shorter, suggesting a tighter complex with the catalytic Mg(2+). In addition, Tyr 54 moves closer to the phenyl ring of the bound intermediate analogues, contributing to an overall constriction of the active site cavity. However, site-directed mutagenesis experiments revealed that the role of Tyr 54 in MR catalysis is relatively minor, suggesting that alterations in enzyme structure that contribute to discrimination between the altered substrate in the transition state and the ground state by this proficient enzyme are extremely subtle. PMID:22264153

  16. Structure of Mandelate Racemase with Bound Intermediate Analogues Benzohydroxamate and Cupferron

    SciTech Connect

    Lietzan, Adam D.; Nagar, Mitesh; Pellmann, Elise A.; Bourque, Jennifer R.; Bearne, Stephen L.; Maurice, Martin St.

    2012-05-09

    Mandelate racemase (MR, EC 5.1.2.2) from Pseudomonas putida catalyzes the Mg{sup 2+}-dependent interconversion of the enantiomers of mandelate, stabilizing the altered substrate in the transition state by 26 kcal/mol relative to the substrate in the ground state. To understand the origins of this binding discrimination, we determined the X-ray crystal structures of wild-type MR complexed with two analogues of the putative aci-carboxylate intermediate, benzohydroxamate and Cupferron, to 2.2-{angstrom} resolution. Benzohydroxamate is shown to be a reasonable mimic of the transition state and/or intermediate because its binding affinity for 21 MR variants correlates well with changes in the free energy of transition state stabilization afforded by these variants. Both benzohydroxamate and Cupferron chelate the active site divalent metal ion and are bound in a conformation with the phenyl ring coplanar with the hydroxamate and diazeniumdiolate moieties, respectively. Structural overlays of MR complexed with benzohydroxamate, Cupferron, and the ground state analogue (S)-atrolactate reveal that the para carbon of the substrate phenyl ring moves by 0.8-1.2 {angstrom} between the ground state and intermediate state, consistent with the proposal that the phenyl ring moves during MR catalysis while the polar groups remain relatively fixed. Although the overall protein structure of MR with bound intermediate analogues is very similar to that of MR with bound (S)-atrolactate, the intermediate-Mg{sup 2+} distance becomes shorter, suggesting a tighter complex with the catalytic Mg{sup 2+}. In addition, Tyr 54 moves closer to the phenyl ring of the bound intermediate analogues, contributing to an overall constriction of the active site cavity. However, site-directed mutagenesis experiments revealed that the role of Tyr 54 in MR catalysis is relatively minor, suggesting that alterations in enzyme structure that contribute to discrimination between the altered substrate in the transition state and the ground state by this proficient enzyme are extremely subtle.

  17. Absolute stereochemistry of a 4?a-hydroxyriboflavin analogue of the key intermediate of the FAD-monooxygenase cycle.

    PubMed

    Iwahana, Soichiro; Iida, Hiroki; Yashima, Eiji; Pescitelli, Gennaro; Di Bari, Lorenzo; Petrovic, Ana G; Berova, Nina

    2014-04-01

    The biological action of flavoenzymes, such as flavin adenine dinucleotide (FAD)-containing monooxygenase, involves the formation of oxygenated flavin derivatives, such as 4?a-hydroperoxyflavin and 4?a-hydroxyflavin, in which a new center of chirality is created at the 4?a position during the enzymatic reactions. So far, the absolute configuration of this center of chirality in natural 4?a-oxygenated flavins has remained unknown in spite of its key importance for the diverse functions of flavoenzymes. Herein, we report the 4?a-hydroxy adduct 3 of 3-benzyl-5-ethyl-10-(tetraacetyl-D-ribityl)flavinium (1), one of the key intermediates involved in the enantioselective organocatalytic oxidation of sulfides to sulfoxides. The 4?a-hydroxyflavin diastereomers (+)-3 and (-)-3, separated by HPLC, were characterized by electronic circular dichroism (CD) spectroscopy. Their absolute configurations at the 4?a position were, for the first time, determined by comparing experimental CD spectra with those calculated by means of time-dependent density functional theory (TDDFT) on DFT-optimized structures obtained after an extensive conformation analysis. PMID:24590890

  18. Crystal structure of the calcium pump with a bound ATP analogue

    NASA Astrophysics Data System (ADS)

    Toyoshima, Chikashi; Mizutani, Tatsuaki

    2004-07-01

    P-type ATPases are ATP-powered ion pumps that establish ion concentration gradients across cell and organelle membranes. Here, we describe the crystal structure of the Ca2+ pump of skeletal muscle sarcoplasmic reticulum, a representative member of the P-type ATPase superfamily, with an ATP analogue, a Mg2+ and two Ca2+ ions in the respective binding sites. In this state, the ATP analogue reorganizes the three cytoplasmic domains (A, N and P), which are widely separated without nucleotide, by directly bridging the N and P domains. The structure of the P-domain itself is altered by the binding of the ATP analogue and Mg2+. As a result, the A-domain is tilted so that one of the transmembrane helices moves to lock the cytoplasmic gate of the transmembrane Ca2+-binding sites. This appears to be the mechanism for occluding the bound Ca2+ ions, before releasing them into the lumen of the sarcoplasmic reticulum.

  19. Phosphorene analogues: Isoelectronic two-dimensional group-IV monochalcogenides with orthorhombic structure

    NASA Astrophysics Data System (ADS)

    Gomes, Ldia C.; Carvalho, A.

    2015-08-01

    The group-IV monochalcogenides SnS, SnSe, GeS, and GeSe form a family within the wider group of semiconductor "phosphorene analogues." Here, we used first-principles calculations to investigate systematically their structural, electronic, and optical properties, analyzing the changes associated with the reduction of dimensionality, from bulk to monolayer or bilayer form. We show that all those binary phosphorene analogues are semiconducting, with band-gap energies covering part of the infrared and visible range, and in most cases higher than phosphorene. Further, we found that they have multiple valleys in the valence and conduction band, the latter with spin-orbit splitting of the order of 19-86 meV.

  20. Characterization of electronic structure and physicochemical properties of antiparasitic nifurtimox analogues: A theoretical study

    NASA Astrophysics Data System (ADS)

    Soriano-Correa, Catalina; Raya, A.; Esquivel, Rodolfo O.

    American trypanosomiasis, also known as Chagas' disease, is caused by Trypanosoma cruzi (T. cruzi). It is well known that trypanosomes, and particularly T. cruzi, are highly sensitive towards oxidative stress, i.e., to compounds than are able to produce free radicals. Generally, nifurtimox (NFX) and benznidazol are most effective in the acute phase of the disease; therefore, nitroheterocycles constitute good models to design other nitrocompounds with specific biological characteristics. Thus, we have performed an ab initio study at the Hartree-Fock and Density Functional Theory levels of theory of several NFX analogues recently synthesized, to characterize them by obtaining their electronic, structural, and physicochemical properties, which might be linked to the observed antichagasic activity. The antitrypanosomal activity scale previously reported for the NFX analogues studied in this work is in good agreement with our theoretical results, from which we can conclude that the activity seems to be related to the reactivity along with the acidity observed for the most active molecules.

  1. Preparation, structure, and redox behavior of bis(diarylmethylene)dihydrothiophene and its ?-extended analogues.

    PubMed

    Takeda, Takashi; Akutagawa, Tomoyuki

    2015-02-20

    The preparation, X-ray structure, and optoelectronic properties of bis(diarylmethylene)dihydrothiophene 1 and its ?-extended analogues 2 are described. The development of a simple, short-step synthetic route allowed us to prepare derivatives with different aryl units. X-ray crystallographic analysis of 1b and 2b revealed their quinoidal structures, which exhibit strong electronic absorption in the visible region. Cyclic voltammetry measurements revealed their strong electron-donating properties. 1b showed two-step electrochromic behavior between the corresponding radical cation and dication. PMID:25634243

  2. Structure optimization of Prussian blue analogue cathode materials for advanced sodium ion batteries.

    PubMed

    Yang, Dezhi; Xu, Jing; Liao, Xiao-Zhen; He, Yu-Shi; Liu, Haimei; Ma, Zi-Feng

    2014-11-11

    A structure optimized Prussian blue analogue Na1.76Ni0.12Mn0.88[Fe(CN)6]0.98 (PBMN) is synthesized and investigated. Coexistence of inactive Ni(2+) (Fe-C?N-Ni group) with active Mn(2+/3+) (Fe-C?N-Mn group) balances the structural disturbances caused by the redox reactions. This cathode material exhibits particularly excellent cycle life with high capacity (118.2 mA h g(-1)). PMID:25233263

  3. Structure-activity relationship studies of flavonol analogues on pollen germination.

    PubMed

    Forbes, Alaina M; Meier, G Patrick; Haendiges, Stacey; Taylor, Loverine P

    2014-03-12

    Flavonoids are polyphenolic compounds required in the fertilization process in many, if not all, plants. However, the exact biological mechanism(s) and the interacting proteins are unknown. To determine the characteristics important in activating or inhibiting the pollination sequence, a structure-activity relationship analysis of natural and synthetic flavonols was conducted. Flavonol analogues were synthesized through a modified "one-pot" procedure that utilized a Baker-Venkataraman type rearrangement and a Suzuki-Miyaura cross-coupling of a halo-flavonol with an organotrifluoroborate. Of the flavonols tested, kaempferol was the only compound to act as a full agonist. The other smaller, less sterically hindered flavonols (galangin, kaempferide, and 4'-methyl flavonol) acted as partial agonists. Larger more hydrophobic flavonol analogues (3'- and 4'-benzoyl, 3'- and 4'-phenyl, and 3'- and 4'-iodo flavonols) had minimal or no agonist activity. Competition assays between kaempferol and these minimally activating flavonols showed that these analogues inhibited the action of kaempferol in a manner consistent with noncompetitive antagonism. The results suggest that steric hindrance is the most important factor in determining a good agonist. Hydrogen bonding also had a positive effect as long as the substituent did not cause any steric hindrance. PMID:24524670

  4. Geometry, Electronic Structure, and Pseudo Jahn-Teller Effect in Tetrasilacyclobutadiene Analogues.

    PubMed

    Liu, Yang; Wang, Ya; Bersuker, Isaac B

    2016-01-01

    We revealed the origin of the structural features of a series of tetrasilacyclobutadiene analogues based on a detailed study of their electronic structure and the pseudo Jahn-Teller effect (PJTE). Starting with the D4h symmetry of the Si4R4 system with a square four-membered silicon ring as a reference geometry, and employing ab initio calculations of energy profiles along lower-symmetry nuclear displacements in the ground and several excited states, we show that the ground-state boat-like and chair-like equilibrium configurations are produced by the PJT interaction with appropriate excited sates. For Si4F4 a full two-mode b1g-b2g adiabatic potential energy surface is calculated showing explicitly the way of transformation from the unstable D4h geometry to the two equilibrium C2h configurations via the D2h saddle point. The PJTE origin of these structural features is confirmed also by estimates of the vibronic coupling parameters. For Si4R4 with large substituents the origin of their structure is revealed by analyzing the PJT interaction between the frontier molecular orbitals. The preferred chair-like structures of Si4R4 analogues with amido substituents, and heavier germanium-containing systems Ge4R4 (potential precursors for semiconducting materials) are predicted. PMID:26996445

  5. Geometry, Electronic Structure, and Pseudo Jahn-Teller Effect in Tetrasilacyclobutadiene Analogues

    PubMed Central

    Liu, Yang; Wang, Ya; Bersuker, Isaac B.

    2016-01-01

    We revealed the origin of the structural features of a series of tetrasilacyclobutadiene analogues based on a detailed study of their electronic structure and the pseudo Jahn-Teller effect (PJTE). Starting with the D4h symmetry of the Si4R4 system with a square four-membered silicon ring as a reference geometry, and employing ab initio calculations of energy profiles along lower-symmetry nuclear displacements in the ground and several excited states, we show that the ground-state boat-like and chair-like equilibrium configurations are produced by the PJT interaction with appropriate excited sates. For Si4F4 a full two-mode b1g−b2g adiabatic potential energy surface is calculated showing explicitly the way of transformation from the unstable D4h geometry to the two equilibrium C2h configurations via the D2h saddle point. The PJTE origin of these structural features is confirmed also by estimates of the vibronic coupling parameters. For Si4R4 with large substituents the origin of their structure is revealed by analyzing the PJT interaction between the frontier molecular orbitals. The preferred chair-like structures of Si4R4 analogues with amido substituents, and heavier germanium-containing systems Ge4R4 (potential precursors for semiconducting materials) are predicted. PMID:26996445

  6. Synthesis of Silicate Zeolite Analogues Using Organic Sulfonium Compounds as Structure-Directing Agents.

    PubMed

    Jo, Changbum; Lee, Sungjune; Cho, Sung June; Ryoo, Ryong

    2015-10-19

    A microporous crystalline silica zeolite of the MEL structure type and three other zeolite analogues composed of germanosilicate frameworks were synthesized using tributylsulfonium, triphenylsulfonium, or tri(para-tolyl)sulfonium as the structure-directing agent. The germanosilicates thus obtained had ISV, ITT, or a new zeolite structure depending on the synthesis conditions. The structure of the new germanosilicate was solved using X-ray powder diffraction data with the aid of a charge-flipping method. The solution indicated a crystal structure belonging to the P63/mmc space group with cell parameters of a=16.2003? and c=21.8579?. After calcination, the new germanosilicate material exhibited two types of accessible micropores with diameters of 0.61 and 0.78?nm. PMID:26302889

  7. Determination of the secondary structure of selected melittin analogues with different haemolytic activities.

    PubMed Central

    Prez-Pay, E; Houghten, R A; Blondelle, S E

    1994-01-01

    In earlier studies, we have reported that minor modifications in the amino acid sequence of melittin result in dramatic changes in its biological activity. In the current study, we have investigated the secondary structure of melittin analogues with either increased or decreased haemolytic activity in order to further our understanding of the structural features involved in the binding and/or insertion of peptides into a phospholipid membrane from solution. This was accomplished by analysing the c.d. spectra of the analogues in solutions of various ionic strength and, separately, in the presence of micelles. These studies permit the assessment of the effect of small sequence modifications (i.e. single amino acid omission or substitution) on the self-association-induced secondary structure of melittin in aqueous solution, as well as its binding affinity to micelles. It was found that amphipathicity, as well as interchain distances and the orientation of hydrophobic residues, were involved in the induction of stabilized structures. PMID:8172621

  8. High resolution structure of an M23 peptidase with a substrate analogue

    PubMed Central

    Grabowska, Maja; Jagielska, Elzbieta; Czapinska, Honorata; Bochtler, Matthias; Sabala, Izabela

    2015-01-01

    LytM is a Staphylococcus aureus autolysin and a homologue of the S. simulans lysostaphin. Both enzymes are members of M23 metallopeptidase family (MEROPS) comprising primarily bacterial peptidoglycan hydrolases. LytM occurs naturally in a latent form, but can be activated by cleavage of an inhibitory N-terminal proregion. Here, we present a 1.45? crystal structure of LytM catalytic domain with a transition state analogue, tetraglycine phosphinate, bound in the active site. In the electron density, the active site of the peptidase, the phosphinate and the diglycine fragment on the P1? side of the transition state analogue are very well defined. The density is much poorer or even absent for the P1 side of the ligand. The structure is consistent with the involvement of His260 and/or His291 in the activation of the water nucleophile and suggests a possible catalytic role for Tyr204, which we confirmed by mutagenesis. Possible mechanisms of catalysis and the structural basis of substrate specificity are discussed based on the structure analysis. PMID:26437833

  9. High resolution structure of an M23 peptidase with a substrate analogue.

    PubMed

    Grabowska, Maja; Jagielska, Elzbieta; Czapinska, Honorata; Bochtler, Matthias; Sabala, Izabela

    2015-01-01

    LytM is a Staphylococcus aureus autolysin and a homologue of the S. simulans lysostaphin. Both enzymes are members of M23 metallopeptidase family (MEROPS) comprising primarily bacterial peptidoglycan hydrolases. LytM occurs naturally in a latent form, but can be activated by cleavage of an inhibitory N-terminal proregion. Here, we present a 1.45? crystal structure of LytM catalytic domain with a transition state analogue, tetraglycine phosphinate, bound in the active site. In the electron density, the active site of the peptidase, the phosphinate and the "diglycine" fragment on the P1' side of the transition state analogue are very well defined. The density is much poorer or even absent for the P1 side of the ligand. The structure is consistent with the involvement of His260 and/or His291 in the activation of the water nucleophile and suggests a possible catalytic role for Tyr204, which we confirmed by mutagenesis. Possible mechanisms of catalysis and the structural basis of substrate specificity are discussed based on the structure analysis. PMID:26437833

  10. Relationship between structure of phenothiazine analogues and their activity on platelet calcium fluxes.

    PubMed Central

    Enouf, J.; Lvy-Toledano, S.

    1984-01-01

    Phenothiazine analogues have been tested for their effect on calcium uptake into platelet membrane vesicles and on ionophore-induced platelet activation, both phenomena being Ca2+-dependent. Both calcium uptake into membrane vesicles and ionophore-induced platelet activation were inhibited by the drugs. Evidence for two inhibitors as potent as chlorpromazine and trifluoperazine was found. These drugs are apparently competitive inhibitors of calcium uptake. A structure-activity relationship has been established. The data suggest that the phenothiazines are able to inhibit calmodulin-insensitive calcium uptake of platelet membrane vesicles and that therefore they cannot be assumed to be selective inhibitors of calmodulin interactions under all circumstances. PMID:6697061

  11. Synthesis of a pladienolide B analogue with the fully functionalized core structure.

    PubMed

    Mller, Sarah; Mayer, Timo; Sasse, Florenz; Maier, Martin E

    2011-08-01

    Starting from (R)-(-)-linalool (6), terminus differentiation and chain extension via aldol type reactions led to ketophosphonate 16 (C1-C8 building block). In a Horner-Wadsworth-Emmons reaction, 16 reacted with aldehyde 22, which contained the vicinal anti-Me-OH pattern and a vinyl iodide function, to provide the C1-C13 part of pladienolide B. After Shiina macrolactonization, reduction of the enone 26 gave the core structure 27. A Stille cross-coupling of vinyl iodide 27 with tributylphenylstannane eventually furnished analogue 30. PMID:21707025

  12. Structures of micelle-bound selected insect neuropeptides and analogues: implications for receptor selection.

    PubMed

    Zdobinsky, Tino; Scherkenbeck, Jürgen; Zerbe, Oliver; Antonicek, Horst; Chen, Heru

    2009-11-01

    Neuropeptides control essential physiological processes in insects such as water balance and muscle activity. Due to their metabolic instability and adverse physiochemical properties, insect neuropeptides are unsuited for a direct application in plant protection. As a first approximation towards the biologically active conformation, the structures of selected neuropeptides from economically important pest insects were determined by NMR spectroscopy and fluorescence measurements in a membrane-mimicking environment. A receptor binding model is suggested for the helicokinins and discussed in connection with biological activities and membrane-bound conformations of linear and cyclic analogues. PMID:19790201

  13. Structure-function studies on positions 17, 18, and 21 replacement analogues of glucagon: the importance of charged residues and salt bridges in glucagon biological activity.

    PubMed

    Sturm, N S; Lin, Y; Burley, S K; Krstenansky, J L; Ahn, J M; Azizeh, B Y; Trivedi, D; Hruby, V J

    1998-07-16

    We have designed and synthesized eight compounds 2-9 which incorporate various amino acid residues in positions 17, 18, and 21 of the glucagon molecule: 2, [Lys17]glucagon amide; 3, [Lys18]glucagon amide; 4, [Nle17,Lys18,Glu21]glucagon amide; 5, [Orn17,18, Glu21]glucagon amide; 6, [d-Arg17]glucagon; 7, [d-Arg18]glucagon; 8, [d-Phe17]glucagon; and 9, [d-Phe18]glucagon. Compared to glucagon (IC50 = 1.5 nM), analogues 2-9 were found to have binding affinity IC50 values (in nM) of 0.7, 4.1, 1.0, 2.0, 5.0, 25.0, 43.0, and 32.0, respectively. When these compounds were tested for their ability to stimulate adenylate cyclase (AC) activity, they were found to be full or partial agonists having maximum stimulation values of 100, 100, 100, 100, 87, 78, 94, and 100%, respectively. On the basis of the X-ray crystal structure of [Lys17,18,Glu21]glucagon amide reported here, the ability to form a salt bridge between Lys18 and Glu21 is probably key to their increased binding and second messenger activities. Among the eight analogues synthesized here, only analogue 4 preserves the ability to form a salt bridge between Lys18 and Glu21. However, since these modifications are minor they do not seem to change the amphiphilic character of the C-terminus, allowing these analogues to reach 78-100% stimulation in the adenylate cyclase assay. Biological data from analogues 6-9 supports the idea that position 18 of glucagon may influence binding only, while position 17 may influence both receptor recognition and transduction. PMID:9667960

  14. Cellular Localization of Dieldrin and StructureActivity Relationship of Dieldrin Analogues in Dopaminergic Cells

    PubMed Central

    Allen, Erin M. G.; Florang, Virginia R.; Davenport, Laurie L.; Jinsmaa, Yunden; Doorn, Jonathan A.

    2015-01-01

    The incidence of Parkinsons disease (PD) correlates with environmental exposure to pesticides, such as the organochlorine insecticide, dieldrin. Previous studies found an increased concentration of the pesticide in the striatal region of the brains of PD patients and also that dieldrin adversely affects cellular processes associated with PD. These processes include mitochondrial function and reactive oxygen species production. However, the mechanism and specific cellular targets responsible for dieldrin-mediated cellular dysfunction and the structural components of dieldrin contributing to its toxicity (toxicophore) have not been fully defined. In order to identify the toxicophore of dieldrin, a structureactivity approach was used, with the toxicity profiles of numerous analogues of dieldrin (including aldrin, endrin, and cis-aldrin diol) assessed in PC6-3 cells. The MTT and lactate dehydrogenase (LDH) assays were used to monitor cell viability and membrane permeability after treatment with each compound. Cellular assays monitoring ROS production and extracellular dopamine metabolite levels were also used. Structure and stereochemistry for dieldrin were found to be very important for toxicity and other end points measured. Small changes in structure for dieldrin (e.g., comparison to the stereoisomer endrin) yielded significant differences in toxicity. Interestingly, the cis-diol metabolite of dieldrin was found to be significantly more toxic than the parent compound. Disruption of dopamine catabolism yielded elevated levels of the neurotoxin, 3,4-dihydroxyphenylacetaldehyde, for many organochlorines. Comparisons of the toxicity profiles for each dieldrin analogue indicated a structure-specific effect important for elucidating the mechanisms of dieldrin neurotoxicity. PMID:23763672

  15. Charge Isomers of Myelin Basic Protein: Structure and Interactions with Membranes, Nucleotide Analogues, and Calmodulin

    PubMed Central

    Wang, Chaozhan; Neugebauer, Ute; Brck, Jochen; Myllykoski, Matti; Baumgrtel, Peter; Popp, Jrgen; Kursula, Petri

    2011-01-01

    As an essential structural protein required for tight compaction of the central nervous system myelin sheath, myelin basic protein (MBP) is one of the candidate autoantigens of the human inflammatory demyelinating disease multiple sclerosis, which is characterized by the active degradation of the myelin sheath. In this work, recombinant murine analogues of the natural C1 and C8 charge components (rmC1 and rmC8), two isoforms of the classic 18.5-kDa MBP, were used as model proteins to get insights into the structure and function of the charge isomers. Various biochemical and biophysical methods such as size exclusion chromatography, calorimetry, surface plasmon resonance, small angle X-ray and neutron scattering, Raman and fluorescence spectroscopy, and conventional as well as synchrotron radiation circular dichroism were used to investigate differences between these two isoforms, both from the structural point of view, and regarding interactions with ligands, including calmodulin (CaM), various detergents, nucleotide analogues, and lipids. Overall, our results provide further proof that rmC8 is deficient both in structure and especially in function, when compared to rmC1. While the CaM binding properties of the two forms are very similar, their interactions with membrane mimics are different. CaM can be used to remove MBP from immobilized lipid monolayers made of synthetic lipids - a phenomenon, which may be of relevance for MBP function and its regulation. Furthermore, using fluorescently labelled nucleotides, we observed binding of ATP and GTP, but not AMP, by MBP; the binding of nucleoside triphosphates was inhibited by the presence of CaM. Together, our results provide important further data on the interactions between MBP and its ligands, and on the differences in the structure and function between MBP charge isomers. PMID:21647440

  16. Buspirone analogues. 2. Structure-activity relationships of aromatic imide derivatives.

    PubMed

    New, J S; Yevich, J P; Eison, M S; Taylor, D P; Eison, A S; Riblet, L A; VanderMaelen, C P; Temple, D L

    1986-08-01

    Several analogues of the novel anxiolytic buspirone were synthesized and evaluated in vivo for tranquilizing activity and their ability to reverse neuroleptic-induced catalepsy. The in vitro binding affinities of these compounds were also examined for both the alpha 1 and dopamine D2 receptor systems. The general structure-activity relationships of this series highlight compounds 17, 21, and 32 as having anticonflict activity. Each of these structures contains the 1-(2-pyrimidinyl)piperazine moiety linked by a tetramethylene chain to a variable cyclic imide moiety. Compound 32 (4,4-dimethyl-1-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,6- piperidinedione) was found to be equipotent with buspirone in its anxiolytic activity and was therefore selected for extensive preclinical characterization. The pharmacology of buspirone and 32 is contrasted, and the potent serotonin agonist properties of 32 are discussed with reference to its potential contribution to the anxioselective mechanism of this compound. PMID:2874226

  17. Structural Basis for Recognition of Guanosine by a Synthetic Tricyclic Cytosine Analogue: Guanidinium G-Clamp

    SciTech Connect

    Wilds, C.J.; Maier, M.A.; Manoharan, M.; Egli, M.

    2010-03-08

    An oligonucleotide analogue containing a novel heterocyclic analogue, the guanidinium G-clamp, was designed to allow formation of five H-bonds to guanosine. The guanidinium group was introduced postsynthetically by treatment of the deprotected oligonucleotide containing a free amino group with a solution of 1H-pyrazole-1-carboxamidine and purified by a combination of size-exclusion chromatography and reversed-phase HPLC. A single incorporation of this modification into an oligodeoxynucleotide sequence was found to increase duplex stability by 13{sup o} and 16{sup o} per modification to RNA and DNA, respectively. Crystals of a self-complementary decamer sequence containing this modification were grown and diffracted to 1-{angstrom} resolution. The structure was solved by molecular replacement and revealed that the modification forms additional H-bonds to O(6) and N(7) of guanosine through the amino and imino N-atoms, respectively. The origins of enhanced duplex stability are also attributed to increased stacking interactions mediated by the phenoxazine moiety of the G-clamp and formation of H-bond networks between the positively charged guanidinium group, H{sub 2}O molecules, and negatively charged O-atoms from phosphates on the adjacent strand.

  18. Structure-activity relationship of tryptamine analogues on the heart of venus mercenaria

    PubMed Central

    Greenberg, M. J.

    1960-01-01

    A number of tryptamine analogues and other exciter agents have been tested on the heart of Venus mercenaria. The method of estimation of potency, especially for irreversibly acting compounds, is discussed. Specificity of action with respect to the site of action of 5-hydroxytryptamine is defined experimentally. The specific activity of tyramine and phenethylamine and the non-specific excitatory action of indole and skatole indicate that the indole ring is neither necessary nor sufficient for 5-hydroxytryptamine-like activity. Tryptamine analogues differ in mode of action as well as potency. Congeners without a 5-hydroxyl group tend to act more slowly and irreversibly as well as less strongly than 5-hydroxytryptamine. Methyl substitution also increases the time of action and difficulty of reversal. However, the potency of such compounds may be increased or decreased depending upon the position of substitution and the presence of the 5-hydroxyl group. The relations between structure and potency and mode of action are discussed. Suggestions are made concerning the effective conformation of the 5-hydroxytryptamine molecule and the nature of its receptor. ImagesFIG. 7 PMID:13708259

  19. Transition state analogues in structures of ricin and saporin ribosome-inactivating proteins

    SciTech Connect

    Ho, Meng-Chiao; Sturm, Matthew B.; Almo, Steven C.; Schramm, Vern L.

    2010-01-12

    Ricin A-chain (RTA) and saporin-L1 (SAP) catalyze adenosine depurination of 28S rRNA to inhibit protein synthesis and cause cell death. We present the crystal structures of RTA and SAP in complex with transition state analogue inhibitors. These tight-binding inhibitors mimic the sarcin-ricin recognition loop of 28S rRNA and the dissociative ribocation transition state established for RTA catalysis. RTA and SAP share unique purine-binding geometry with quadruple {pi}-stacking interactions between adjacent adenine and guanine bases and 2 conserved tyrosines. An arginine at one end of the {pi}-stack provides cationic polarization and enhanced leaving group ability to the susceptible adenine. Common features of these ribosome-inactivating proteins include adenine leaving group activation, a remarkable lack of ribocation stabilization, and conserved glutamates as general bases for activation of the H{sub 2}O nucleophile. Catalytic forces originate primarily from leaving group activation evident in both RTA and SAP in complex with transition state analogues.

  20. Electronic structure and vibrational spectra of cis-diammine(orotato)platinum(II), a potential cisplatin analogue: DFT and experimental study

    NASA Astrophysics Data System (ADS)

    Wysoki?ski, Rafa?; Hernik, Katarzyna; Szostak, Roman; Michalska, Danuta

    2007-03-01

    Orotic acid (vitamin B 13) is a key intermediate in biosynthesis of the pyrimidine nucleotides in living organisms, moreover, it may serve as the biological carrier for some metal ions. cis-Diammine(orotato)platinum(II), cis-[Pt(C 5H 2N 2O 4)(NH 3) 2] can be considered as a new potential cisplatin analogue. The FT-Raman and FT-IR spectra of the title complex are reported, for the first time. The molecular structure, vibrational frequencies, and the theoretical infrared and Raman intensities have been calculated by the density functional mPW1PW91 method. The detailed vibrational assignment has been made on the basis of the calculated potential energy distribution. The theoretically predicted IR and Raman spectra show very good agreement with experiment. Natural bond orbital (NBO) analyses were performed for cisplatin, carboplatin and the title complex. The results provided new data on the nature of platinum-ligand bonding in these compounds. Strong intramolecular hydrogen bond between the orotate ligand and the coordinated ammonia group stabilizes the structure of the platinum(II) complex. Thus, it is suggested that the orotate ligand in the title complex is more inert to the substitution reactions than the chloride ligands in cisplatin.

  1. Structural Influences on Preferential Oxazolone versus Diketopiperazine b2+ Ion Formation for Histidine Analogue-containing Peptides

    PubMed Central

    Gucinski, Ashley C.; Chamot-Rooke, Julia; Nicol, Edith; Somogyi, rpd; Wysocki, Vicki H.

    2012-01-01

    Studies of peptide fragment ion structures are important to aid in the accurate kinetic modeling and prediction of peptide fragmentation pathways for a given sequence. Peptide b2+ ion structures have been of recent interest. While previously studied b2+ ions that contain only aliphatic or simple aromatic residues are oxazolone structures, the HA b2+ ion consists of both oxazolone and diketopiperazine structures. The structures of a series of histidine-analogue-containing Xxx-Ala b2+ ions were studied by using action infrared multiphoton dissociation (IRMPD) spectroscopy, fragment ion hydrogen-deuterium exchange (HDX), and density functional theory (DFT) calculations to systematically probe the influence of different side chain structural elements on the resulting b2+ ion structures formed. The b2+ ions studied include His-Ala (HA), methylated histidine analogues, including pi-methyl-HA and tau-methyl-HA, pyridylalanine (pa) analogues, including 2-(pa)A, 3-(pa)A, and 4-(pa)A, and linear analogues, including diaminobutanoic acid (DabA) and Lys-Ala (KA). The location and accessibility of the histidine pi nitrogen, or an amino nitrogen on an aliphatic side chain, were seen to be essential for diketopiperazine formation in addition to the more typical oxazolone structure formation, while blocking or removal of the tau nitrogen did not change the b2+ ion structures formed. Linear histidine analogues, DabA and KA, formed only diketopiperazine structures, suggesting that a steric interaction in the HisAla case may interfere with the complete trans-cis isomerization of the first amide bond that is necessary for diketopiperazine formation. PMID:22448972

  2. Structure-based optimization of Cephalothin-analogue boronic acids as ?-lactamase inhibitors

    PubMed Central

    Morandi, Stefania; Morandi, Federica; Caselli, Emilia; Shoichet, Brian K.; Prati, Fabio

    2008-01-01

    Boronic acids have proved to be promising selective inhibitors of ?-lactamases, acting as transition state analogues. Starting from a previously described nanomolar inhibitor of AmpC ?-lactamase, three new inhibitors were designed to gain interactions with highly conserved residues, such as Asn343, and to bind more tightly to the enzyme. Among these, one was obtained by stereoselective synthesis and succeeded in placing its anionic group into the carboxylate binding site of the enzyme, as revealed by X-ray crystallography of the complex inhibitor/AmpC. Nevertheless, it failed at improving affinity, when compared to the lead from which it was derived. The origins of this structural and energetic discrepancy are discussed. PMID:17997318

  3. Extrapolating surface structures to depth in transpressional systems: the role of rheology and convergence angle deduced from analogue experiments

    NASA Astrophysics Data System (ADS)

    Hsieh, Shang Yu; Neubauer, Franz; Cloetingh, Sierd; Willingshofer, Ernst; Sokoutis, Dimitrios

    2014-05-01

    The internal structure of major strike-slip faults is still poorly understood, particularly how the deep structure could be inferred from its surface expression (Molnar and Dayem, 2011 and references therein). Previous analogue experiments suggest that the convergence angle is the most influential factor (Leever et al., 2011). Further analogue modeling may allow a better understanding how to extrapolate surface structures to the subsurface geometry of strike-slip faults. Various scenarios of analogue experiments were designed to represent strike-slip faults in nature from different geological settings. As such key parameters, which are investigated in this study include: (a) the angle of convergence, (b) the thickness of brittle layer, (c) the influence of a rheological weak layer within the crust, and (d) influence of a thick and rheologically weak layer at the base of the crust. The latter aimed to simulate the effect of a hot metamorphic core complex or an alignment of uprising plutons bordered by a transtensional/transpressional strike-slip fault. The experiments are aimed to explain first order structures along major transcurrent strike-slip faults such as the Altyn, Kunlun, San Andrea and Greendale (Darfield earthquake 2010) faults. The preliminary results show that convergence angle significantly influences the overall geometry of the transpressive system with greater convergence angles resulting in wider fault zones and higher elevation. Different positions, densities and viscosities of weak rheological layers have not only different surface expressions but also affect the fault geometry in the subsurface. For instance, rheological weak material in the bottom layer results in stretching when experiment reaches a certain displacement and a buildup of a less segmented, wide positive flower structure. At the surface, a wide fault valley in the middle of the fault zone is the reflection of stretching along the velocity discontinuity at depth. In models with a thin and rheologically weaker layer in the middle of the brittle layer, deformation is distributed over more faults and the geometry of the fault zone below and above the weak zone shows significant differences, suggesting that the correlation of structures across a weak layer has to be supported by geophysical data, which help constraining the geometry of the deep part. This latter experiment has significantly similar phenomena in reality, such as few pressure ridges along Altyn fault. The experimental results underline the need to understand the role of the convergence angle and the influence of rheology on fault evolution, in order to connect between surface deformation and subsurface geometry. References Leever, K. A., Gabrielsen, R. H., Sokoutis, D., Willingshofer, E., 2011. The effect of convergence angle on the kinematic evolution of strain partitioning in transpressional brittle wedges: Insight from analog modeling and high-resolution digital image analysis. Tectonics, 30(2), TC2013. Molnar, P., Dayem, K.E., 2010. Major intracontinental strike-slip faults and contrasts in lithospheric strength. Geosphere, 6, 444-467.

  4. 3-Hydroxyflavone and structural analogues differentially activate pregnane X receptor: Implication for inflammatory bowel disease.

    PubMed

    Lau, Aik Jiang; Chang, Thomas K H

    2015-10-01

    Pregnane X receptor (PXR; NR1I2) is a member of the superfamily of nuclear receptors that regulates the expression of genes involved in various biological processes, including drug transport and biotransformation. In the present study, we investigated the effect of 3-hydroxyflavone and its structurally-related analogues on PXR activity. 3-Hydroxyflavone, galangin, kaempferol, querceetin, isorhamnetin, and tamarixetin, but not but not datiscetin, morin, myricetin, or syringetin, activated mouse PXR, as assessed in a cell-based reporter gene assay. By comparison, 3-hydroxyflavone activated rat PXR, whereas 3-hydroxyflavone, galangin, quercetin, isorhamnetin, and tamarixetin activated human PXR (hPXR). A time-resolved fluorescence resonance energy transfer competitive ligand-binding assay showed binding to the ligand-binding domain of hPXR by 3-hydroxyflavone, galangin, quercetin, isorhamnetin, and tamarixetin. 3-Hydroxyflavone and galangin, but not quercetin, isorhamnetin, or tamarixetin, recruited steroid receptor coactivator (SRC)-1, SRC-2, and SRC-3 to hPXR. In LS180 human colon adenocarcinoma cells, 3-hydroxyflavone, quercetin, and tamarixetin increased CYP3A4, CYP3A5, and ABCB1 mRNA expression, whereas galangin and isorhamnetin increased CYP3A4 and ABCB1 but not CYP3A5 mRNA expression. Datiscetin, kaempferol, morin, myricetin, and syringetin did not attenuate the extent of hPXR activation by rifampicin, suggesting they are not hPXR antagonists. Overall, flavonols activate PXR in an analogue-specific and species-dependent manner. Substitution at the C2' or C5' position of 3-hydroxyflavone with a hydroxyl or methoxy group rendered it incapable of activating hPXR. Understanding the structure-activity relationship of flavonols in hPXR activation may facilitate nutraceutical development efforts in the treatment of PXR-associated intestinal diseases, such as inflammatory bowel disease. PMID:26238175

  5. Structure elucidation of a novel analogue of sildenafil detected as an adulterant in an herbal dietary supplement.

    PubMed

    Reepmeyer, John C; Woodruff, Jeffrey T; d'Avignon, D Andr

    2007-04-11

    A new analogue of sildenafil was detected in an herbal dietary supplement, which was sold over the internet and promoted as a product for the enhancement of sexual performance. The structure of the compound was established using LC-MS, UV spectroscopy, MS-MS, and NMR. In addition, the compound was cleaved at its sulfonamide S-N bond yielding a sulfonic acid and an amine, which were independently characterized using LC-MS, GC-MS, and derivatization. The compound, named methisosildenafil, is a novel synthetic analogue of sildenafil in which the N-methylpiperazine moiety has been replaced with 2,6-dimethylpiperazine. PMID:17207601

  6. Structural requirements of sulphonylureas and analogues for interaction with sulphonylurea receptor subtypes.

    PubMed

    Meyer, M; Chudziak, F; Schwanstecher, C; Schwanstecher, M; Panten, U

    1999-09-01

    1. The structure-activity relationship for hypoglycaemic sulphonylureas and analogues was examined. Binding affinities were compared using membranes from HIT-T15 cells (beta-cell line) and from COS-7 cells transiently expressing sulphonylurea receptor subtypes (SUR1, SUR2A and SUR2B). Inhibition of adenosine-triphosphate-sensitive K+ channels (KATP-channels) was measured in mouse pancreatic beta-cells. 2. The tested compounds displayed similar binding affinities for SUR2A and SUR2B. 3. Meglitinide (benzoic acid derivative) bound to SUR1 and the SUR2 isoforms with similar affinities. Replacement of the carboxyl group of meglitinide by a methyl group significantly decreased the binding affinities for SUR1 and the SUR2 isoforms (>4 fold) and the potency to inhibit KATP-channel activity of beta-cells (24 fold). Replacement of the carboxyl group of meglitinide by a sulphonylurea group significantly increased the affinities for SUR1 (5 fold) and the SUR2 isoforms (13 - 16 fold). 4. Glibenclamide bound to the SUR2 isoforms with 300 - 500 fold lower affinity than to SUR1. Exchanging the cyclohexyl ring of glibenclamide by a methyl group or removal of the lipophilic side chain of glibenclamide (5-chloro-2-methoxy-benzamidoethyl chain) markedly reduced but did not abolish the selectivity for SUR1. 5. In conclusion, interaction of sulphonylureas and acidic analogues with SUR1, SUR2A and SUR2B is favoured by the anionic group of these drugs. Hypoglycaemic sulphonylureas (e.g. glibenclamide) owe selectivity for SUR1 to lipophilic substitution on their urea group. Sulphonylureas without lipophilic substitution on the urea group could represent lead compounds for the development of SUR2-selective drugs. PMID:10498831

  7. Structural requirements of sulphonylureas and analogues for interaction with sulphonylurea receptor subtypes

    PubMed Central

    Meyer, Miriam; Chudziak, Franz; Schwanstecher, Christina; Schwanstecher, Mathias; Panten, Uwe

    1999-01-01

    The structure-activity relationship for hypoglycaemic sulphonylureas and analogues was examined. Binding affinities were compared using membranes from HIT-T15 cells (?-cell line) and from COS-7 cells transiently expressing sulphonylurea receptor subtypes (SUR1, SUR2A and SUR2B). Inhibition of adenosine-triphosphate-sensitive K+ channels (KATP-channels) was measured in mouse pancreatic ?-cells. The tested compounds displayed similar binding affinities for SUR2A and SUR2B. Meglitinide (benzoic acid derivative) bound to SUR1 and the SUR2 isoforms with similar affinities. Replacement of the carboxyl group of meglitinide by a methyl group significantly decreased the binding affinities for SUR1 and the SUR2 isoforms (>4 fold) and the potency to inhibit KATP-channel activity of ?-cells (24 fold). Replacement of the carboxyl group of meglitinide by a sulphonylurea group significantly increased the affinities for SUR1 (5 fold) and the SUR2 isoforms (1316 fold). Glibenclamide bound to the SUR2 isoforms with 300500 fold lower affinity than to SUR1. Exchanging the cyclohexyl ring of glibenclamide by a methyl group or removal of the lipophilic side chain of glibenclamide (5-chloro-2-methoxy-benzamidoethyl chain) markedly reduced but did not abolish the selectivity for SUR1. In conclusion, interaction of sulphonylureas and acidic analogues with SUR1, SUR2A and SUR2B is favoured by the anionic group of these drugs. Hypoglycaemic sulphonylureas (e.g. glibenclamide) owe selectivity for SUR1 to lipophilic substitution on their urea group. Sulphonylureas without lipophilic substitution on the urea group could represent lead compounds for the development of SUR2-selective drugs. PMID:10498831

  8. An NHC-Stabilized Silicon Analogue of Acylium Ion: Synthesis, Structure, Reactivity, and Theoretical Studies.

    PubMed

    Ahmad, Syed Usman; Szilvsi, Tibor; Irran, Elisabeth; Inoue, Shigeyoshi

    2015-05-01

    The silicon analogues of an acylium ion, namely, sila-acylium ions 2a and 2b [RSi(O)(NHC)2]Cl stabilized by two N-heterocyclic carbenes (NHC = 1,3,4,5-tetramethylimidazol-2-ylidene), and having chloride as a countercation were successfully synthesized by the reduction of CO2 using the donor stabilized silyliumylidene cations 1a and 1b [RSi(NHC)2]Cl (1a, 2a; R = m-Ter = 2,6-Mes2C6H3, Mes = 2,4,6-Me3C6H2 and 1b, 2b; R = Tipp = 2,4,6-iPr3C6H2). Structurally, compound 2a features a four coordinate silicon center together with a double bond between silicon and oxygen atoms. The reaction of sila-acylium ions 2a and 2b with water afforded different products which depend on the bulkiness of aryl substituents. Although the exposure of 2a to H2O afforded a stable silicon analogue of carboxylate anion as a dimer form, [m-TerSi(O)O]2(2-)2[NHC-H](+) (3), the same reaction with the less bulkier triisopropylphenyl substituted sila-acylium ion 2b afforded cyclotetrasiloxanediol dianion [{TippSi(O)}4{(O)OH}2](2-)2[NHC-H](+) (4). Metric and DFT (Density Functional Theory) evidence support that 2a and 2b possess strong Si?O double bond character, while 3 and 4 contain more ionic terminal Si-O bonds. Mechanistic details of the formation of different (SiO)n (n = 2, 3, 4) core rings were explored using DFT to explain the experimentally characterized products and a proposed stable intermediate was identified with mass spectrometry. PMID:25871835

  9. Antineoplastic activities of MT81 and its structural analogue in ehrlich ascites carcinoma-bearing swiss albino mice

    PubMed Central

    Gupta, Malaya; Majumder, Upal Kanti

    2010-01-01

    Many fungal toxins exhibit in vitro and in vivo antineoplastic effects on various cancer cell types. Luteoskyrin, a hydroxyanthraquinone has been proved to be a potent inhibitor against Ehrlich ascites tumor cells. The comparative antitumor activity and antioxidant status of MT81 and its structural analogue [Acetic acid-MT81 (Aa-MT81)] having polyhydroxyanthraquinone structure were assessed against Ehrlich ascites carcinoma (EAC ) tumor in mice. The in vitro cytotoxicity was measured by the viability of EAC cells after direct treatment of the said compounds. In in vivo study, MT81 and its structural analogue were administered (i.p.) at the two different doses (5, 7 mg MT81; 8.93, 11.48 mg Aa-MT81/kg body weight) for 7 days after 24 hrs. of tumor inoculation. The activities were assessed using mean survival time (MST), increased life span (ILS), tumor volume, viable tumor cell count, peritoneal cell count, protein percentage and hematological parameters. Antioxidant status was determined by malondialdehyde (MDA) and reduced glutathione (GSH ) content, and by the activity of superoxide dismutase (SOD) and catalase (CA T). MT81 and its structural analogues increased the mean survival time, normal peritoneal cell count. They decreased the tumor volume, viable tumor cell count, hemoglobin percentage and packed cell volume. Differential counts of WBC, total counts of RBC & WBC that altered by EAC inoculation, were restored in a dose-dependent manner. Increased MDA and decreased GSH content and reduced activity of SOD, and catalase in EAC bearing mice were returned towards normal after the treatment of MT81 and its structural analogue. Being less toxic than parent toxin MT81, the structural analogue showed more prominent antineoplastic activities against EAC cells compared to MT81. At the same time, both compounds exhibit to some extent antioxidant potential for the EAC-bearing mice. PMID:20716929

  10. Experimental and Theoretical Studies of the Structures and Interactions of Vancomycin Antibiotics with Cell Wall Analogues

    SciTech Connect

    Yang, Zhibo; Vorpagel, Erich R.; Laskin, Julia

    2008-10-01

    Surface-induced dissociation (SID) of the singly protonated complex of vancomycin antibiotic with cell wall peptide analogue (Nα,Nε-diacetyl-L-Lys-D-Ala-D-Ala) was studied using a 6 T Fourier Transform Ion Cyclotron Resonance Mass Spectrometer (FT-ICR MS) specially configured for SID experiments. The binding energy between the vancomycin and the peptide was obtained from the RRKM modeling of the time- and energy resolved fragmentation efficiency curves (TFECs) of the precursor ion and its fragments. Electronic structure calculations of the geometries, proton affinities and binding energies were performed for several model systems including vancomycin (V), vancomycin aglycon (VA), Nα,Nε-diacetyl-L-Lys-D-Ala-D-Ala, and non-covalent complexes of VA with N-acetyl-D-Ala-D-Ala and Nα,Nε-diacetyl-L-Lys-D-Ala-D-Ala at the B3LYP/6-31G(d) level of theory. Comparison between the experimental and computational results suggests that the most probable structure of the complex observed in our experiments corresponds to the neutral peptide bound to the vancomycin protonated at the secondary amino group of the N-methyl-leucine residue. The experimental binding energy of 30.9 ± 1.8 kcal/mol is in good agreement with the binding energy of 29.3 ± 2.5 kcal/mol calculated for the model system representing the preferred structure of the complex.

  11. Effects of substrate structural analogues on the enzymatic activities of aspartate aminotransferase isoenzymes.

    PubMed

    Martins, L L; Mourato, M P; de Varennes, A

    2001-01-01

    Aspartate aminotransferase (AAT, EC 2.6.1.1) catalyses the transamination of L-asparate to oxaloacetate. It has been reported that AAT from different plant sources can catalyse the transamination of other compounds structurally similar to the natural substrates. Specificity and kinetic studies were performed with two aspartate aminotransferase isoenzymes (AAT-1 and AAT-2) from leaves of Lupinus albus L. cv Estoril using different amino donors and acceptors. Both isoenzymes showed residual activity for some of the substrates tested. Competitive inhibition was found with most of the structural analogues which is typical of a ping-pong bi-bi kinetic mechanism. It was found that both isoenzymes can use 2-amino-4-methoxy-4-oxobutanoic acid as amino donor. AAT-2 uses 2-amino-4-methoxy-4-oxobutanoic acid at a similar rate as L-aspartate but AAT-1 uses this substrate at a slower rate. The use of this amino donor by AAT isoenzymes has not been reported previously, and our results indicate structural differences between both isoenzymes. PMID:11697045

  12. Cellular DNA breakage by soy isoflavone genistein and its methylated structural analogue biochanin A.

    PubMed

    Ullah, Mohd Fahad; Shamim, Uzma; Hanif, Sarmad; Azmi, Asfar S; Hadi, Sheikh M

    2009-11-01

    Epidemiological studies have indicated that populations with high isoflavone intake through soy consumption have lower rates of breast, prostate, and colon cancer. The isoflavone polyphenol genistein in soybean is considered to be a potent chemopreventive agent against cancer. In order to explore the chemical basis of chemopreventive activity of genistein, in this paper we have examined the structure-activity relationship between genistein and its structural analogue biochanin A. We show that both genistein and its methylated derivative biochanin A are able to mobilize nuclear copper in human lymphocyte, leading to degradation of cellular DNA. However, the relative rate of DNA breakage was greater in the case of genistein. Further, the cellular DNA degradation was inhibited by copper chelator (neocuproine/bathocuproine) but not by compounds that specifically bind iron and zinc (desferrioxamine mesylate and histidine, respectively). We also compared the antioxidant activity of the two isoflavones against tert-butylhydroperoxide-induced oxidative breakage in lymphocytes. Again genistein was found to be more effective than biochanin A in providing protection against oxidative stress induced by tert-butylhydroperoxide. It would therefore appear that the structural features of isoflavones that are important for antioxidant properties are also the ones that contribute to their pro-oxidant action through a mechanism that involves redox cycling of chromatin-bound nuclear copper. PMID:19743405

  13. Structure of synthetic peptide analogues of an eggshell protein of Schistosoma mansoni.

    PubMed Central

    Middaugh, C. R.; Thomson, J. A.; Burke, C. J.; Mach, H.; Naylor, A. M.; Bogusky, M. J.; Ryan, J. A.; Pitzenberger, S. M.; Ji, H.; Cordingley, J. S.

    1993-01-01

    The peptide (Gly-L-Tyr-L-Asp-L-Lys-L-Tyr)6, referred to as F4-6, was synthesized as a model for a schistosome eggshell protein in which the Gly-Tyr-Asp-Lys-Tyr consensus sequence is repeated over 40 times. Analysis by CD, Fourier transform infrared spectroscopy, potentiometric and spectrophotomertric titrations, NMR, and molecular modeling suggests that F4-6 forms some type of left-handed structure. A likely possibility appears to be a left-handed alpha-helix stabilized by Lysi-Aspi +4 salt bridges and possibly Aspi-Tyri +4 hydrogen bonding and Tyr-Tyr interactions. Spectroscopic studies of a number of F4-6 analogues support this conclusion. For example, substitution of D-Ala for Gly produces a peptide with enhanced left-handed helical spectral characteristics, whereas an L-Ala substitution results in a peptide with minimal structure. These studies suggest that the F4 protein from Schistosoma mansoni may be the first example of a naturally occurring protein devoid of proline and carbohydrate that forms a left-handed helix composed of L-amino acids, although alternative forms of other left-handed structures have yet to be rigorously excluded. PMID:8318895

  14. Phenyl-imidazolo-cytidine analogues: structure-photophysical activity relationship and ability to detect single DNA mismatch.

    PubMed

    Kovaliov, Marina; Weitman, Michal; Major, Dan Thomas; Fischer, Bilha

    2014-08-01

    To expand the arsenal of fluorescent cytidine analogues for the detection of genetic material, we synthesized para-substituted phenyl-imidazolo-cytidine ((Ph)ImC) analogues 5a-g and established a relationship between their structure and fluorescence properties. These analogues were more emissive than cytidine (?em 398-420 nm, ? 0.009-0.687), and excellent correlation was found between ? of 5a-g and ?p(-) of the substituent on the phenyl-imidazolo moiety (R(2) = 0.94). Calculations suggested that the dominant tautomer of (Ph)ImC in methanol solution is identical to that of cytidine. DFT calculations of the stable tautomer of selected (Ph)ImC analogues suggested a relationship between the HOMO-LUMO gap and ? and explained the loss of fluorescence in the nitro analogue. Incorporation of the CF3-(Ph)ImdC analogue into a DNA probe resulted in 6-fold fluorescence quenching of the former. A 17-fold reduction of fluorescence was observed for the G-matched duplex vs ODN(CF3-(Ph)ImdC), while for A-mismatched duplex, only a 2-fold decrease was observed. Furthermore, since the quantum yield of ODN(CF3-(Ph)ImdC):ODN(G) was reduced 17-fold vs that of a single strand, whereas that of ODN(CF3-(Ph)ImdC):ORN(G) was reduced only 3.8-fold, ODN(CF3-(Ph)ImdC) appears to be a DNA-selective probe. We conclude that the ODN(CF3-(Ph)ImdC) probe, exhibiting emission sensitivity upon single nucleotide replacement, may be potentially useful for DNA single nucleotide polymorphism (SNP) typing. PMID:24992467

  15. Structure-Activity Relationships (SAR) studies of benzoxazinones, their degradation products and analogues. phytotoxicity on standard target species (STS).

    PubMed

    Macías, Francisco A; Marín, David; Oliveros-Bastidas, Alberto; Castellano, Diego; Simonet, Ana M; Molinillo, José M G

    2005-02-01

    Benzoxazinones 2,4-dihydroxy-7-methoxy-(2H)-1,4-benzoxazin-3(4H)-one (DIMBOA) and 2,4-dihydroxy-(2H)-1,4-benzoxazin-3(4H)-one (DIBOA) have been considered key compounds for understanding allelopathic phenomena in Gramineae crop plants such as corn (Zea mays L.), wheat (Triticum aestivum L.), and rye (Secale cereale L.). The degradation processes in the environment observed for these compounds, in which soil microbes are directly involved, could affect potential allelopathic activity of these plants. We present in this work a complete structure-activity relationships study based on the phytotoxic effects observed for DIMBOA, DIBOA, and their main degradation products, in addition to several synthetic analogues of them. Their effects were evaluated on standard target species (STS), which include Triticum aestivum L. (wheat) and Allium cepa L. (onion) as monocots and Lepidium sativum L. (cress), Lactuca sativa L. (lettuce), and Lycopersicon esculentum Will. (tomato) as dicots. This permitted us to elucidate their ecological role and to propose new herbicide models based on their structures. The best phytotoxicity results were shown by the degradation chemical 2-aminophenoxazin-3-one (APO) and several 2-deoxy derivatives of natural benzoxazinones, including 4-acetoxy-(2H)-1,4-benzoxazin-3(4H)-one (ABOA), 4-hydroxy-(2H)-1,4-benzoxazin-3(4H)-one (D-DIBOA), and 4-hydroxy-7-methoxy-(2H)-1,4-benzoxazin-3(4H)-one (D-DIMBOA). They showed high inhibitory activity over almost all species growth. The fact that APO is a degradation product from DIBOA with high phytotoxicity and stability makes it possible to assign an important ecological role regarding plant defense mechanisms. 2-Deoxy derivatives of natural benzoxazinones display a wide range of activities that allow proposing them as new leads for natural herbicide models with a 1,4-benzoxazine skeleton. PMID:15686399

  16. Intraparticle mass transfer kinetics on molecularly imprinted polymers of structural analogues of a template

    SciTech Connect

    Kim, Hyunjung; Kaczmarski, Krzysztof; Guiochon, Georges A

    2005-09-01

    The intraparticle mass transfer kinetics of the structural analogues of a template on a Fmoc-L-Tryptophan (Fmoc-L-Trp) imprinted polymer (MIP) and on the corresponding non-imprinted polymer (NIP) were quantitatively studied using the lumped pore diffusion model (POR) of chromatography. The best equilibrium isotherm models of these compounds were used to calculate the high-concentration band profiles of different substrates on the MIP and the NIP with the POR model. These profiles were compared to experimental band profiles. The numerical values of the intraparticle pore and surface diffusion coefficients were adjusted to determine those that minimized the differences between calculated and experimental profiles. The results of this exercise show that surface diffusion is the dominant intraparticle mass transfer process for the substrates on the polymers and that the energetic heterogeneity of the surface should be considered in accounting for the surface diffusion of the L-enantiomers on the MIP. The surface diffusion coefficient increases with decreasing overall affinity of each substrate for the polymers.

  17. Relationships between the structure of dexoxadrol and etoxadrol analogues and their NMDA receptor affinity.

    PubMed

    Sax, Michael; Wnsch, Bernhard

    2006-01-01

    In the mid 1960s the (dioxolan-4-yl)piperidine derivatives dexoxadrol ((S,S)-1a) and etoxadrol ((S,S,S)-2a) were synthesized. Their pharmacological potential as analgesics, anesthetics and local anesthetics was evaluated in animal models and later on in clinical trials with patients. However, severe side effects including psychotomimetic effects, unpleasant dreams and aberrations stopped the clinical evaluation of dexoxadrol and etoxadrol. Both dioxolane derivatives represent NMDA receptor antagonists, which possess high affinity to the phencyclidine binding site within the NMDA receptor associated ion channel. In this review relationships between the structure of acetalic dexoxadrol analogues and homologues and their affinity toward the phencyclidine binding site of the NMDA receptor are summarized. In particular, high affinity is attained with compounds bearing two phenyl residues or one phenyl residue and an alkyl residue with two or three carbon atoms at the acetalic center. At least one oxygen atom of the oxygen heterocycle is necessary. Instead of the entire piperidine ring aminoalkyl substructures are sufficient for strong receptor interactions. Compounds with a primary amino moiety generally display the highest receptor affinity, whereas tertiary amines possess low affinity. Enlargement of the 1,3-dioxolane ring to a 1,3-dioxane ring or elongation of the oxygen heterocycle / amino group distance results in compounds with considerable NMDA receptor affinity. PMID:16719812

  18. Structural Requirements of N-Substituted Spiropiperidine Analogues as Agonists of Nociceptin/Orphanin FQ Receptor

    PubMed Central

    Bao, Pingping; Zhang, Xiaole; Ren, Hong; Li, Yan; Mu, Zulin; Zhang, Shuwei; Li, Guohui; Yang, Ling

    2011-01-01

    The nociceptin/orphanin FQ (NOP) receptor is involved in a wide range of biological functions, including pain, anxiety, depression and drug abuse. Especially, its agonists have great potential to be developed into anxiolytics. In this work, both the ligand- and receptor-based three-dimensional quantitative structureactivity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on 103 N-substituted spiropiperidine analogues as NOP agonists. The resultant optimal ligand-based CoMSIA model exhibited Q2 of 0.501, R2ncv of 0.912 and its predictive ability was validated by using an independent test set of 26 compounds which gave R2pred value of 0.818. In addition, docking analysis and molecular dynamics simulation (MD) were also applied to elucidate the probable binding modes of these agonists. Interpretation of the 3D contour maps, in the context of the topology of the active site of NOP, provided insight into the NOP-agonist interactions. The information obtained from this work can be used to accurately predict the binding affinity of related agonists and also facilitate the future rational design of novel agonists with improved activity. PMID:22272114

  19. Structural and Functional Characterization of a Multifunctional Alanine-Rich Peptide Analogue from Pleuronectes americanus

    PubMed Central

    Migliolo, Ludovico; Silva, Osmar N.; Silva, Paula A.; Costa, Maysa P.; Costa, Carolina R.; Nolasco, Diego O.; Barbosa, João A. R. G.; Silva, Maria R. R.; Bemquerer, Marcelo P.; Lima, Lidia M. P.; Romanos, Maria T. V.; Freitas, Sonia M.; Magalhães, Beatriz S.; Franco, Octavio L.

    2012-01-01

    Recently, defense peptides that are able to act against several targets have been characterized. The present work focuses on structural and functional evaluation of the peptide analogue Pa-MAP, previously isolated as an antifreeze peptide from Pleuronectes americanus. Pa-MAP showed activities against different targets such as tumoral cells in culture (CACO-2, MCF-7 and HCT-116), bacteria (Escherichia coli ATCC 8739 and Staphylococcus aureus ATCC 25923), viruses (HSV-1 and HSV-2) and fungi (Candida parapsilosis ATCC 22019, Trichophyton mentagrophytes (28d&E) and T. rubrum (327)). This peptide did not show toxicity against mammalian cells such as erythrocytes, Vero and RAW 264.7 cells. Molecular mechanism of action was related to hydrophobic residues, since only the terminal amino group is charged at pH 7 as confirmed by potentiometric titration. In order to shed some light on its structure-function relations, in vitro and in silico assays were carried out using circular dichroism and molecular dynamics. Furthermore, Pa-MAP showed partial unfolding of the peptide changes in a wide pH (3 to 11) and temperature (25 to 95°C) ranges, although it might not reach complete unfolding at 95°C, suggesting a high conformational stability. This peptide also showed a conformational transition with a partial α-helical fold in water and a full α-helical core in SDS and TFE environments. These results were corroborated by spectral data measured at 222 nm and by 50 ns dynamic simulation. In conclusion, data reported here show that Pa-MAP is a potential candidate for drug design against pathogenic microorganisms due to its structural stability and wide activity against a range of targets. PMID:23056574

  20. Spectroscopic, thermal and single crystal structure investigations of 2-bromotrimesic acid and its trimethyl ester analogue

    NASA Astrophysics Data System (ADS)

    Münch, Alexander S.; Katzsch, Felix; Gruber, Tobias; Mertens, Florian O. R. L.

    2014-09-01

    Two analogues of the well investigated trimesic acid viz. the 2-bromobenzene-1,3,5-tricarboxylic acid 1 and their ester trimethyl 2-bromobenzene-1,3,5-tricarboxylate 2, have been synthesised and their X-ray structures were solved. Acid 1 crystallises as 1:1 inclusion compound with water in a layer structure. Like in the solid state structure of trimesic acid, we found strong Osbnd HṡṡṡO hydrogen bonds between one of the carboxyl groups and a neighbouring molecule to form a hydrogen bonding motif R22(8). Additionally, a water molecule and a second acid function of 1 are involved in further hydrogen bonding featuring the graph set R44(12) forming what might be called a water inserted dimer. As shown by TG-DSC measurements the water molecule in the 1:1 inclusion compound of 1 is engaged in two strong Osbnd HṡṡṡO hydrogen bonds, it escapes at a rather low temperature of 99 °C. Bromine monosubstitution at the benzene ring forces the third carboxylic acid out of the mean plane of the molecule, which disturbs the coplanar arrangement of the three COOH moieties. Thus, the typical “chicken-wire” network formation is hindered. In the trimethyl 2-bromobenzene-1,3,5-tricarboxylate (2), the formation of strong Osbnd HṡṡṡO hydrogen bonds is disabled by esterification of the acid functions. Nevertheless, the packing of 2 features solvent free molecular layers formed by BrṡṡṡO contacts and connected van der Waals interactions. These layers are linked to each other by inverse bifurcated hydrogen bonds in term weak Csbnd HṡṡṡO contacts. The results of the X-ray analysis could be confirmed by infrared spectroscopy.

  1. Sweet and bitter taste: structure and conformations of two aspartame dipeptide analogues.

    PubMed

    Benedetti, E; Gavuzzo, E; Santini, A; Kent, D R; Zhu, Y F; Zhu, Q; Mahr, C; Goodman, M

    1995-01-01

    The synthesis and X-ray diffraction analysis of two dipeptide taste ligands have been carried out as part of our study of the molecular basis of taste. The compounds L-aspartyl-D-alpha-methylphenylalanine methyl ester [L-Asp-D-(alpha Me)Phe-OMe] and L-aspartyl-D-alanyl-2,2,5, 5-tetramethylcyclopentanyl ester [L-Asp-D-Ala-OTMCP] elicit bitter and sweet taste, respectively. The C-terminal residues of the two analogues adopt distinctly different conformations in the solid state. The aspartyl moiety assumes the same conformation found in other dipeptide taste ligands with the side-chain carboxylate and the amino groups forming a zwitterionic ring with a conformation defined by psi, chi 1 = 157.7 degrees, -61.5 degrees for L-Asp-D-Ala-OTMCP and 151.0 degrees, -68.8 degrees for L-Asp-D-(alpha Me)Phe-OMe. In the second residue, a left-handed helical conformation is observed for the (alpha Me)Phe residue of L-Asp-D-(alpha Me)Phe-OMe with phi 2 = 49.0 degrees and psi 2 = 47.9 degrees, while the Ala residue of L-Asp-D-Ala-OTMCP adopts a semi-extended conformation characterized by dihedral angles phi 2 = 62.8 degrees and psi 2 = -139.9 degrees. The solid-state structure of the bitter L-Asp-D-(alpha Me)Phe-OMe is extended: while the crystal structure of the sweet L-Asp-D-OTMCP roughly adopts the typical L-shaped structure shown by other sweeteners. The data of L-Asp-D-(alpha Me)Phe-OMe are compared with those of its diastereoisomer L-Asp-L-(alpha Me)Phe-OMe. Conformational analysis of the two taste ligands in solution by NMR and computer simulations agrees well with our model for sweet and bitter tastes. PMID:9223014

  2. Synthesis of boroxifen, a nido-carborane analogue of tamoxifen.

    PubMed

    Valliant, John F; Schaffer, Paul; Stephenson, Karin A; Britten, James F

    2002-01-25

    A nido-carborane analogue of tamoxifen, the widely employed breast cancer therapy agent, was prepared as an archetype of a potential new class of antiestrogen and boron neutron capture therapy agent in which the carborane is incorporated within the framework of the parent compound. The carborane was introduced through the reaction of 6,9-bis(acetonitrile)decaborane with a unique and highly conjugated ene-yne, which was prepared stereoselectively. NMR spectroscopy and a crystal structure of a key intermediate, the carborane analogue of chloro-tamoxifen, demonstrated the structural similarities between the tamoxifen carboranes and their corresponding phenyl analogues. PMID:11798307

  3. Elucidation of Structural Elements for Selectivity across Monoamine Transporters: Novel 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues

    PubMed Central

    2015-01-01

    2-[(Diphenylmethyl)sulfinyl]acetamide (modafinil, ()-1) is a unique dopamine uptake inhibitor that binds the dopamine transporter (DAT) differently than cocaine and may have potential for the treatment of psychostimulant abuse. To further investigate structural requirements for this divergent binding mode, novel thio- and sulfinylacetamide and ethanamine analogues of ()-1 were synthesized wherein (1) the diphenyl rings were substituted with methyl, trifluoromethyl, and halogen substituents and (2) substituents were added to the terminal amide/amine nitrogen. Halogen substitution of the diphenyl rings of ()-1 gave several amide analogues with improved binding affinity for DAT and robust selectivity over the serotonin transporter (SERT), whereas affinity improved at SERT over DAT for the p-halo-substituted amine analogues. Molecular docking studies, using a subset of analogues with DAT and SERT homology models, and functional data obtained with DAT (A480T) and SERT (T497A) mutants defined a role for TM10 in the substrate/inhibitor S1 binding sites of DAT and SERT. PMID:24494745

  4. Elucidation of structural elements for selectivity across monoamine transporters: novel 2-[(diphenylmethyl)sulfinyl]acetamide (modafinil) analogues.

    PubMed

    Okunola-Bakare, Oluyomi M; Cao, Jianjing; Kopajtic, Theresa; Katz, Jonathan L; Loland, Claus J; Shi, Lei; Newman, Amy Hauck

    2014-02-13

    2-[(Diphenylmethyl)sulfinyl]acetamide (modafinil, ()-1) is a unique dopamine uptake inhibitor that binds the dopamine transporter (DAT) differently than cocaine and may have potential for the treatment of psychostimulant abuse. To further investigate structural requirements for this divergent binding mode, novel thio- and sulfinylacetamide and ethanamine analogues of ()-1 were synthesized wherein (1) the diphenyl rings were substituted with methyl, trifluoromethyl, and halogen substituents and (2) substituents were added to the terminal amide/amine nitrogen. Halogen substitution of the diphenyl rings of ()-1 gave several amide analogues with improved binding affinity for DAT and robust selectivity over the serotonin transporter (SERT), whereas affinity improved at SERT over DAT for the p-halo-substituted amine analogues. Molecular docking studies, using a subset of analogues with DAT and SERT homology models, and functional data obtained with DAT (A480T) and SERT (T497A) mutants defined a role for TM10 in the substrate/inhibitor S1 binding sites of DAT and SERT. PMID:24494745

  5. Biofunctional constituent isolated from Citrullus colocynthis fruits and structure-activity relationships of its analogues show acaricidal and insecticidal efficacy.

    PubMed

    Jeon, Ju-Hyun; Lee, Hoi-Seon

    2014-08-27

    The acaricidal and insecticidal potential of the active constituent isolated from Citrullus colocynthis fruits and its structurally related analogues was evaluated by performing leaf disk, contact toxicity, and fumigant toxicity bioassays against Tetranychus urticae, Sitophilus oryzae, and Sitophilus zeamais adults. The active constituent of C. colocynthis fruits was isolated by chromatographic techniques and was identified as 4-methylquinoline on the basis of spectroscopic analyses. To investigate the structure-activity relationships, 4-methylquinoline and its structural analogues were tested against mites and two insect pests. On the basis of the LC50 values, 7,8-benzoquinoline was the most effective against T. urticae. Quinoline, 8-hydroxyquinoline, 2-methylquinoline, 4-methylquinoline, 6-methylquinoline, 8-methylquinoline, and 7,8-benzoquinoline showed high insecticidal activities against S. oryzae and S. zeamais regardless of the application method. These results indicate that introduction of a functional group into the quinoline skeleton and changing the position of the group have an important influence on the acaricidal and insecticidal activities. Furthermore, 4-methylquinoline isolated from C. colocynthis fruits, along with its structural analogues, could be effective natural pesticides for managing spider mites and stored grain weevils. PMID:25110971

  6. Adsorption on molecularly imprinted polymers of structural analogues of a template. Single-component adsorption isotherm data

    SciTech Connect

    Kim, Hyunjung; Guiochon, Georges A

    2005-10-01

    The equilibrium adsorption isotherms on two otherwise identical polymers, one imprinted with Fmoc-L-tryptophan (Fmoc-L-Trp) (MIP), the other nonimprinted (NIP), of compounds that are structural analogues of the template were acquired by frontal analysis (FA) in an acetonitrile/acetic acid (99/1 v/v) mobile phase, over a wide concentration range (from 0.005 to 50 mM). These analogues were Fmoc-L-tyrosine, Fmoc-L-serine, Fmoc-L-phenyalanine, Fmoc-glycine (Fmoc-Gly), Fmoc-L-tryptophan pentafluorophenyl ester (Fmoc-L-Trp(OPfp)), and their antipodes. These substrates have different numbers of functional groups able to interact with the 4-vinylpyridine groups of the polymer. For a given number of the functional groups, these substrates have different hydrophobicities of their side groups (as indicated by their partition coefficients (log P{sub ow}) in the octanol-water system (e.g., from 4.74 for Fmoc-Trp to 2.53 for Fmoc-Gly)). Statistical results from the fitting of the FA data to Langmuirian isotherm models, the calculation of the affinity energy distribution, and the comparison of calculated and experimental band profiles show that all these sets of FA data are best accounted for by a tri-Langmuir isotherm model, except for the data of Fmoc-L-Trp(OPfp) that are best modeled by a simple Langmuir isotherm. So, all compounds but Fmoc-L-Trp(OPfp) find three different types of adsorption sites on both the MIP and the NIP. The properties of these different types of sites were studied systematically. The results show that the affinity of the structural analogues for the NIP is controlled mostly by the number of the functional groups on the substrates and somewhat by the hydrophobicity of their side groups. These two factors control also the MIP affinity toward the enantiomers of the structural analogues that have a stereochemistry different from that of the template. In contrast, the affinity of the highest affinity sites of the MIP toward the enantiomers of these structural analogues that have the same stereochemistry as the template is highest for the imprinted molecule (Fmoc-L-Trp). The separation of the template from the substrates with the same stereochemistry is influenced by the number of the functional groups on the substrates that can interact with the highest affinity sites on the MIP. The separation of the enantiomers of the analogues of the substrates was also achieved on the MIP, and these enantiomeric separations are influenced by the hydrophobicity of the substrates.

  7. Comparative Structure-Activity Relationships of Benztropine Analogues at the Dopamine Transporter and Histamine H1 Receptors

    PubMed Central

    Kulkarni, Santosh S.; Kopajtic, Theresa A.; Katz, Jonathan L.; Newman, Amy Hauck

    2006-01-01

    Benztropine (BZT) and its analogues inhibit dopamine uptake and bind with moderate to high affinity to the dopamine transporter (DAT). However, many of these compounds, in contrast to other monoamine uptake inhibitors, lack cocaine-like behavioral effects and fail to potentiate the effects of cocaine. The BZT analogues also exhibit varied binding affinities for muscarinic M1 and histamine H1 receptors. In this study a comparative analysis was conducted of pharmacophoric features with respect to the activities of BZT analogues at the DAT and at the histamine H1 receptor. The BZT analogues showed a wide range of histamine H1 receptor (Ki =16-37600 nM) and DAT (Ki=8.5-6370 nM) binding affinities. A stereoselective histamine H1-antagonist pharmacophore, using a five-point superimposition of classical antagonists on the template, cyproheptadine, was developed. A series of superimpositions and comparisons were performed with various analogues of BZT. In general, smaller substituents were well tolerated on the aromatic rings of the diphenyl methoxy group for both the DAT and H1 receptor, however for the H1 receptor, substitution at only one of the aromatic rings was preferred. The substituents at the 2- and N-positions of the tropane ring were preferred for DAT however these groups seem to overlap receptor essential regions in the histamine H1 receptor. Molecular models at the DAT and the histamine H1 receptor provide further insight into the structural requirements for binding affinity and selectivity that can be implemented in future drug design. PMID:16460947

  8. Synthesis and StructureActivity Relationship Study of 5a-Carbasugar Analogues of SL0101

    PubMed Central

    2014-01-01

    The Ser/Thr protein kinase, RSK, is associated with oncogenesis, and therefore, there are ongoing efforts to develop RSK inhibitors that are suitable for use in vivo. SL0101 is a natural product that demonstrates selectivity for RSK inhibition. However, SL0101 has a short biological half-life in vivo. To address this issue we designed a set of eight cyclitol analogues, which should be resistant to acid catalyzed anomeric bond hydrolysis. The analogues were synthesized and evaluated for their ability to selectively inhibit RSK in vitro and in cell-based assays. All the analogues were prepared using a stereodivergent palladium-catalyzed glycosylation/cyclitolization for installing the aglycon. The l-cyclitol analogues were found to inhibit RSK2 in in vitro kinase activity with a similar efficacy to that of SL0101, however, the analogues were not specific for RSK in cell-based assays. In contrast, the d-isomers showed no RSK inhibitory activity in in vitro kinase assay. PMID:25589938

  9. Osmium NAMI-A analogues: synthesis, structural and spectroscopic characterization, and antiproliferative properties.

    PubMed

    Cebrin-Losantos, Berta; Krokhin, Artem A; Stepanenko, Iryna N; Eichinger, Rene; Jakupec, Michael A; Arion, Vladimir B; Keppler, Bernhard K

    2007-06-11

    The osmium(III) complex [(DMSO)2H][trans-OsIIICl4(DMSO)2] (1) has been prepared via stepwise reduction of OsO4 in concentrated HCl using N2H(4).2HCl and SnCl(2).2H2O in DMSO. 1 reacts with a number of azole ligands, namely, indazole (Hind), pyrazole (Hpz), benzimidazole (Hbzim), imidazole (Him), and 1H-1,2,4-triazole (Htrz), in organic solvents, affording novel complexes (H2ind)[OsIIICl4(Hind)(DMSO)] (2), (H2pz)[OsIIICl4(Hpz)(DMSO)] (3), (H2bzim)[OsIIICl4(Hbzim)(DMSO)] (4), (H2im)[OsIIICl4(Him)(DMSO)] (6), and (H2trz)[OsIIICl4(Htrz)(DMSO)] (7), which are close analogues of the antimetastatic complex NAMI-A. Metathesis reaction of 4 with benzyltriphenylphosphonium chloride in methanol led to the formation of (Ph3PCH2Ph)[OsIIICl4(Hbzim)(DMSO)] (5). The complexes were characterized by IR, UV-vis, ESI mass spectrometry, 1H NMR spectroscopy, cyclic voltammetry, and X-ray crystallography. In contrast to NAMI-A, 2-4, 6, and 7 are kinetically stable in aqueous solution and resistant to hydrolysis. Surprisingly, they show reasonable antiproliferative activity in vitro in two human cell lines, HT-29 (colon carcinoma) and SK-BR-3 (mammary carcinoma), when compared with analogous ruthenium compounds. Structure-activity relationships and the potential of the prepared complexes for further development are discussed. PMID:17497853

  10. Actinomycin Analogues Containing Pipecolic Acid: Relationship of Structure to Biological Activity

    PubMed Central

    Formica, Joseph V.; Shatkin, Aaron J.; Katz, Edward

    1968-01-01

    Streptomyces antibioticus synthesizes a mixture of actinomycins which differ at the “imino acid” site of the peptide chains. In the presence of exogenous pipecolic acid, several new actinomycins were synthesized and 70% of the proline in the antibiotic mixture was replaced by the analogue. Three new antibiotics (designated Pip 1α, Pip 1β, and Pip 2) were isolated from culture filtrates, purified, and crystallized. The molar ratio of pipecolic acid to proline was: Pip 1α, 1:0; Pip 1β, 1:1; Pip 2, 2:0. These compounds inhibited the growth and cell division of gram-positive, but not gram-negative, bacteria. The relative inhibitory activity against bacteria, Escherichia coli deoxyribonucleic acid (DNA)-dependent ribonucleic acid (RNA) polymerase in vitro, and RNA synthesis in Bacillus subtilis and mouse L-929 cells was: actinomycin IV = Pip 1β > Pip 2 > Pip 1α. Protein synthesis in B. subtilis was less affected, and DNA synthesis was inhibited only at higher concentrations of antibiotic tested. In L cells, DNA formation was reduced less than RNA synthesis, whereas protein synthesis was not blocked under the experimental conditions employed. Kinetic studies with B. subtilis revealed that RNA synthesis was inhibited rapidly followed by an inhibition of protein synthesis. All four antibiotics markedly inhibited the replication of vaccinia virus and reovirus in tissue culture cells, but the production of poliovirus was resistant to the antibiotics. These actinomycins bind to DNA, resulting in an elevation of its Tm and a decrease in the peak extinction of the actinomycins. The mode of action, as well as the structure-activity relationships among the actinomycins, are discussed relative to a previously proposed model of binding. PMID:4174667

  11. Carbocyclic nucleoside analogues: classification, target enzymes, mechanisms of action and synthesis

    NASA Astrophysics Data System (ADS)

    Matyugina, E. S.; Khandazhinskaya, A. P.; Kochetkov, Sergei N.

    2012-08-01

    Key biological targets (S-adenosyl-L-homocysteine hydrolase, telomerase, human immunodeficiency virus reverse transcriptase, herpes virus DNA polymerase and hepatitis B virus DNA polymerase) and the mechanisms of action of carbocyclic nucleoside analogues are considered. Structural types of analogues are discussed. Methods of synthesis for the most promising compounds and the spectrum of their biological activities are described. The bibliography includes 126 references.

  12. Fluorinated pseudopeptide analogues of the neuropeptide 26RFa: synthesis, biological, and structural studies.

    PubMed

    Pierry, Camille; Couve-Bonnaire, Samuel; Guilhaudis, Laure; Neveu, Cindy; Marotte, Amlie; Lefranc, Benjamin; Cahard, Dominique; Sgalas-Milazzo, Isabelle; Leprince, Jrme; Pannecoucke, Xavier

    2013-09-01

    A series of four fluorinated dipeptide analogues each containing a fluoro-olefin moiety as peptide bond surrogate has been designed and synthesized. These motifs have been successfully introduced into the bioactive C-terminal heptapeptide of the neuropeptide 26RFa by conventional SPPS. We then evaluated the ability of the generated pseudopeptides to increase [Ca?](i) in GPR103-transfected cells. For these fluorinated analogues, greater stability in human serum was observed. Their conformations were also investigated, leading to the valuable identification of differences depending on the position of the fluoro-olefin moiety in the sequence. PMID:23940098

  13. Analogue modelling of deformation structures at Mt Cameroon analysed with a digital image correlation technique

    NASA Astrophysics Data System (ADS)

    Kervyn, Matthieu; Walter, Thomas R.; van Wyk de Vries, Benjamin; Ernst, Gerald G. J.

    2010-05-01

    Mt. Cameroon is a large, 4090 m high, continental volcano. It is characterized by repetitive basaltic lava flow eruptions, the most recent ones occurring in 1999 and 2000. Upper flanks of Mt Cameroon are exceptionally steep (~30) for a lava-dominated volcano and are constrained by sharp breaks-in-slope. Field work enabled to identified well-defined inward-dipping structures bordering a flat summit plateau and thrust faults associated with topographic terraces around Mt Cameroon's base, suggesting summit subsidence and gravitational spreading of the volcano flanks above its sedimentary base. To better understand the structural configuration and morphology observed, scaled analogue experiments were designed. A volcanic ridge, made out of fine quartz sand, was let spread under gravitational forces above a ductile silicone layer. Experiments were conducted in 2D and 3D configurations. A digital image correlation (DIC) procedure was used to record fault formation and evolution through time. 3D spreading of an elongated edifice favors displacement perpendicular to the long axis, and formation of a summit graben and basal thrusts or folds parallel to this axis. Results of the DIC highlights the strain concentration in the central part of the main graben and along specific strike-slip faults bordering secondary grabens. This deformation is however not associated with slope increase or instabilities. 2D spreading of a volcanic ridge between two glass panes is associated either with two outward-dipping listric normal faults and inward-dipping antithetic faults or with two sets of deep and shallow normal faults, defining a central graben and forming steep mid-slopes with local instabilities, depending on the thickness of the underlying ductile material. Results from the experiments are compared with structural lineaments mapped at Mt Cameroon. It is concluded that the elongated morphology of Mt Cameroon promotes directional spreading perpendicular to its long axis, probably enhanced by local buttressing. Directional spreading is associated with both deep-seated normal listric faults causing summit subsidence as well as shallow outward dipping normal faults causing large scale slumps at mid-flanks. These shallow slumps, combined with inflation of upper flank through magma intrusion, account for the unusual steep slopes and flank landslides observed at Mt Cameroon.

  14. Information Theoretic Secret Key Generation: Structured Codes and Tree Packing

    ERIC Educational Resources Information Center

    Nitinawarat, Sirin

    2010-01-01

    This dissertation deals with a multiterminal source model for secret key generation by multiple network terminals with prior and privileged access to a set of correlated signals complemented by public discussion among themselves. Emphasis is placed on a characterization of secret key capacity, i.e., the largest rate of an achievable secret key,

  15. Information Theoretic Secret Key Generation: Structured Codes and Tree Packing

    ERIC Educational Resources Information Center

    Nitinawarat, Sirin

    2010-01-01

    This dissertation deals with a multiterminal source model for secret key generation by multiple network terminals with prior and privileged access to a set of correlated signals complemented by public discussion among themselves. Emphasis is placed on a characterization of secret key capacity, i.e., the largest rate of an achievable secret key,…

  16. Parrots as key multilinkers in ecosystem structure and functioning.

    PubMed

    Blanco, Guillermo; Hiraldo, Fernando; Rojas, Abraham; Dénes, Francisco V; Tella, José L

    2015-09-01

    Mutually enhancing organisms can become reciprocal determinants of their distribution, abundance, and demography and thus influence ecosystem structure and dynamics. In addition to the prevailing view of parrots (Psittaciformes) as plant antagonists, we assessed whether they can act as plant mutualists in the dry tropical forest of the Bolivian inter-Andean valleys, an ecosystem particularly poor in vertebrate frugivores other than parrots (nine species). We hypothesised that if interactions between parrots and their food plants evolved as primarily or facultatively mutualistic, selection should have acted to maximize the strength of their interactions by increasing the amount and variety of resources and services involved in particular pairwise and community-wide interaction contexts. Food plants showed different growth habits across a wide phylogenetic spectrum, implying that parrots behave as super-generalists exploiting resources differing in phenology, type, biomass, and rewards from a high diversity of plants (113 species from 38 families). Through their feeding activities, parrots provided multiple services acting as genetic linkers, seed facilitators for secondary dispersers, and plant protectors, and therefore can be considered key mutualists with a pervasive impact on plant assemblages. The number of complementary and redundant mutualistic functions provided by parrots to each plant species was positively related to the number of different kinds of food extracted from them. These mutually enhancing interactions were reflected in species-level properties (e.g., biomass or dominance) of both partners, as a likely consequence of the temporal convergence of eco-(co)evolutionary dynamics shaping the ongoing structure and organization of the ecosystem. A full assessment of the, thus far largely overlooked, parrot-plant mutualisms and other ecological linkages could change the current perception of the role of parrots in the structure, organization, and functioning of ecosystems. PMID:26445664

  17. Gyrase ATPase domain as an antitubercular drug discovery platform: structure-based design and lead optimization of nitrothiazolyl carboxamide analogues.

    PubMed

    Jeankumar, Variam Ullas; Renuka, Janupally; Kotagiri, Sonali; Saxena, Shalini; Kakan, Shruti Singh; Sridevi, Jonnalagadda Padma; Yellanki, Swapna; Kulkarni, Pushkar; Yogeeswari, Perumal; Sriram, Dharmarajan

    2014-08-01

    In this study, we explored the pharmaceutically underexploited mycobacterial gyrase ATPase (GyrB) domain as a template for a structure-based virtual screening of our in-house (BITS Pilani) compound collection to discover new inhibitors targeting Mycobacterium tuberculosis (M.tb.) The hit identified was further customized by using a combination of molecular docking and medicinal chemistry strategies to obtain an optimized analogue displaying considerable in vitro enzyme efficacy and bactericidal properties against the M.tb. H37 Rv strain. The binding affinity of the ligand toward the GyrB domain was reascertained by differential scanning fluorimetry experiments. Further evaluation of the hERG toxicity (a major limitation among the previously reported N-linked aminopiperidine analogues) indicated these molecules to be completely devoid of cardiotoxicity, a significant achievement within this class. PMID:24962352

  18. Adenosine Analogues as Selective Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase of Trypanosomatidae via Structure-Based Drug Design

    PubMed Central

    Bressi, Jerome C.; Verlinde, Christophe L. M. J.; Aronov, Alex M.; Shaw, My Le; Shin, Sam S.; Nguyen, Lisa N.; Suresh, Stephen; Buckner, Frederick S.; Van Voorhis, Wesley C.; Kuntz, Irwin D.; Hol, Wim G. J.; Gelb, Michael H.

    2010-01-01

    In our continuation of the structure-based design of anti-trypanosomatid drugs, parasite-selective adenosine analogues were identified as low micromolar inhibitors of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Crystal structures of Trypanosoma brucei, Trypanosoma cruzi, Leishmania mexicana, and human GAPDHs provided details of how the adenosyl moiety of NAD+ interacts with the proteins, and this facilitated the understanding of the relative affinities of a series of adenosine analogues for the various GAPDHs. From exploration of modifications of the naphthalenemethyl and benzamide substituents of a lead compound, N6-(1-naphthalenemethyl)-2?-deoxy-2?-(3-methoxybenzamido)adenosine (6e), N6-(substituted-naphthalenemethyl)-2?-deoxy-2?-(substituted-benzamido)adenosine analogues were investigated. N6-(1-Naphthalenemethyl)-2?-deoxy-2?-(3,5-dimethoxybenzamido)adenosine (6m), N6-[1-(3-hydroxy-naphthalene)methyl]-2?-deoxy-2?-(3,5-dimethoxybenzamido)adenosine (7m), N6-[1-(3-methoxy-naphthalene)methyl]-2?-deoxy-2?-(3,5-dimethoxybenzamido)adenosine (9m), N6-(2-naphthalene-methyl)-2?-deoxy-2?-(3-methoxybenzamido)adenosine (11e), and N6-(2-naphthalenemethyl)-2?-deoxy-2?-(3,5-dimethoxybenzamido)adenosine (11m) demonstrated a 2- to 3-fold improvement over 6e and a 7100- to 25000-fold improvement over the adenosine template. IC50s of these compounds were in the range 212 ?M for T. brucei, T. cruzi, and L. mexicana GAPDHs, and these compounds did not inhibit mammalian GAPDH when tested at their solubility limit. To explore more thoroughly the structureactivity relationships of this class of compounds, a library of 240 N6-(substituted)-2?-deoxy-2?-(amido)adenosine analogues was generated using parallel solution-phase synthesis with N6 and C2? substituents chosen on the basis of computational docking scores. This resulted in the identification of 40 additional compounds that inhibit parasite GAPDHs in the low micromolar range. We also explored adenosine analogues containing 5?-amido substituents and found that 2?,5?-dideoxy-2?-(3,5-dimethoxy-benzamido)-5?-(diphenylacetamido)adenosine (49) displays an IC50 of 60100 ?M against the three parasite GAPDHs. PMID:11405646

  19. Synthesis, properties and structures of NbOF3 complexes and comparisons with NbOCl3 analogues.

    PubMed

    Levason, William; Reid, Gillian; Trayer, Jonathan; Zhang, Wenjian

    2014-03-01

    The first series of complexes of niobium(v) oxide trifluoride, [NbOF3(OPR3)2] (R = Me or Ph), [NbOF3(dppmO2)] (dppmO2 = Ph2P(O)CH2P(O)Ph2), [NbOF3(dmso)2], [NbOF3(tmeda)] (tmeda = Me2N(CH2)2NMe2) and [NbOF3(diimine)] (diimine = 2,2'-bipy, 1,10-phen) have been prepared, either by reaction of the corresponding complexes of NbF5 and hexamethyldisiloxane (HMDSO) in CH2Cl2-MeCN solution, or directly from NbF5, ligand and HMDSO. They were characterised by IR, (1)H, (31)P{(1)H} and (19)F{(1)H} NMR spectroscopy, and X-ray crystal structures are reported for [NbOF3(OPR3)2] (R = Me or Ph) and [NbOF3(dppmO2)]. Complexes of NbOCl3, [NbOCl3(OPPh3)2], [NbOCl3(dppmO2)], [NbOCl3(dppeO2)] (dppeO2 = Ph2P(O)(CH2)2P(O)Ph2), [NbOCl3(tmeda)] and [NbOCl3(diimine)] were made from NbCl5 and HMDSO in MeCN (which forms [NbOCl3(MeCN)2] in situ), followed by addition of the neutral ligand. Their properties are compared with the oxide fluoride analogues. X-ray structures are reported for [NbOCl3(dppmO2)], [NbOCl3(dppeO2)], [NbOCl3(tmeda)] and [NbOCl3(2,2'-bipy)]. The synthesis and spectroscopic characterisation of [MF5L] (M = Nb or Ta; L = OPR3, OAsPh3) and [MF4(diimine)2][MF6] are also described, and the key properties of the four series of complexes compared. PMID:24413623

  20. Combinatorial libraries: a tool to design antimicrobial and antifungal peptide analogues having lytic specificities for structure-activity relationship studies.

    PubMed

    Blondelle, S E; Lohner, K

    2000-01-01

    In the race for supremacy, microbes are sprinting ahead. This warning by the World Health Organization clearly demonstrates that the spread of antibiotic-resistant bacteria leads to a global health problem and that antibiotics never seen before by bacteria are urgently needed. Antimicrobial peptides represent such a source for novel antibiotics due to their rapid lytic activity (within minutes) through disruption of cell membranes. However, due to the similarities between bacterial, fungal, and mammalian plasma cell membranes, a large number of antimicrobial peptides have low lytic specificities and exhibit a broad activity spectrum and/or significant toxic effect toward mammalian cells. Mutation strategies have allowed the development of analogues of existing antimicrobial peptides having greater lytic specificities, although such methods are lengthy and would be more efficient if the molecular mechanisms of action of antimicrobial peptides were clearly elucidated. Synthetic combinatorial library approaches have brought a new dimension to the design of novel biologically active compounds. Thus, a set of peptide analogues were generated based on the screening of a library built around an existing lytic peptide, and on a deconvolution strategy directed toward activity specificity. These peptide analogues also served as model systems to further study the effect of biomembrane mimetic systems on the peptides structural behavior relevant to their biological activities. PMID:10931443

  1. Effect of gambierol and its tetracyclic and heptacyclic analogues in cultured cerebellar neurons: a structure-activity relationships study.

    PubMed

    Prez, Sheila; Vale, Carmen; Alonso, Eva; Fuwa, Haruhiko; Sasaki, Makoto; Konno, Yu; Goto, Tomomi; Suga, Yuto; Vieytes, Mercedes R; Botana, Luis M

    2012-09-17

    The polycyclic ether class of marine natural products has attracted the attention of researchers due to their complex and large chemical structures and diverse biological activities. Gambierol is a marine polycyclic ether toxin, first isolated along with ciguatoxin congeners from the dinoflagellate Gambierdiscus toxicus. The parent compound gambierol and the analogues evaluated in this work share the main crucial elements for biological activity, previously described to be the C28=C29 double bond within the H ring and the unsaturated side chain [Fuwa, H., Kainuma, N., Tachibana, K., Tsukano, C., Satake, M., and Sasaki, M. (2004) Diverted total synthesis and biological evaluation of gambierol analogues: Elucidation of crucial structural elements for potent toxicity. Chem. Eur. J. 10, 4894-4909]. With the aim to gain a deeper understanding of the cellular mechanisms involved in the biological activity of these compounds, we compared its activity in primary cultured neurons. The three compounds inhibited voltage-gated potassium channels (Kv) in a concentration-dependent manner and with similar potency, caused a small inhibition of voltage-gated sodium channels (Nav), and evoked cytosolic calcium oscillations. Moreover, the three compounds elicited a "loss of function" effect on Kv channels at concentrations of 0.1 nM. Additionally, both the tetracyclic and the heptacyclic derivatives of gambierol elicited synchronous calcium oscillations similar to those previously described for gambierol in cultured cerebellar neurons. Neither gambierol nor its tetracyclic derivative elicited cell toxicity, while the heptacyclic analogue caused a time-dependent decrease in cell viability. Neither the tetracyclic nor the heptacyclic analogues of gambierol exhibited lethality in mice after ip injection of 50 or 80 ?g/kg of each compound. Altogether, the results presented in this work support an identical mechanism of action for gambierol and its tetracyclic and heptacyclic analogues and indicate a "loss of function" effect on potassium channels even after administration of the three compounds at subnanomolar concentrations. In addition, because gambierol is known to stabilize the closed state of Kv3 channels, the results presented in this paper may have implications for understanding of channel functions and for future development of therapies against ciguatera poisoning and potassium channel-related diseases. PMID:22894724

  2. Identification and structural elucidation of three new tadalafil analogues found in a dietary supplement.

    PubMed

    Lee, Ji Hyun; Mandava, Suresh; Baek, Sun Young; Lee, Yong-Moon

    2016-05-10

    Compounds elucidated as new tadalafil analogues were found to be adulterated in a dietary supplement and detected during routine analysis by HPLC with photodiode array detection. The UV spectra of these compounds were found to be almost identical to that of tadalafil. The unknown compounds were isolated by preparative HPLC and elucidated by quadrupole-time-of-flight MS and NMR spectroscopy. Two compounds were identified as cyclopentyltadalafil and trans-cyclopentyltadalafil, from the substitution of the tadalafil N-methyl group with a cyclopentyl group. Another analogue was a dimeric form of tadalafil with an N-cyclopentyl group. This represents the first report of the elucidation of compounds used as adulterants in a dietary supplement. PMID:26855379

  3. Structure-function relationship studies of PTH(1-11) analogues containing D-amino acids.

    PubMed

    Caporale, Andrea; Biondi, Barbara; Schievano, Elisabetta; Wittelsberger, Angela; Mammi, Stefano; Peggion, Evaristo

    2009-06-01

    Parathyroid hormone (PTH) is an 84-amino acid peptide hormone. Produced in the parathyroid glands, it acts primarily on bone and kidney to maintain extracellular calcium levels within normal limits. It has been shown that the 1-34 amino acid fragment of PTH is sufficient to bind and activate the PTH type-I receptor. Recent investigations focusing on the interaction of N-terminal fragments of PTH with PTH type-I receptor showed that certain modifications can increase signalling potency in peptides as short as 11 amino acids. To understand the role of the side chains of all the amino acid residues in PTH(1-11), we synthesized all-D PTH, three retro-inverso analogues of the most active modified PTH(1-11), H-Aib-Val-Aib-Glu-Ile-Gln-Leu-Nle-His-Gln-Har-NH(2), and we substituted every L-AA of the latter with the corresponding D-AA, obtaining a library of PTH(1-11) analogues that were tested as agonists. The library was synthesized by SPPS, employing the Fmoc protocol. The biological tests showed that the activity of the D-Har11 analogue is of the same order of magnitude of that of the most active modified PTH(1-11). This behaviour is paralleled by an increase of the helical content on going from the D-Val(2) to the D-Har(11) analogue. This is in agreement with previous work where a correlation between activity and helical content has been demonstrated. The importance of a positively charged group in the C-terminal position is shown to be independent of the configuration of the C(alpha)-carbon. PMID:19303868

  4. New route to unsymmetrical phthalocyanine analogues by the use of structurally distorted subphthalocyanines

    SciTech Connect

    Kobayashi, Nagao; Kondo, Ryoko; Nakajima, Shinichiro; Osa, Tetsuo )

    1990-12-19

    In addition to traditional uses as dyes and in photocopying devices, phthalocyanines (Pcs) are now rapidly growing in importance in many fields such as chemical sensors, electrochromism, batteries, photodynamic cancer therapy, molecular metals, photochemical hole burning, and liquid crystals. In this communication, the authors present a completely new method for the preparation of monosubstituted type unsymmetrical Pcs and Pc analogues, which utilizes the so-called subphthalocyanines (SubPcs).

  5. Structure-activity relationship studies on cholecystokinin: Analogues with partial agonist activity

    SciTech Connect

    Galas, M.C.; Lignon, M.F.; Rodriguez, M.; Mendre, C.; Fulcrand, P.; Laur, J.; Martinez, J. )

    1988-02-01

    In the present study, hepta- and octapeptide analogues of the C-terminal part of cholecystokinin, modified on the C-terminal phenylalanine residue, were synthesized. CCK analogues were prepared in which the peptide bond between aspartic acid and phenylalanine had or had not been modified and were lacking the C-terminal primary amide function. These CCK derivatives were able to cause full stimulation of amylase release from rat pancreatic acini but without a decrease in amylase release at supramaximal concentrations. There was a close relationship between the abilities of these derivatives to stimulate amylase release and their abilities to inhibit binding of {sup 125}I-BH-CCK-9 to CCK receptors on rat and guinea pig pancreatic acini. These CCK analogues were also able to recognize the guinea pig brain CCK receptors, some of them being particularly potent. The findings indicate that the aromatic ring of phenylalanine is important for the binding to brain and pancreatic CCK receptors, whereas the C-terminal primary amide function is not essential for the binding to pancreatic CCK receptors but is crucial for biological activity of rat pancreatic acini.

  6. Constrained nucleoside analogues - Crystal and molecular structure of 6,5?-O-anhydrouridines fixed in the anti conformation

    NASA Astrophysics Data System (ADS)

    Gajda, Roman; Bagi?ski, Maciej; Tomczyk, Ewelina; Mieczkowski, Adam; Wo?niak, Krzysztof

    2015-10-01

    A series of analogues of anhydrouridine have been synthesized and their crystal structures established using X-ray diffraction. For all cases, the ribose ring has O(4?)-exo, C(4?)-endo pucker and the pyrimidine base is in the anti conformation. Investigated compounds crystallize in different crystal systems (monoclinic, orthorhombic), have different space group symmetry (P21, P212121) and exhibit different intermolecular interactions (halogen and hydrogen bonds) among molecules in their crystal lattices. Moreover, in the case of the 5-benzyl-6,5?-O-anhydrouridine a significant positional disorder is present with the phenyl rings existing in two orientations.

  7. Structural differences in diarylheptanoids analogues from Alnus viridis and Alnus glutinosa influence their activity and selectivity towards cancer cells.

    PubMed

    Dinić, Jelena; Novaković, Miroslav; Podolski-Renić, Ana; Vajs, Vlatka; Tešević, Vele; Isaković, Aleksandra; Pešić, Milica

    2016-04-01

    Diarylheptanoids represent a group of plant secondary metabolites that possess multiple biological properties and are increasingly recognized for their therapeutic potential. A comparative study was performed on structurally analogous diarylheptanoids isolated from the bark of green (Alnus viridis) and black alder (Alnus glutinosa) to address their biological effects and determine structure-activity relationship. The structures and configurations of all compounds were elucidated by NMR, HR-ESI-MS, UV and IR. Diarylheptanoids actions were studied in human non-small cell lung carcinoma cells (NCI-H460) and normal keratinocytes (HaCaT). A. viridis compounds 3v, 5v, 8v and 9v that possess a carbonyl group at C-3 were considerably more potent than compounds without this group. A. viridis/A. glutinosa analogue pairs, 5v/5g and 9v/9g, which differ in the presence of 3' and 3″-OH groups, were evaluated for anticancer activity and selectivity. 5v and 9v that do not possess 3' and 3″-OH groups showed significantly higher cytotoxicity compared to analogues 5g and 9g. In addition, these two A. viridis compounds induced a more prominent apoptosis in both cell lines and an increase in subG0 cell cycle phase, compared to their A. glutinosa analogues. 5v and 9v treatment triggered intracellular superoxide anion accumulation and notably decreased mitochondrial transmembrane potential. In HaCaT cells, 9v and 9g with a 4,5 double bond caused a more prominent loss of mitochondrial transmembrane potential compared to 5v and 5g which possess a 5-methoxy group instead. Although green alder diarylheptanoids 5v and 9v displayed higher cytotoxicity, their analogues from black alder 5g and 9g could be more favorable for therapeutic use since they were more active in cancer cells than in normal keratinocytes. These results indicate that minor differences in the chemical structure can greatly influence the effect of diarylheptanoids on apoptosis and redox status and determine their selectivity towards cancer cells. PMID:26944434

  8. Crystal Structure of Baeyer-Villiger Monooxygenase MtmOIV, the Key Enzyme of the Mithramycin Biosynthetic Pathway

    PubMed Central

    Beam, Miranda P.; Bosserman, Mary A.; Noinaj, Nicholas; Wehenkel, Marie; Rohr, Jrgen

    2009-01-01

    Baeyer-Villiger monooxygenases (BVMOs), mostly flavoproteins, were shown to be powerful biocatalysts for synthetic organic chemistry applications and were also suggested to play key roles for the biosyntheses of various natural products. Here we present the three-dimensional structure of MtmOIV, a 56 kD homo-dimeric FAD- and NADPH-dependent monooxygenase, which catalyzes the key frame-modifying step of the mithramycin biosynthetic pathway and currently the only BVMO proven to react with its natural substrate via a Baeyer-Villiger reaction. MtmOIVs structure was determined by X-ray crystallography using molecular replacement to a resolution of 2.9. MtmOIV cleaves a C-C bond, essential for the conversion of the biologically inactive precursor, premithramycin B, into the active drug mithramycin. The MtmOIV structure combined with substrate docking calculations and site-directed mutagenesis experiments implicate several residues to participate in co-factor and substrate binding. Future experimentation aimed at broadening the substrate specificity of the enzyme could facilitate the generation of chemically diverse mithramycin analogues through combinatorial biosynthesis. PMID:19364090

  9. Three-dimensional quantitative structure-activity relationship study on antioxidant capacity of curcumin analogues

    NASA Astrophysics Data System (ADS)

    Chen, Bohong; Zhu, Zhibo; Chen, Min; Dong, Wenqi; Li, Zhen

    2014-03-01

    A comparative molecular similarity indices analysis (CoMSIA) was performed on a set of 27 curcumin-like diarylpentanoid analogues with the radical scavenging activities. A significant cross-validated correlation coefficient Q2 (0.784), SEP (0.042) for CoMSIA were obtained, indicating the statistical significance of the correlation. Further we adopt a rational approach toward the selection of substituents at various positions in our scaffold,and finally find the favored and disfavoured regions for the enhanced antioxidative activity. The results have been used as a guide to design compounds that, potentially, have better activity against oxidative damage.

  10. Two Active Site Divalent Ions in the Crystal Structure of the Hammerhead Ribozyme Bound to a Transition State Analogue.

    PubMed

    Mir, Aamir; Golden, Barbara L

    2016-02-01

    The crystal structure of the hammerhead ribozyme bound to the pentavalent transition state analogue vanadate reveals significant rearrangements relative to the previously determined structures. The active site contracts, bringing G10.1 closer to the cleavage site and repositioning a divalent metal ion such that it could, ultimately, interact directly with the scissile phosphate. This ion could also position a water molecule to serve as a general acid in the cleavage reaction. A second divalent ion is observed coordinated to O6 of G12. This metal ion is well-placed to help tune the pKA of G12. On the basis of this crystal structure as well as a wealth of biochemical studies, we propose a mechanism in which G12 serves as the general base and a magnesium-bound water serves as a general acid. PMID:26551631

  11. Evidence for Phenylalanine Zipper-Mediated Dimerization in the X-Ray Crystal Structure of a Magainin 2 Analogue

    PubMed Central

    Kreitler, Dale F.; Weisblum, Bernard; Forest, Katrina T.; Gellman, Samuel H.

    2014-01-01

    High-resolution structure elucidation has been challenging for the large group of host-defense peptides that form helices on or within membranes but do not manifest a strong folding propensity in aqueous solution. Here we report the crystal structure of an analogue of the widely-studied host-defense peptide magainin 2. Ala8,13,18-magainin 2 is a designed variant that displays enhanced antibacterial activity relative to the natural peptide. The crystal structure of Ala8,13,18-magainin 2, obtained for the racemic form, features a dimerization mode that has previously been proposed to play a role in the antibacterial activity of magainin 2 and related peptides. PMID:24102563

  12. Similarity in drugs: reflections on analogue design.

    PubMed

    Wermuth, Camille G

    2006-04-01

    A survey of novel small-molecule therapeutics reveals that the majority of them result from analogue design and that their market value represents two-thirds of all small-molecule sales. In natural science, the term analogue, derived from the Latin and Greek analogia, has always been used to describe structural and functional similarity. Extended to drugs, this definition implies that the analogue of an existing drug molecule shares structural and pharmacological similarities with the original compound. Formally, this definition allows the establishment of three categories of drug analogues: analogues possessing chemical and pharmacological similarities (direct analogues); analogues possessing structural similarities only (structural analogues); and chemically different compounds displaying similar pharmacological properties (functional analogues). PMID:16580977

  13. 3CAPS – a structural AP–site analogue as a tool to investigate DNA base excision repair

    PubMed Central

    Schuermann, David; Scheidegger, Simon P.; Weber, Alain R.; Bjørås, Magnar; Leumann, Christian J.; Schär, Primo

    2016-01-01

    Abasic sites (AP-sites) are frequent DNA lesions, arising by spontaneous base hydrolysis or as intermediates of base excision repair (BER). The hemiacetal at the anomeric centre renders them chemically reactive, which presents a challenge to biochemical and structural investigation. Chemically more stable AP-site analogues have been used to avoid spontaneous decay, but these do not fully recapitulate the features of natural AP–sites. With its 3′–phosphate replaced by methylene, the abasic site analogue 3CAPS was suggested to circumvent some of these limitations. Here, we evaluated the properties of 3CAPS in biochemical BER assays with mammalian proteins. 3CAPS-containing DNA substrates were processed by APE1, albeit with comparably poor efficiency. APE1-cleaved 3CAPS can be extended by DNA polymerase β but repaired only by strand displacement as the 5′–deoxyribophosphate (dRP) cannot be removed. DNA glycosylases physically and functionally interact with 3CAPS substrates, underlining its structural integrity and biochemical reactivity. The AP lyase activity of bifunctional DNA glycosylases (NTH1, NEIL1, FPG), however, was fully inhibited. Notably, 3CAPS-containing DNA also effectively inhibited the activity of bifunctional glycosylases on authentic substrates. Hence, the chemically stable 3CAPS with its preserved hemiacetal functionality is a potent tool for BER research and a potential inhibitor of bifunctional DNA glycosylases. PMID:26733580

  14. 3CAPS - a structural AP-site analogue as a tool to investigate DNA base excision repair.

    PubMed

    Schuermann, David; Scheidegger, Simon P; Weber, Alain R; Bjørås, Magnar; Leumann, Christian J; Schär, Primo

    2016-03-18

    Abasic sites (AP-sites) are frequent DNA lesions, arising by spontaneous base hydrolysis or as intermediates of base excision repair (BER). The hemiacetal at the anomeric centre renders them chemically reactive, which presents a challenge to biochemical and structural investigation. Chemically more stable AP-site analogues have been used to avoid spontaneous decay, but these do not fully recapitulate the features of natural AP-sites. With its 3'-phosphate replaced by methylene, the abasic site analogue 3CAPS was suggested to circumvent some of these limitations. Here, we evaluated the properties of 3CAPS in biochemical BER assays with mammalian proteins. 3CAPS-containing DNA substrates were processed by APE1, albeit with comparably poor efficiency. APE1-cleaved 3CAPS can be extended by DNA polymerase β but repaired only by strand displacement as the 5'-deoxyribophosphate (dRP) cannot be removed. DNA glycosylases physically and functionally interact with 3CAPS substrates, underlining its structural integrity and biochemical reactivity. The AP lyase activity of bifunctional DNA glycosylases (NTH1, NEIL1, FPG), however, was fully inhibited. Notably, 3CAPS-containing DNA also effectively inhibited the activity of bifunctional glycosylases on authentic substrates. Hence, the chemically stable 3CAPS with its preserved hemiacetal functionality is a potent tool for BER research and a potential inhibitor of bifunctional DNA glycosylases. PMID:26733580

  15. Quantitative structure-activity analysis of acetylcholinesterase inhibition by oxono and thiono analogues of organophosphorus compounds. (Reannouncement with new availability information)

    SciTech Connect

    Maxwell, D.M.; Brecht, K.M.

    1992-02-01

    A comparison of the bimolecular rate constants (ki) for inhibition of electric eel acetylcholinesterase (AChE) by the oxono (i.e., P=O) and thiono (i.e., P=S) analogues of parathion, methylparathion, leptophos, fonofos, sarin, and soman revealed that the oxono/thiono ratios of ki values varied from 14 for soman to 1240 for parathion. Analysis of the relative importance of the dissociation equilibrium constant and the phosphorylation rate constant in producing this variation in ki values indicated that the oxono analogues had phosphorylation rate constant values that varied in a narrow range from 8- to 14-fold greater than their thiono counterparts, while the oxono/thiono ratios for dissociation constants varied widely from 1 for soman to 82 for fonofos. The lower affinities of thiono analogues for AChE probably resulted from differences in the hydrophobic binding of oxono and thiono analogues to the active site of AChE, inasmuch as the hydrophobicities (i.e., octanol/water partition coefficients) of thiono organophosphorus compounds were much greater than the hydrophobicities of their oxono analogues. Quantitative structure-activity analysis indicated that the hydrophobic effects of oxono and thiono moieties correlated with log ki for AChE inhibition to a greater extent (r2 = 0.79) than their electronic effects (r2 equal to or less than 0.48). These observations suggest that the differences in hydrophobicity of oxono and thiono analogues of organophosphorus compounds may be as important as their electronic differences in determining their effectiveness as AChE inhibitors. Acetylcholinesterase, soman (GD), structure-activity analysis inhibition, oxono analogues, thiono analogues.

  16. StructureActivity Relationships of Cyclic Lactam Analogues of ?-Melanocyte-Stimulating Hormone (?-MSH) Targeting the Human Melanocortin-3 Receptor

    PubMed Central

    Mayorov, Alexander V.; Cai, Minying; Palmer, Erin S.; Dedek, Matthew M.; Cain, James P.; Van Scoy, April R.; Tan, Bahar; Vagner, Josef; Trivedi, Dev; Hruby, Victor J.

    2008-01-01

    A variety of dicarboxylic acid linkers introduced between the ?-amino group of Pro6 and the ?-amino group of Lys10 of the cyclic lactam ?-melanocyte-stimulating hormone (?-MSH)-derived Pro6-D-Phe7/D-Nal(2?)7-Arg8-Trp9-Lys10-NH2 pentapeptide template lead to nanomolar range and selective hMC3R agonists and antagonists. Replacement of the Pro6 residue and the dicarboxylic acid linker with 2,3-pyrazine-dicarboxylic acid furnished a highly selective nanomolar range hMC3R partial agonist (analogue 12, c[CO-2,3-pyrazine-CO-D-Phe-Arg-Trp-Lys]-NH2, EC50 = 27 nM, 70% max cAMP) and an hMC3R antagonist (analogue 13, c[CO-2,3-pyrazine-CO-D-Nal(2?)-Arg-Trp-Lys]-NH2, IC50 = 23 nM). Modeling experiments suggest that 2,3-pyrazinedicarboxylic acid stabilizes a ?-turn-like structure with the D-Phe/D-Nal(2?) residues, which explains the high potency of the corresponding peptides. Placement of a Nle residue in position 6 produced a hMC3R/hMC5R antagonist (analogue 15, c[CO-(CH2)2-CO-Nle-D-Nal(2?)-Arg-Trp-Lys]-NH2, IC50 = 12 and 17 nM, respectively), similarly to the previously described cyclic ?-melanocyte-stimulating hormone (?-MSH)-derived hMC3R/hMC5R antagonists. These newly developed melanotropins will serve as critical biochemical tools for elucidating the full spectrum of functions performed by the physiologically important melanocortin-3 receptor. PMID:18088090

  17. Thyroxine analogues. 23. Quantitative structure-activity correlation studies of in vivo and in vitro thyromimetic activities.

    PubMed

    Dietrich, S W; Bolger, M B; Kollman, P A; Jorgensen, E C

    1977-07-01

    Quantitative structure-activity correlation studies of thyroid hormone analogues have been utilized to examine (1) in vivo rat antigoiter activities; (2) in vitro binding affinities to intact rat hepatic nuclei, solubilized rat hepatic nuclear protein receptors, and the plasma protein thyroxine binding globulin; and (3) correlations between in vivo antigoiter activities and in vitro binding to nuclear receptors. These studies provide a more precise elucidation of the relative importance of the physiochemical factors which influence thyromimetic activities. In particular, they (1) provide the first systematic QSAR examination of drug-receptor interactions and of the dependence of in vivo activity on such interactions; (2) demonstrate the importance of the interactive effects of the 3' and 5' substituents and of the 4'-OH with each other as well as with nuclear receptors in influencing binding affinity; (3) support the hypothesis that binding to nuclear receptors is the first step in initiating the events which lead to subsequent hormonal expression; (4) show that the free energy of binding to nuclear receptors can be factored into the contributing physicochemical properties of the substituents; and (5) suggest factors that need to be considered in designing new analogues. PMID:195056

  18. Spatial Configuration and Three-Dimensional Conformation Directed Design, Synthesis, Antiviral Activity, and Structure-Activity Relationships of Phenanthroindolizidine Analogues.

    PubMed

    Su, Bo; Cai, Chunlong; Deng, Meng; Wang, Qingmin

    2016-03-16

    Our recent investigation on the antiviral activities against tobacco mosaic virus (TMV) of phenanthroindolizidine alkaloid analogues preliminarily revealed that the basic skeleton and substitution pattern at the C13a position of the molecule, which are closely related to the spatial arrangement of the molecule, have great effects on the biological activity. To further study the in-depth influence of spatial configuration and three-dimensional (3D) conformation of the molecules on their anti-TMV activities and related structure-activity relationship (SAR), a series of D-ring opened derivatives 3, 4, 5a-5j, 6, and 7, chiral 13a- and/or 14-substituted phenanthroindolizidine analogues 10-12 and 18-20, and their enantiomers ent-10-ent-12 and ent-18-ent-20 were synthesized and evaluated for their anti-TMV activities. Bioassay results showed that most of the chiral phenanthroindolizidines displayed good to excellent in vivo anti-TMV activity. Among these compounds, ent-11 showed more potent activity than Ningnanmycin (one of the most successful commercial antiviral agents), thus emerging as a potential inhibitor of the plant virus. Further SARs were also discussed for the first time under the chiral scenario, demonstrating that both spatial configuration and 3D conformation of the molecules are crucial for keeping high anti-TMV activity. PMID:26923726

  19. Social Structure: The Key to an Intelligent Lineage

    NASA Astrophysics Data System (ADS)

    Antonio, M. R. S.; Schulze-Makuch, D.

    2010-04-01

    Social structure is likely to be the most important factor in the development of complex behavior. Social stability needs to be achieved in order for the investment in acquisition and transmissibility of knowledge becomes favorable.

  20. Valles Marineris as a Cryokarstic Structure Formed by a Giant Dyke System: Support From New Analogue Experiments

    NASA Astrophysics Data System (ADS)

    Ozeren, M. S.; Sengor, A. M. C.; Acar, D.; Ülgen, S. C.; Onsel, I. E.

    2014-12-01

    Valles Marineris is the most significant near-linear depression on Mars. It is some 4000 km long, up to about 200 km wide and some 7 km deep. Although its margins look parallel at first sight, the entire structure has a long spindle shape with significant enlargement in its middle (Melas Chasma) caused by cuspate slope retreat mechanisms. Farther to its north is Hebes Chasma which is an entirely closed depression with a more pronounced spindle shape. Tithonium Chasma is a parallel, but much narrower depression to its northeast. All these chasmae have axes parallel with one another and such structures occur nowhere else on Mars. A scabland surface exists to the east of the Valles Marineris and the causative water mass seems to have issued from it. The great resemblance of these chasmae on mars to poljes in the karstic regions on earth have led us to assume that they owed their existence to dissolution of rock layers underlying them. We assumed that the dissolving layer consisted of water ice forming substantial layers, in fact entirely frozen seas of several km depth. We have simulated this geometry by using bentonite and flour layers (in different experiments) overlying layers of ice in which a resistant coil was used to simulate a dyke. We used different thicknesses of bentonite and flour overlying ice layers again of various thicknesses. The flour seems to simulate the Martian crust better because on Mars, g is only about 3/8ths of its value on Earth, so (for equal crustal density) the depth to which the cohesion term C remains important in the Mohr-Coulomb shear failure criterion is about 8/3 times greater. As examples we show two of those experiments in which both the rock analogue and ice layers were of 1.5 cm. thick. Perfect analogues of the Valles Marineris formed above the dyke analogue thermal source complete with the near-linear structure, overall flat spindle shape, cuspate margins, a central ridge, parallel side faults, parallel depressions resembling the Tithonium Chasma. When water was allowed to drain from the beginning, closed depressions formed that have an amazing resemblance to Hebes chasma. We postulate that the entire system of chasmae here discussed formed atop a major dyke swarm some 4000 km length, not dissimilar to the 3500 km long Mesoproterozoic (Ectasian) dyke swarm disrupting the Canadian Shield.

  1. Nuclear lamins: key regulators of nuclear structure and activities

    PubMed Central

    Prokocimer, Miron; Davidovich, Maya; Nissim-Rafinia, Malka; Wiesel-Motiuk, Naama; Bar, Daniel Z; Barkan, Rachel; Meshorer, Eran; Gruenbaum, Yosef

    2009-01-01

    The nuclear lamina is a proteinaceous structure located underneath the inner nuclear membrane (INM), where it associates with the peripheral chromatin. It contains lamins and lamin-associated proteins, including many integral proteins of the INM, chromatin modifying proteins, transcriptional repressors and structural proteins. A fraction of lamins is also present in the nucleoplasm, where it forms stable complexes and is associated with specific nucleoplasmic proteins. The lamins and their associated proteins are required for most nuclear activities, mitosis and for linking the nucleoplasm to all major cytoskeletal networks in the cytoplasm. Mutations in nuclear lamins and their associated proteins cause about 20 different diseases that are collectively called laminopathies’. This review concentrates mainly on lamins, their structure and their roles in DNA replication, chromatin organization, adult stem cell differentiation, aging, tumorogenesis and the lamin mutations leading to laminopathic diseases. PMID:19210577

  2. Characterizing, identifying and mapping structural domains at rifted continental margins: insights from the Bay of Biscay margins and its Pyrenean fossil analogue

    NASA Astrophysics Data System (ADS)

    Tugend, Julie; Manatschal, Gianreto; Kusznir, Nick J.

    2014-05-01

    The occurrence of hyperextended domains at rifted continental margins consisting of extremely thinned crust and/or exhumed mantle has been increasingly recognized over the past decades, both at present-day rifted margins and in deformed remnants preserved in collisional orogens. At present, most studies aiming to characterize rifted continental margin structure and the extreme thinning of the continental crust and lithosphere are either focused offshore using geophysical methods, or onshore on fossil analogues relying on geological field observations. Marine and onland examples provide complementary datasets, but their different scale and resolution of observations prevent straightforward correlations to be done. In this contribution, we use the Bay of Biscay and Western Pyrenees to develop and apply a geological/geophysical approach to characterize and identify distinctive rifted margin domains both in offshore and onshore settings. The Bay of Biscay and Western Pyrenees represent a unique natural laboratory that offer the possibility to have access to seismically imaged, drilled and exposed parts of one and the same hyperextended rift system. Quantitative techniques (gravity inversion and flexural backstripping) are used on offshore examples (Western Approach margin and Parentis basin) to estimate accommodation space, crustal thickness and lithosphere thinning while seismic interpretations enable the recognition of extensional settings (low- and high-? settings). Field observations (Maulon basin) and drill-hole data (Parentis basin) focused on key outcrops enables the description of the nature of sediment and basement rocks and of the structures forming fossil remnants of rifted margins. This qualitative and quantitative characterisation provides diagnostic elements to identify and map structural domains at magma-poor rifted margins and their fossil analogues. We name these 5 domains proximal, necking, hyperthinned, exhumed mantle and oceanic. This new geological/geophysical approach can be further used as an interface between onshore and offshore observations. Offshore seismic interpretations can take advantage of onshore observations on the nature of sediment, basement and of their interface. The large scale geometry and stratigraphic architecture imaged offshore can be used to restore onshore fossil remnants back into a rifted margin context. The application of this multidisciplinary approach to the Bay of Biscay margins and their onshore Pyrenean fossils remnants enables us to propose a new map of the different rift systems preserved at the transition between the European and Iberian plates. The approach underlying this mapping has general global application to unravelling the spatial and temporal complexity of rifted margin structural domains.

  3. Structural and thermodynamic aspects of the interaction between heparan sulfate and analogues of melittin.

    PubMed

    Gonçalves, Elisabete; Kitas, Eric; Seelig, Joachim

    2006-03-01

    Melittin is an amphipathic cationic peptide derived from honeybee venom with well-known cytolytic and antimicrobial properties. When coupled to cationic polymers or lipid molecules, it forms conjugates with high transfection efficiency and low toxicity with promising applications in gene therapy. A first step in the internalization of melittin and its conjugates is their binding to the cell surface, a reaction likely to involve heparan sulfate proteoglycans (HSPG). In the present work, we characterize the binding equilibrium of heparan sulfate (HS) with two melittin analogues, [Cys(1)]melittin (mel-SH) and retro-inverso [Cys(1)]melittin (ri-mel-SH). The terminal cysteine found in these peptides replaces the N-terminal glycine present in native melittin and allows covalent binding to other molecules. Isothermal titration calorimetry (ITC) reveals a high affinity of each melittin analogue to HS. Association constants of 4.7 x 10(4) and 3.5 x 10(5) M(-)(1) are found at physiological ionic strength and 15 degrees C for ri-mel-SH and mel-SH, respectively. The reaction enthalpy measured under these conditions is DeltaH(degrees)pep= 4.2 kcal/mol for ri-mel-SH and DeltaH(degrees)pep= 1.1 kcal/mol for mel-SH. The peptide-to-HS stoichiometry is approximately 20 for ri-mel-SH and approximately 14 for mel-SH under the same conditions. Temperature dependence studies using ri-mel-SH (mel-SH) show that DeltaH(degrees)pep decreases in magnitude upon increase in temperature, which results in a molar heat capacity of DeltaH(degrees)pep= -322 cal mol(-)(1) K(-)(1) (-45 cal mol(-)(1) K(-)(1)). Such a negative heat capacity change is not expected for a purely electrostatic interaction and indicates that hydrophobic and other interactions are also involved in the binding equilibrium. Salt dependence studies of the binding constants confirm that nonelectrostatic forces are an important component of the HS-melittin interaction. Binding to HS induces conformational changes in both peptides, with ri-mel-SH showing a 6-fold increase of the alpha-helix content when incubated with HS under saturation conditions. PMID:16503664

  4. Toward a biorelevant structure of protein kinase C bound modulators: design, synthesis, and evaluation of labeled bryostatin analogues for analysis with rotational echo double resonance NMR spectroscopy.

    PubMed

    Loy, Brian A; Lesser, Adam B; Staveness, Daryl; Billingsley, Kelvin L; Cegelski, Lynette; Wender, Paul A

    2015-03-18

    Protein kinase C (PKC) modulators are currently of great importance in preclinical and clinical studies directed at cancer, immunotherapy, HIV eradication, and Alzheimer's disease. However, the bound conformation of PKC modulators in a membrane environment is not known. Rotational echo double resonance (REDOR) NMR spectroscopy could uniquely address this challenge. However, REDOR NMR requires strategically labeled, high affinity ligands to determine interlabel distances from which the conformation of the bound ligand in the PKC-ligand complex could be identified. Here we report the first computer-guided design and syntheses of three bryostatin analogues strategically labeled for REDOR NMR analysis. Extensive computer analyses of energetically accessible analogue conformations suggested preferred labeling sites for the identification of the PKC-bound conformers. Significantly, three labeled analogues were synthesized, and, as required for REDOR analysis, all proved highly potent with PKC affinities (?1 nM) on par with bryostatin. These potent and strategically labeled bryostatin analogues are new structural leads and provide the necessary starting point for projected efforts to determine the PKC-bound conformation of such analogues in a membrane environment, as needed to design new PKC modulators and understand PKC-ligand-membrane structure and dynamics. PMID:25710634

  5. Structural changes at microtubule ends accompanying GTP hydrolysis: Information from a slowly hydrolyzable analogue of GTP, guanylyl (?,?)methylenediphosphonate

    PubMed Central

    Mller-Reichert, Thomas; Chrtien, Denis; Severin, Fedor; Hyman, Anthony A.

    1998-01-01

    Microtubules are dynamic polymers that interconvert between periods of slow growth and fast shrinkage. The energy driving this nonequilibrium behavior comes from the hydrolysis of GTP, which is required to destabilize the microtubule lattice. To understand the mechanism of this destabilization, cryo-electron microscopy was used to compare the structure of the ends of shrinking microtubules assembled in the presence of either GTP or the slowly hydrolyzable analogue guanylyl (?,?)methylenediphosphonate (GMPCPP). Depolymerization was induced by cold or addition of calcium. With either nucleotide, we have observed curled oligomers at the ends of shrinking microtubules. However, GDP oligomers were consistently more curved than GMPCPP oligomers. This difference in curvature between depolymerizing GDP and GMPCPP protofilaments suggests that GTP hydrolysis is accompanied by an increase in curvature of the protofilaments, thereby destabilizing the lateral interactions between tubulin subunits in the microtubule lattice. PMID:9520422

  6. Synthesis, structure, and properties of SrC(NH)3 , a nitrogen-based carbonate analogue with the trinacria motif.

    PubMed

    Missong, Ronja; George, Janine; Houben, Andreas; Hoelzel, Markus; Dronskowski, Richard

    2015-10-01

    Strontium guanidinate, SrC(NH)3 , the first compound with a doubly deprotonated guanidine unit, was synthesized from strontium and guanidine in liquid ammonia and characterized by X-ray and neutron diffraction, IR spectroscopy, and density-functional theory including harmonic phonon calculations. The compound crystallizes in the hexagonal space group P63 /m, constitutes the nitrogen analogue of strontium carbonate, SrCO3 , and its structure follows a layered motif between Sr(2+) ions and complex anions of the type C(NH)3 (2-) ; the anions adopt the peculiar trinacria shape. A comparison of theoretical phonons with experimental IR bands as well as quantum-chemical bonding analyses yield a first insight into bonding and packing of the formerly unknown anion in the crystal. PMID:26308739

  7. Kinetic, thermodynamic and X-ray structural insights into the interaction of melatonin and analogues with quinone reductase 2

    SciTech Connect

    Calamini, Barbara; Santarsiero, Bernard D.; Boutin, Jean A.; Mesecar, Andrew D.

    2008-09-12

    Melatonin exerts its biological effects through at least two transmembrane G-protein-coupled receptors, MT1 and MT2, and a lower-affinity cytosolic binding site, designated MT3. MT3 has recently been identified as QR2 (quinone reductase 2) (EC 1.10.99.2) which is of significance since it links the antioxidant effects of melatonin to a mechanism of action. Initially, QR2 was believed to function analogously to QR1 in protecting cells from highly reactive quinones. However, recent studies indicate that QR2 may actually transform certain quinone substrates into more highly reactive compounds capable of causing cellular damage. Therefore it is hypothesized that inhibition of QR2 in certain cases may lead to protection of cells against these highly reactive species. Since melatonin is known to inhibit QR2 activity, but its binding site and mode of inhibition are not known, we determined the mechanism of inhibition of QR2 by melatonin and a series of melatonin and 5-hydroxytryptamine (serotonin) analogues, and we determined the X-ray structures of melatonin and 2-iodomelatonin in complex with QR2 to between 1.5 and 1.8 {angstrom} (1 {angstrom} = 0.1 nm) resolution. Finally, the thermodynamic binding constants for melatonin and 2-iodomelatonin were determined by ITC (isothermal titration calorimetry). The kinetic results indicate that melatonin is a competitive inhibitor against N-methyldihydronicotinamide (K{sub i} = 7.2 {mu}M) and uncompetitive against menadione (K{sub i} = 92 {mu}M), and the X-ray structures shows that melatonin binds in multiple orientations within the active sites of the QR2 dimer as opposed to an allosteric site. These results provide new insights into the binding mechanisms of melatonin and analogues to QR2.

  8. Kinetic, thermodynamic and X-ray structural insights into the interaction of melatonin and analogues with quinone reductase 2

    PubMed Central

    CALAMINI, Barbara; SANTARSIERO, Bernard D.; BOUTIN, Jean A.; MESECAR, Andrew D.

    2011-01-01

    Melatonin exerts its biological effects through at least two transmembrane G-protein-coupled receptors, MT1 and MT2, and a lower-affinity cytosolic binding site, designated MT3. MT3 has recently been identified as QR2 (quinone reductase 2) (EC 1.10.99.2) which is of significance since it links the antioxidant effects of melatonin to a mechanism of action. Initially, QR2 was believed to function analogously to QR1 in protecting cells from highly reactive quinones. However, recent studies indicate that QR2 may actually transform certain quinone substrates into more highly reactive compounds capable of causing cellular damage. Therefore it is hypothesized that inhibition of QR2 in certain cases may lead to protection of cells against these highly reactive species. Since melatonin is known to inhibit QR2 activity, but its binding site and mode of inhibition are not known, we determined the mechanism of inhibition of QR2 by melatonin and a series of melatonin and 5-hydroxytryptamine (serotonin) analogues, and we determined the X-ray structures of melatonin and 2-iodomelatonin in complex with QR2 to between 1.5 and 1.8 (1 =0.1 nm) resolution. Finally, the thermodynamic binding constants for melatonin and 2-iodomelatonin were determined by ITC (isothermal titration calorimetry). The kinetic results indicate that melatonin is a competitive inhibitor against N-methyldihydronicotinamide (Ki = 7.2 ?M) and uncompetitive against menadione (Ki = 92 ?M), and the X-ray structures shows that melatonin binds in multiple orientations within the active sites of the QR2 dimer as opposed to an allosteric site. These results provide new insights into the binding mechanisms of melatonin and analogues to QR2. PMID:18254726

  9. Structure-based design of a streptavidin mutant specific for an artificial biotin analogue.

    PubMed

    Kawato, Tatsuya; Mizohata, Eiichi; Shimizu, Yohei; Meshizuka, Tomohiro; Yamamoto, Tomohiro; Takasu, Noriaki; Matsuoka, Masahiro; Matsumura, Hiroyoshi; Kodama, Tatsuhiko; Kanai, Motomu; Doi, Hirofumi; Inoue, Tsuyoshi; Sugiyama, Akira

    2015-06-01

    For a multistep pre-targeting method using antibodies, a streptavidin mutant with low immunogenicity, termed low immunogenic streptavidin mutant No. 314 (LISA-314), was produced previously as a drug delivery tool. However, endogenous biotins (BTNs) with high affinity (Kd < 10(-10) M) for the binding pocket of LISA-314 prevents access of exogenous BTN-labelled anticancer drugs. In this study, we improve the binding pocket of LISA-314 to abolish its affinity for endogenous BTN species, therefore ensuring that the newly designed LISA-314 binds only artificial BTN analogue. The replacement of three amino acid residues was performed in two steps to develop a mutant termed V212, which selectively binds to 6-(5-((3aS,4S,6aR)-2-iminohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)hexanoic acid (iminobiotin long tail, IMNtail). Surface plasmon resonance results showed that V212 has a Kd value of 5.9 10(-7) M towards IMNtail, but no binding affinity for endogenous BTN species. This V212/IMNtail system will be useful as a novel delivery tool for anticancer therapy. PMID:25645976

  10. Multilevel polarization shift keying: Optimum receiver structure and performance evaluation

    SciTech Connect

    Benedetto, S.; Poggiolini, P.T.

    1994-02-01

    Multilevel digital coherent optical modulation schemes based on the state of polarization of a fully polarized lightwave are proposed and analyzed. Based on the complete statistical characterization of the Stokes parameters, extracted though appropriate signal processing in the presence of shot and additive gaussian noise, the optimum maximum likelihood receiver operating symbol by symbol is derived. The exact performance in terms of the average symbol error probability is found. Optimum constellations for the case of equipower 4, 8, 16 and 32 signals are found on the basis of the minimization of the error probability for a given average power. Their performance turns out to be promising as compared to other standard modulation techniques. The spectral analysis of polarization modulated signals is presented. A new receiver structure, which solves the problem of the excess penalties incurred in the presence of channel dichroism, is proposed and analyzed. 22 refs.

  11. The crystal and electronic structures of Cd(3)As(2), the three-dimensional electronic analogue of graphene.

    PubMed

    Ali, Mazhar N; Gibson, Quinn; Jeon, Sangjun; Zhou, Brian B; Yazdani, Ali; Cava, R J

    2014-04-21

    The structure of Cd3As2, a high-mobility semimetal reported to host electrons that act as Dirac particles, is reinvestigated by single-crystal X-ray diffraction. It is found to be centrosymmetric rather than noncentrosymmetric as previously reported. It has a distorted superstructure of the antifluorite (M2X) structure type with a tetragonal unit cell of a = 12.633(3) and c = 25.427(7) in the centrosymmetric I41/acd space group. The antifluorite superstructure can be envisioned as consisting of distorted Cd6?2 cubes (where ? = an empty cube vertex) in parallel columns, stacked with opposing chirality. Electronic structure calculations performed using the experimentally determined centrosymmetric structure are similar to those performed with the inversion symmetry absent but with the important implication that Cd3As2 is a three-dimensional (3D)-Dirac semimetal with no spin splitting; all bands are spin degenerate and there is a 4-fold degenerate bulk Dirac point at the Fermi energy along ?-Z in the Brillouin zone. This makes Cd3As2 a 3D electronic analogue of graphene. Scanning tunneling microscopy experiments identify a 2 2 surface reconstruction in the (112) cleavage plane of single crystals; needle crystals grow with a [110] long axis direction. PMID:24679042

  12. Functional and Structural Analysis of a Key Region of the Cell Wall Inhibitor Moenomycin

    SciTech Connect

    Fuse, Shinichiro; Tsukamoto, Hirokazu; Yuan, Yanqiu; Wang, Tsung-Shing Andrew; Zhang, Yi; Bolla, Megan; Walker, Suzanne; Sliz, Piotr; Kahne, Daniel

    2010-09-03

    Moenomycin A (MmA) belongs to a family of natural products that inhibit peptidoglycan biosynthesis by binding to the peptidoglycan glycosyltransferases, the enzymes that make the glycan chains of peptidoglycan. MmA is remarkably potent, but its clinical utility has been hampered by poor physicochemical properties. Moenomycin contains three structurally distinct regions: a pentasaccharide, a phosphoglycerate, and a C25 isoprenyl (moenocinyl) lipid tail that gives the molecule its name. The phosphoglycerate moiety links the pentasaccharide to the moenocinyl chain. This moiety contains two negatively charged groups, a phosphoryl group and a carboxylate. Both the phosphoryl group and the carboxylate have previously been implicated in target binding but the role of the carboxylate has not been explored in detail. Here we report the synthesis of six MmA analogues designed to probe the importance of the phosphoglycerate. These analogues were evaluated for antibacterial and enzyme inhibitory activity; the specific contacts between the phosphoglycerate and the protein target were assessed by X-ray crystallography in conjunction with molecular modeling. Both the phosphoryl group and the carboxylate of the phosphoglycerate chain play roles in target binding. The negative charge of the carboxylate, and not its specific structure, appears to be the critical feature in binding since replacing it with a negatively charged acylsulfonamide group produces a more active compound than replacing it with the isosteric amide. Analysis of the ligand-protein contacts suggests that the carboxylate makes a critical contact with an invariant lysine in the active site. The reported work provides information and validated computational methods critical for the design of analogues based on moenomycin scaffolds.

  13. COMPARATIVE ANALYSIS OF THE ELECTROSTATIC POTENTIALS OF SOME STRUCTURAL ANALOGUES OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN AND OF RELATED AROMATIC SYSTEMS

    EPA Science Inventory

    We have carried out an ab initio STO-5G computational analysis of the electrostatic potential of four structural analogues of the highly toxic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and four related aromatic systems: benzo[a]pyrene, benz[a]anthracene and two isomeric benzofla...

  14. Facilitation of the cellular uptake of a triplex-forming oligonucleotide by novel polyamine analogues: structure-activity relationships.

    PubMed

    Thomas, R M; Thomas, T; Wada, M; Sigal, L H; Shirahata, A; Thomas, T J

    1999-10-01

    The inefficient uptake of oligodeoxynucleotides, including that of TFO, through the cell membrane is a limiting factor in developing gene therapy approaches for cancer and other diseases. To develop a new strategy for oligonucleotide delivery into the nucleus, we synthesized a series of novel polyamine analogues and examined their effects on the uptake of a 37-mer [32P]-labeled TFO, targeted to the promoter region of c-myc oncogene. We used MCF-7 breast cancer cells to investigate the efficacy of polyamines on the internalization of the TFO. The uptake of TFO was enhanced by complexing it with several unsubstituted polyamine analogues at 0. 1-5 microM concentrations, with up to 6-fold increase in TFO uptake in the presence of a hexamine, 1,21-diamino-4,9,13, 18-tetraazahenicosane (H2N(CH2)(3)NH(CH2)(4)NH(CH2)(3)NH(CH2)(4)NH(CH2)(3)NH(2) or 3-4-3-4-3). TFO uptake increased with the cationicity of the polyamines; however, bis(ethyl) substitution and structural features of the methylene bridging region had significant effects on TFO uptake. The majority of labeled TFO was recovered from the nuclear fraction containing genomic DNA. Electrophoretic mobility shift assay revealed enhanced binding of TFO to a target duplex containing promoter region sequence of c-myc oncogene. Treatment of MCF-7 cells with the TFO complexed with 0.5 microM 3-4-3-4-3 suppressed c-myc mRNA level by 65%, as determined by Northern blot analysis. These data indicate a novel approach to deliver oligodeoxynucleotides to the cell nucleus, and suppress the expression of target genes, and provide new insights into the mechanism of oligonucleotide transport in living cells. PMID:10529208

  15. A dinaphtho[8,1,2-cde:2',1',8'-uva]pentacene derivative and analogues: synthesis, structures, photophysical and electrochemical properties.

    PubMed

    Li, Xiao-Jun; Li, Meng; Lu, Hai-Yan; Chen, Chuan-Feng

    2015-07-28

    Dinaphtho[8,1,2-cde:2',1',8'-uva]pentacene and analogues as a new type of acene derivatives with scorpion-shaped structures were conveniently synthesized. Their structures, photophysical and electrochemical properties were experimentally and theoretically investigated. It was found that the pentacene derivative has a twisted configuration, but shows marked intermolecular ?-? interactions, strong electronic delocalization, and a small HOMO-LUMO bandgap, which are different from those of pentacene and pentatwistacene derivatives with similar structures. PMID:26104736

  16. A review of the archaeological analogue approaches to predict the long-term corrosion behaviour of carbon steel overpack and reinforced concrete structures in the French disposal systems

    NASA Astrophysics Data System (ADS)

    Neff, Delphine; Saheb, Mandana; Monnier, Judith; Perrin, Stphane; Descostes, Michael; L'Hostis, Valrie; Crusset, Didier; Millard, Alain; Dillmann, Philippe

    2010-07-01

    This paper gives a review of several years of research on archaeological analogues in order to predict the long term behaviour of the steel canisters or the reinforced concrete structures involved in disposal or interim storage of nuclear wastes in France. This article aims at showing the specific methodology, the complementariness with different other approaches and the complete integration of the research on analogues in the frame of research programs on long term prediction. Archaeological sites on which field measurement can be performed were referenced and described. A significant number of artefacts collected from these sites was selected for study. Detailed chemical and microstructural characterisation of the artefacts were undertaken by a combination of microbeam analytical techniques (?Raman, ?XRD, ?Raman spectroscopy,). Hypotheses on the corrosion mechanisms were then tested using specific isotopic markers during re-corroding experiments on analogues. Specific parameters were measured, allowing crucial steps in modelling long-term corrosion of steel.

  17. Influence of the Convergence and Stepover Angles in the Structural Style of Strike-Slip Systems: Analogue Models

    NASA Astrophysics Data System (ADS)

    Gonzalez, D.; Pinto, L.

    2008-12-01

    The presented results of analogue models analyze the influence of the relation between the convergence angle and the stepover angle on strike-slip systems. The experiments include 2 stepovers arrays to generate both transpressional and transtensional zones. These experiments were prepared using 5 cm thick sandpack (sand diameter <500 ?m, internal friction angle 30, density 1,400 kg/m3) to simulate brittle deformation; the base of the model was formed by thin zinc base plates, one of them mobile, cut in such a way so as to produce restraining and releasing strike-slip stepovers; the rate convergence was constant. We carried out 3 series of experiments in which the convergence angles (0-60) and stepover angles (30-60) were varied systematically. Preliminary results indicate that by increasing the angle between the stepover and the convergence vector: a) the restraining area generated a positive flower structure that is progressively wider; b) progressively more reverse faults which absorb more shortening were generated. Locally, strike-slip faults in the positive flowers were accommodated by the geometry of the stepover base. Areas most complex involved the development of normal faults, which subsequently were inverted. In conclusion, the relation between the convergence and stepover angles is a main factor that determines the structural style of flowers structures on strike-slip systems. This work was done through the ACT-18 PBCT project.

  18. Synthesis, screening and quantitative structure-activity relationship (QSAR) studies of some glutamine analogues for possible anticancer activity.

    PubMed

    Srikanth, K; Kumar, Ch Anil; Ghosh, Balaram; Jha, Tarun

    2002-07-01

    We described the syntheses, biological activities and QSAR studies of 36 new 5-n-substituted-2-(substituted benzenesulphonyl) glutamines 6-41 with different substitutions. These compounds were designed as structural analogues of most reactive amino acid, 'glutamine' (GLN), especially in the tumor cells. They present the new basic lateral chains at R(5) position as well as different substitutions at 2', 3', 4', and 5' positions on the benzene ring. The synthesized compounds have been tested for antitumor activity against Ehrlich ascites carcinoma (EAC) in Swiss albino mice using percentage inhibition of tumor weight as inhibitory parameter. In order to elucidate the structural requirements for antitumor activity, quantitative structure-activity relationship (QSAR) studies have been performed using extra thermodynamic model of Hansch. QSAR equations showed that the electronic parameter (sigma) on the aromatic ring system, steric parameter (Es) and to some extent Sterimol length of the substituent (L) on the aliphatic side chain correlate significantly with the antitumor activity. Resonance factor occupies the major electronic contribution on the aromatic ring system to the activity. PMID:11983508

  19. Symmetric Key Structural Residues in Symmetric Proteins with Beta-Trefoil Fold

    PubMed Central

    Huang, Yanzhao; Xiao, Yi

    2010-01-01

    To understand how symmetric structures of many proteins are formed from asymmetric sequences, the proteins with two repeated beta-trefoil domains in Plant Cytotoxin B-chain family and all presently known beta-trefoil proteins are analyzed by structure-based multi-sequence alignments. The results show that all these proteins have similar key structural residues that are distributed symmetrically in their structures. These symmetric key structural residues are further analyzed in terms of inter-residues interaction numbers and B-factors. It is found that they can be distinguished from other residues and have significant propensities for structural framework. This indicates that these key structural residues may conduct the formation of symmetric structures although the sequences are asymmetric. PMID:21152439

  20. Natural Analogue Synthesis Report

    SciTech Connect

    A. M. Simmons

    2002-05-01

    The purpose of this report is to present analogue studies and literature reviews designed to provide qualitative and quantitative information to test and provide added confidence in process models abstracted for performance assessment (PA) and model predictions pertinent to PA. This report provides updates to studies presented in the ''Yucca Mountain Site Description'' (CRWMS M and O 2000 [151945], Section 13) and new examples gleaned from the literature, along with results of quantitative studies conducted specifically for the Yucca Mountain Site Characterization Project (YMP). The intent of the natural analogue studies was to collect corroborative evidence from analogues to demonstrate additional understanding of processes expected to occur during postclosure at a potential Yucca Mountain repository. The report focuses on key processes by providing observations and analyses of natural and anthropogenic (human-induced) systems to improve understanding and confidence in the operation of these processes under conditions similar to those that could occur in a nuclear waste repository. The process models include those that represent both engineered and natural barrier processes. A second purpose of this report is to document the various applications of natural analogues to geologic repository programs, focusing primarily on the way analogues have been used by the YMP. This report is limited to providing support for PA in a confirmatory manner and to providing corroborative inputs for process modeling activities. Section 1.7 discusses additional limitations of this report. Key topics for this report are analogues to emplacement drift degradation, waste form degradation, waste package degradation, degradation of other materials proposed for the engineered barrier, seepage into drifts, radionuclide flow and transport in the unsaturated zone (UZ), analogues to coupled thermal-hydrologic-mechanical-chemical processes, saturated zone (SZ) transport, impact of radionuclide release on the biosphere, and potentially disruptive events. Results of these studies will be used to corroborate estimates of the magnitude and limitation of operative processes in order to build realism into conceptual and numerical process models used as a foundation for PA in the representative case of postclosure safety.

  1. Analysis of Wave Propagation in Stratified Structures Using Circuit Analogues, with Application to Electromagnetic Absorbers

    ERIC Educational Resources Information Center

    Sjoberg, Daniel

    2008-01-01

    This paper presents an overview of how circuit models can be used for analysing wave propagation in stratified structures. Relatively complex structures can be analysed using models which are accessible to undergraduate students. Homogeneous slabs are modelled as transmission lines, and thin sheets between the slabs are modelled as lumped

  2. Synthesis, solution and crystal structure of the coenzyme B(12) analogue Co(?)-2'-fluoro-2',5'-dideoxyadenosylcobalamin.

    PubMed

    Hunger, Miriam; Wurst, Klaus; Krutler, Bernhard

    2015-07-01

    Crystal structure analyses have helped to decipher the mode of binding of coenzyme B12 (AdoCbl) in the active site of AdoCbl-dependent enzymes. However, the question of how such enzymes perform their radical reactions is still incompletely answered. A pioneering study by Gruber and Kratky of AdoCbl-dependent glutamate mutase (GLM) laid out a path for the movement of the catalytically active 5'-deoxyadenosyl radical, in which H-bonds between the protein and the 2'- and 3'-OH groups of the protein bound AdoCbl would play a decisive role. Studies with correspondingly modified coenzyme B12-analogues are of interest to gain insights into cofactor binding and enzyme mechanism. Here we report the preparation of Co?-2'-fluoro-2',5'-dideoxyadenosylcobalamin (2'FAdoCbl), which lacks the 2'-OH group critical for the interaction in enzymes. 2'FAdoCbl was prepared by alkylation of cob(I)alamin, obtained from the electrochemical reduction of aquocobalamin. Spectroscopic data and a single crystal X-ray analysis of 2'FAdoCbl established its structure, which was very similar to that one of coenzyme B12. 2'FAdoCbl is a (19)F NMR active mimic of coenzyme B12 that may help to gain insights into binding interactions of coenzyme B12 with AdoCbl-dependent enzymes, proteins of B12 transport and of AdoCbl-biosynthesis, as well as with B12-riboswitches. PMID:25726330

  3. Non-natural acetogenin analogues as potent Trypanosoma brucei inhibitors

    PubMed Central

    Florence, Gordon J.; Fraser, Andrew L.; Gould, Eoin R.; King, Elizabeth F.; Menzies, Stefanie K.; Morris, Joanne C.; Tulloch, Lindsay B.; Smith, Terry K.

    2015-01-01

    A series of novel bis-tetrahydropyran 1,4-triazole analogues based on the acetogenin framework display low micromolar trypanocidal activities towards both bloodstream and insect forms of Trypanosoma brucei, the causative agent of African sleeping sickness. A divergent synthetic strategy was adopted for the synthesis of the key tetrahydropyran intermediates to enable rapid access to diastereochemical variation either side of the 1,4-triazole core. The resulting diastereomeric analogues displayed varying degrees of trypanocidal activity and selectivity in structure activity relationship studies. PMID:25145275

  4. Structural and theoretical investigation of 2-iminoimidazolines--carbene analogues of iminophosphoranes.

    PubMed

    Tamm, Matthias; Petrovic, Dejan; Randoll, Sren; Beer, Stephan; Bannenberg, Thomas; Jones, Peter G; Grunenberg, Jrg

    2007-02-01

    The preparation of 2-iminoimidazolines - has been accomplished by the Staudinger reaction of the carbenes 1,3-di-tert-butylimidazolin-2-ylidene (), 1,3-diisopropyl-4,5-dimethylimidazolin-2-ylidene (), 1,3-diisopropylimidazolin-2-ylidene (), 1,3-bis(2,4,6-trimethylphenyl)imidazolin-2-ylidene (), 1,3-bis(2,6-diisopropylphenylimidazolin-2-ylidene () and 1,3,4,5-tetramethylimidazolin-2-ylidene () with trimethylsilyl azide (Me3SiN3) followed by desilylation of the resulting 2-trimethylsilyliminoimidazolines -. The X-ray crystal structures of and have been established, revealing C1-N1-Si1 angles that are more obtuse than the corresponding P-N-Si angles observed in related trimethylsilyl iminophosphoranes. Together with , the disilylated side product 1,3-diisopropyl-2-(trimethylsilylimino)-4-trimethylsilylimidazoline () has been isolated and structurally characterized. Cleavage of the N-Si bonds in and formation of is easily achieved by stirring in methanol. The molecular structures of the 2-iminoimidazolines are reported, indicating that the structural parameters are best described by non-ylidic resonance structures and that electron delocalization within the imidazole heterocycle does not play a crucial role in these imine systems. Compound forms a head-to-head dimer in the solid state via weak intermolecular N-H...N contacts, which have additionally been characterized by means of compliance constants. To further analyze the electronic structure of these imines in comparison to related guanidine ligands, the proton affinities (PAs) of the model compounds 2-imino-1,3-dimethylimidazoline (), 2-imino-1,3-dimethylimidazolidine () and tetramethylguanidine () have been calculated by means of density functional theory. Finally, the charge distribution in - and the relative contribution of relevant resonance structures have been determined using natural bond orbitals (NBO) and natural resonance theory (NRT). PMID:17252136

  5. Structure of the p300 Histone Acetyltransferase Bound to Acetyl-Coenzyme A and Its Analogues

    PubMed Central

    2015-01-01

    The p300 and CBP transcriptional coactivator paralogs (p300/CBP) regulate a variety of different cellular pathways, in part, by acetylating histones and more than 70 non-histone protein substrates. Mutation, chromosomal translocation, or other aberrant activities of p300/CBP are linked to many different diseases, including cancer. Because of its pleiotropic biological roles and connection to disease, it is important to understand the mechanism of acetyl transfer by p300/CBP, in part so that inhibitors can be more rationally developed. Toward this goal, a structure of p300 bound to a Lys-CoA bisubstrate HAT inhibitor has been previously elucidated, and the enzymes catalytic mechanism has been investigated. Nonetheless, many questions underlying p300/CBP structure and mechanism remain. Here, we report a structural characterization of different reaction states in the p300 activity cycle. We present the structures of p300 in complex with an acetyl-CoA substrate, a CoA product, and an acetonyl-CoA inhibitor. A comparison of these structures with the previously reported p300/Lys-CoA complex demonstrates that the conformation of the enzyme active site depends on the interaction of the enzyme with the cofactor, and is not apparently influenced by protein substrate lysine binding. The p300/CoA crystals also contain two poly(ethylene glycol) moieties bound proximal to the cofactor binding site, implicating the path of protein substrate association. The structure of the p300/acetonyl-CoA complex explains the inhibitory and tight binding properties of the acetonyl-CoA toward p300. Together, these studies provide new insights into the molecular basis of acetylation by p300 and have implications for the rational development of new small molecule p300 inhibitors. PMID:24819397

  6. Aspartame and Its Analogues

    NASA Astrophysics Data System (ADS)

    Pavlova, L. A.; Komarova, T. V.; Davidovich, Yurii A.; Rogozhin, S. V.

    1981-04-01

    The results of studies on the biochemistry of the sweet taste are briefly reviewed. The methods of synthesis of "aspartame" — a sweet dipeptide — are considered, its structural analogues are described, and quantitative estimates are made of the degree of sweetness relative to sucrose. Attention is concentrated mainly on problems of the relation between the structure of the substance and its taste in the series of aspartyl derivatives. The bibliography includes 118 references.

  7. Disguise and the Structured Self-Report Assessment of Psychopathology: I. An Analogue Investigation.

    ERIC Educational Resources Information Center

    Holden, Ronald R.; Jackson, Douglas N.

    1985-01-01

    Explored utility of disguise in structured self-report assessment of psychopathology, using university students. Data indicated that under normal test-taking circumstances, use of disguised test items was not advantageous. This relationship was moderated by several dimensional parameters. Results supported rational strategy of test construction,

  8. Indoleamine 2,3-dioxygenase inhibitors isolated from the sponge Xestospongia vansoesti: structure elucidation, analogue synthesis, and biological activity.

    PubMed

    Centko, Ryan M; Stein, Anne; Rosell, Federico I; Patrick, Brian O; de Voogd, Nicole; Mauk, A Grant; Andersen, Raymond J

    2014-12-19

    Two new IDO inhibitory meroterpenoids, xestolactone A (1) and xestosaprol O (2), have been isolated from the sponge Xestospongia vansoesti. Xestolactone A (1) has an unprecedented degraded meroterpenoid carbon skeleton. A short synthesis of the xestosaprol O (2) analogues 3 and 4 features the application of a rarely used photochemical coupling reaction. Synthetic analogue 3 is ?40 times more potent than the inspirational natural product 2. PMID:25495618

  9. Interactions of taurine and structurally related analogues with the GABAergic system and taurine binding sites of rabbit brain

    PubMed Central

    Frosini, Maria; Sesti, Casilde; Dragoni, Stefania; Valoti, Massimo; Palmi, Mitri; Dixon, Henry B F; Machetti, Fabrizio; Sgaragli, Giampietro

    2003-01-01

    The aim of this study was to find taurinergic compounds that do not interact with brain GABA ergic systems. Washed synaptic membranes (SM) from whole rabbit brain were able to bind [3H]muscimol. Saturation experiments of the binding of [3H]GABA to GABAB receptors showed that SM possess two binding components; twice Triton X-100-treated SM contained 0.048 mmol endogenous taurine/kg protein and bound [3H]taurine in a saturable manner (Kd=249.0±6.3 nM and Bmax=3.4±1.0 pmol mg−1 prot). Among the 19 structural analogues of taurine, 6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (TAG), 2-aminoethylarsonic (AEA), 2-hydroxyethanesulfonic (ISE) and (±)cis-2-aminocyclohexane sulfonic acids (CAHS) displaced [3H]taurine binding (Ki=0.13, 0.13, 13.5 and 4.0 μM, respectively). These analogues did not interact with GABAA and GABAB receptors and did not affect taurine- and GABA-uptake systems and GABA-transaminase activity. 3-Aminopropanesulfonic acid (OMO), β-alanine, pyridine-3-sulfonic acid, N,N,N-trimethyltaurine (TMT), 2-(guanidino)ethanesulfonic acid (GES), ethanolamine-O-sulphate, N,N-dimethyltaurine (DMT), taurine and (±)piperidine-3-sulfonic acid (PSA) inhibited [3H]muscimol binding to GABAA receptors with different affinities (Ki=0.013, 7.9, 24.6, 47.5, 52.0, 91.0, 47.5, 118.1 and 166.3 μM, respectively). Taurine, 2-aminoethylphosphonic acid, DMT, TMT and OMO inhibited the binding of [3H]GABA to GABAB receptors with Ki's in the μM range (0.8, 3.5, 4.4, 11.3 and 5.0, respectively). GES inhibited taurine uptake (IC50=3.72 μM) and PSA GABA transaminase activity (IC50=103.0 μM). In conclusion, AEA, TAG, ISE and CAHS fulfill the criteria for taurinergic agents. PMID:12684273

  10. Structure-activity studies on the anti-proliferation activity of ajoene analogues in WHCO1 oesophageal cancer cells.

    PubMed

    Kaschula, Catherine H; Hunter, Roger; Stellenboom, Nashia; Caira, Mino R; Winks, Susan; Ogunleye, Thozama; Richards, Philip; Cotton, Jonathan; Zilbeyaz, Kani; Wang, Yabing; Siyo, Vuyolwethu; Ngarande, Ellen; Parker, M Iqbal

    2012-04-01

    The organosulfur compound ajoene derived from the rearrangement of allicin found in crushed garlic can inhibit the proliferation of tumour cells by inducing G(2)/M cell cycle arrest and apoptosis. We report on the application of a concise four-step synthesis (Hunter etal., 2008 [1]) that allows access to ajoene analogues with the end allyl groups substituted. A library of twelve such derivatives tested for their anti-proliferation activity against WHCO1 oesophageal cancer cells has identified a derivative containing p-methoxybenzyl (PMB)-substituted end groups that is twelve times more active than Z-ajoene, with an IC(50) of 2.1?M (Kaschula etal., 2011 [2]). Structure-activity studies involving modification of the sulfoxide and vinyl disulfide groups of this lead have revealed that the disulfide is the ajoene pharmacophore responsible for inhibiting WHCO1 cell growth, inducing G(2)/M cell cycle arrest and apoptosis by caspase-3 activation, and that the vinyl group serves to enhance the anti-proliferation activity a further eightfold. Reaction of the lead with cysteine in refluxing THF as a model reaction for ajoene's mechanism of action based on a thiol/disulfide exchange reveals that the allylic sulfur of the vinyl disulfide is the site of thiol attack in the exchange. PMID:22381354

  11. Anion Recognition by Pyrylium Cations and Thio-, Seleno- and Telluro- Analogues: A Combined Theoretical and Cambridge Structural Database Study.

    PubMed

    Quionero, David

    2015-01-01

    Pyrylium salts are a very important class of organic molecules containing a trivalent oxygen atom in a six-membered aromatic ring. In this manuscript, we report a theoretical study of pyrylium salts and their thio-, seleno- and telluro- analogues by means of DFT calculations. For this purpose, unsubstituted 2,4,6-trimethyl and 2,4,6-triphenyl cations and anions with different morphologies were chosen (Cl-, NO3- and BF4-). The complexes were characterized by means of natural bond orbital and "atoms-in-molecules" theories, and the physical nature of the interactions has been analyzed by means of symmetry-adapted perturbation theory calculations. Our results indicate the presence of anion-? interactions and chalcogen bonds based on both ?- and ?-hole interactions and the existence of very favorable ?-complexes, especially for unsubstituted cations. The electrostatic component is dominant in the interactions, although the induction contributions are important, particularly for chloride complexes. The geometrical features of the complexes have been compared with experimental data retrieved from the Cambridge Structural Database. PMID:26114926

  12. Thermodynamic functions and intraparticle mass transfer kinetics of structural analogues of a template on molecularly imprinted polymers in liquid chromatography

    SciTech Connect

    Kim, Hyunjung; Guiochon, Georges A

    2005-08-01

    The parameters of the thermodynamics and mass transfer kinetics of the structural analogues (L-enantiomers) of the template were measured on an Fmoc-L-tryptophan (Fmoc-L-Trp) imprinted polymer, at different temperatures. The equilibrium isotherm data and the overloaded band profiles of these compounds were measured at temperatures of 298, 313, 323, and 333 K. The isotherm data were modeled. The thermodynamic functions of the different adsorption sites were derived from the isotherm parameters, using van't Hoff plots. The mass transfer parameters were derived by comparing the experimental peak profiles and profiles calculated using the lumped pore diffusion (POR) model for chromatography. These data show that (1) the strength between the substrate molecules and the MIP increases with increasing number of functional groups on the substrates; (2) enthalpy is the driving force for the affinity of the substrates for the MIP; (3) surface diffusion is the dominant mass transfer mechanism of the substrates through the porous MIP. For those substrate molecules that have the same stereochemistry as the template, the energetic surface heterogeneity needs to be incorporated into the surface diffusion coefficients. Heterogeneous surface diffusivities decrease with increasing affinity of the substrates for the MIP.

  13. Structure Activity Relationship and Mechanism of Action Studies of Manzamine Analogues for the Control of Neuroinflammation and Cerebral Infections

    PubMed Central

    Peng, Jiangnan; Kudrimoti, Sucheta; Prasanna, Sivaprakasam; Odde, Srinivas; Doerksen, Robert J.; Pennaka, Hari K; Choo, Yeun-Mun; Rao, Karumanchi V.; Tekwani, Babu L.; Madgula, Vamsi; Khan, Shabana I.; Wang, Bin; Mayer, Alejandro M. S.; Jacob, Melissa R.; Tu, Lan Chun; Gertsch, Jürg; Hamann, Mark T.

    2010-01-01

    Structure-activity relationship studies were carried out by chemical modification of manzamine A (1), 8-hydroxymanzamine A (2), manzamine F (14), and ircinol isolated from the sponge Acanthostrongylophora. The derived analogues were evaluated for antimalarial, antimicrobial, and antineuroinflammatory activities. Several modified products exhibited potent and improved in vitro antineuroinflammatory, antimicrobial, and antimalarial activity. 1 showed improved activity against malaria compared to chloroquine in both multi- and single-dose in vivo experiments. The significant antimalarial potential was revealed by a 100% cure rate of malaria in mice with one administration of 100 mg/kg of 1. The potent antineuroinflammatory activity of the manzamines will provide great benefit for the prevention and treatment of cerebral infections (e.g. Cryptococcus and Plasmodium). In addition, 1 was shown to permeate across the blood-brain barrier (BBB) in an in vitro model using a MDR-MDCK monolayer. Docking studies support that 2 binds to the ATP-noncompetitive pocket of glycogen synthesis kinase-3β (GSK-3β), which is a putative target of manzamines. Based on the results presented here it will be possible to initiate rational drug design efforts around this natural product scaffold for the treatment of several different diseases. PMID:20017491

  14. Structural perturbation of a dipalmitoylphosphatidylcholine (DPPC) bilayer by warfarin and its bolaamphiphilic analogue: A molecular dynamics study.

    PubMed

    Ayee, Manuela Aseye Ayele; Roth, Charles William; Akpa, Belinda Sena

    2016-04-15

    Compounds with nominally similar biological activity may exhibit differential toxicity due to differences in their interactions with cell membranes. Many pharmaceutical compounds are amphiphilic and can be taken up by phospholipid bilayers, interacting strongly with the lipid-aqueous interface whether or not subsequent permeation through the bilayer is possible. Bolaamphiphilic compounds, which possess two hydrophilic ends and a hydrophobic linker, can likewise undergo spontaneous uptake by bilayers. While membrane-spanning bolaamphiphiles can stabilize membranes, small molecules with this characteristic have the potential to create membrane defects via disruption of bilayer structure and dynamics. When compared to the amphiphilic therapeutic anticoagulant, warfarin, the bolaamphiphilic analogue, brodifacoum, exhibits heightened toxicity that goes beyond superior inhibition of the pharmacological target enzyme. We explore, herein, the consequences of anticoagulant accumulation in a dipalmitoylphosphatidylcholine (DPPC) bilayer. Coarse-grained molecular dynamics simulations reveal that permeation of phospholipid bilayers by brodifacoum causes a disruption of membrane barrier function that is driven by the bolaamphiphilic nature and size of this molecule. We find that brodifacoum partitioning into bilayers causes membrane thinning and permeabilization and promotes lipid flip-flop - phenomena that are suspected to play a role in triggering cell death. These phenomena are either absent or less pronounced in the case of the less toxic, amphiphilic compound, warfarin. PMID:26852346

  15. Synthesis, biological activities, and quantitative structure-activity relationship (QSAR) study of novel camptothecin analogues.

    PubMed

    Wu, Dan; Zhang, Shao-Yong; Liu, Ying-Qian; Wu, Xiao-Bing; Zhu, Gao-Xiang; Zhang, Yan; Wei, Wei; Liu, Huan-Xiang; Chen, An-Liang

    2015-01-01

    In continuation of our program aimed at the development of natural product-based pesticidal agents, three series of novel camptothecin derivatives were designed, synthesized, and evaluated for their biological activities against T. Cinnabarinus, B. brassicae, and B. xylophilus. All of the derivatives showed good-to-excellent activity against three insect species tested, with LC50 values ranging from 0.00761 to 0.35496 mmol/L. Remarkably, all of the compounds were more potent than CPT against T. Cinnabarinus, and compounds 4d and 4c displayed superior activity (LC50 0.00761 mmol/L and 0.00942 mmol/L, respectively) compared with CPT (LC50 0.19719 mmol/L) against T. Cinnabarinus. Based on the observed bioactivities, preliminary structure-activity relationship (SAR) correlations were also discussed. Furthermore, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model using comparative molecular field analysis (CoMFA) was built. The model gave statistically significant results with the cross-validated q2 values of 0.580 and correlation coefficient r2 of 0.991 and  of 0.993. The QSAR analysis indicated that the size of the substituents play an important in the activity of 7-modified camptothecin derivatives. These findings will pave the way for further design, structural optimization, and development of camptothecin-derived compounds as pesticidal agents. PMID:25985362

  16. Structure-activity relationship of piperine and its synthetic analogues for their inhibitory potentials of rat hepatic microsomal constitutive and inducible cytochrome P450 activities.

    PubMed

    Koul, S; Koul, J L; Taneja, S C; Dhar, K L; Jamwal, D S; Singh, K; Reen, R K; Singh, J

    2000-01-01

    Inhibitors of drug metabolism have important implications in pharmaco-toxicology and agriculture. We have reported earlier that piperine, a major alkaloid of black and long peppers inhibits both constitutive and inducible cytochrome P450 (CYP)-dependent drug metabolising enzymes. In the present study, an attempt has been made to prepare several novel synthetic analogues so as to relate various modifications in the parent molecule to the inhibition of CYP activities. Two types of mono-oxygenase reactions arylhydrocarbon hydroxylase (AHH) and 7-methoxycoumarin-O-demethylase (MOCD) have been studied. Inhibition studies were investigated in rat microsomal fraction prepared from untreated, 3MC- and PB- treated rat liver in vitro. Modifications were introduced into the piperine molecule: (i) in the phenyl nucleus, (ii) in the side chain and (iii) in the basic moiety. Thus, 38 compounds have been subjected to such studies, and simultaneously an attempt has also been made to arrive at the structure-activity relationship of synthetic analogues. In general, most of the inhibitory potential of the parent molecule is lost with modification in either of the three components of piperine. Saturation of the side chain resulted in significantly enhanced inhibition of CYP while modifications in the phenyl and basic moieties in few analogues offered maximal selectivity in inhibiting either constitutive or inducible CYP activities. Thus few novel analogues as CYP inactivators have been synthesized which may have important consequences in pharmacokinetics and bioavailability of drugs. PMID:10968285

  17. Synthesis and structure of dirhodium analogue of octaborane-12 and decaborane-14.

    PubMed

    Roy, Dipak Kumar; Bose, Shubhankar Kumar; Anju, R S; Ramkumar, V; Ghosh, Sundargopal

    2012-10-15

    We present the results of our investigation of a thermally driven cluster expansion of rhodaborane systems with BH(3)THF. Four novel rhodaborane clusters, for example, nido-[(Cp*Rh)(2)B(6)H(10)], 1; nido-[(Cp*Rh)B(9)H(13)], 2; nido-[(Cp*Rh)(2)B(8)H(12)], 3; and nido-[(Cp*Rh)(3)B(8)H(9)(OH)(3)], 4 (Cp* = ?(5)-C(5)Me(5)), have been isolated from the thermolysis of [Cp*RhCl(2)](2) and borane reagents in modest yields. Rhodaborane 1 has a nido geometry and is isostructural with [B(8)H(12)]. The low temperature (11)B and (1)H NMR data demonstrate that compound 1 exists in two isomeric forms. The framework geometry of 2 and 3 is similar to that of [B(10)H(14)] with one BH group in 2 (3-position), and two BH groups in 3 (3, 4-positions) are replaced by an isolobal {Cp*Rh} fragment. The 11 vertex cluster 4 has a nido structure based on the 12 vertex icosahedron, having three rhodium and eight boron atoms. In addition, the reaction of rhodaborane 1 with [Fe(2)(CO)(9)] yielded a condensed cluster [(Cp*Rh)(2){Fe(CO)(3)}(2)B(6)H(10)], 5. The geometry of 5 consists of [Fe(2)B(2)] tetrahedron and an open structure of [(Cp*Rh)(2)B(6)], fused through two boron atoms. The accuracy of these results in each case is established experimentally by spectroscopic characterization in solution and structure determinations in the solid state. PMID:22998603

  18. Inhibition and Structure of Trichomonas vaginalis Purine Nucleoside Phosphorylase with Picomolar Transition State Analogues

    SciTech Connect

    Rinaldo-Matthis,A.; Wing, C.; Ghanem, M.; Deng, H.; Wu, P.; Gupta, A.; Tyler, P.; Evans, G.; Furneaux, R.; et al.

    2007-01-01

    Trichomonas vaginalis is a parasitic protozoan purine auxotroph possessing a unique purine salvage pathway consisting of a bacterial type purine nucleoside phosphorylase (PNP) and a purine nucleoside kinase. Thus, T. vaginalis PNP (TvPNP) functions in the reverse direction relative to the PNPs in other organisms. Immucillin-A (ImmA) and DADMe-Immucillin-A (DADMe-ImmA) are transition stte mimics of adenosine with geometric and electrostatic features that resemble early and late transition states of adenosine at the transition state stabilized by TvPNP. ImmA demonstrates slow-onset tight-binding inhibition with TvPNP, to give an equilibrium dissociation constant of 87 pM, an inhibitor release half-time of 17.2 min, and a K{sub m}/K{sub d} ratio of 70,100. DADMe-ImmA resembles a late ribooxacarbenium ion transition state for TvPNP to give a dissociation constant of 30 pM, an inhibitor release half-time of 64 min, and a K{sub m}/K{sub d} ratio of 203,300. The tight binding of DADMe-ImmA supports a late S{sub N}1 transition state. Despite their tight binding to TvPNP, ImmA and DADMe-ImmA are weak inhibitors of human and P. falciparum PNPs. The crystal structures of the TvPNP-ImmA{center_dot}PO{sub 4} and TvPNP{center_dot}DADMe-ImmA{center_dot}PO{sub 4} ternary complexes differ from previous structures with substrate anologues. The tight binding with DADMe-ImmA is in part due to a 2.7 {angstrom} ionic interaction between a PO{sub 4} oxygen and the N1 cation of the hydroxypyrrolidine and is weaker in the TvPNP{center_dot}ImmA{center_dot}PO{sub 4} structure at 3.5 {angstrom}. However, the TvPNP{center_dot}ImmA{center_dot}PO{sub 4} structure includes hydrogen bonds between the 2'-hydroxyl and the protein that are not present in TvPNP{center_dot}DADMe-ImmA{center_dot}PO{sub 4}. These structures explain why DADMe-ImmA binds tighter than ImmA. Immucillin-H is a 12 nM inhibitor of TvPNP but a 56 pM inhibitor of human PNP. And this difference is explained by isotope-edited difference infrared spectroscopy with [6-{sup 18}O]ImmH to establish that O6 is the keto tautomer in TvPNP{center_dot}ImmH{center_dot}PO{sub 4}, causing an unfavorable leaving-group interaction.

  19. Structure Determination of Cisplatin-Amino Acid Analogues by Infrared Multiple Photon Dissociation Action Spectroscopy

    NASA Astrophysics Data System (ADS)

    He, Chenchen; Bao, Xun; Zhu, Yanlong; Strobehn, Stephen; Kimutai, Bett; Nei, Y.-W.; Chow, C. S.; Rodgers, M. T.; Gao, Juehan; Oomens, J.

    2015-06-01

    To gain a better understanding of the binding mechanism and assist in the optimization of relevant drug and chemical probe design, both experimental and theoretical studies were performed on a series of amino acid-linked cisplatin derivatives, including glycine-, lysine-, and ornithine-linked cisplatin, Gplatin, Kplatin, and Oplatin, respectively. Cisplatin, the first FDA-approved platinum-based anticancer drug, has been widely used in cancer chemotherapy. Its pharmacological mechanism has been identified as its ability to coordinate to genomic DNA, and guanine is its major target. In previous reports, cisplatin was successfully utilized as a chemical probe to detect solvent accessible sites in ribosomal RNA (rRNA). Among the amino-acid-linked cisplatin derivatives, Oplatin exhibits preference for adenine over guanine. The mechanism behind its different selectivity compared to cisplatin may relate to its potential of forming a hydrogen bond between the carboxylate group in Pt (II) complex and the 6-amino moiety of adenosine stabilizes A-Oplatin products. Tandem mass spectrometry analysis also indicates that different coordination sites of Oplatin on adenosine affect glycosidic bond stability. Infrared multiple photon dissociation (IRMPD) action spectroscopy experiments were performed on all three amino acid-linked cisplatin to characterize their structures. An extensive theoretical study has been performed on Gplatin to guide the selection of the most effective theory and basis set based on its geometric information. The results for Gplatin provide the foundation for characterization of the more complex amino acid-linked cisplatin derivatives, Oplatin and Kplatin. Structural and energetic information elucidated for these compounds, particularly Oplatin reveal the reason for its alternative selectivity compared to cisplatin.

  20. Analysis of structure-activity relationships in renin substrate analogue inhibitory peptides.

    PubMed

    Hui, K Y; Carlson, W D; Bernatowicz, M S; Haber, E

    1987-08-01

    On the basis of the minimal octapeptide sequence of the renin substrate, a series of peptides was synthesized containing (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid (statine) or (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoic acid (AHPPA) at the P1P1' position. Some of these peptides also contained Nin-formyltryptophan at the P5, P3, or P3' position. Renin-inhibitory potency varied over a wide range (from inactive to IC50 = 3 nM). Potency was reduced by at least 10-fold when the peptide was shortened by two residues at either the amino or carboxy terminus. The AHPPA-containing inhibitors were several-fold less potent than the statine-containing inhibitors. Analysis of models for the three-dimensional structure of inhibitors at the active site of human renin suggests that the diminished potency of the AHPPA peptides in comparison with the statine-containing peptides was caused by a shift in the peptide backbone due to a steric conflict between the phenyl ring of the AHPPA residue and the S1 subsite. The importance of the side chain and the 3(S)-hydroxyl group of the statine residue was demonstrated by substituting 5-aminovaleric acid for a dipeptide unit at the P1P1' position, which resulted in a peptide devoid of renin-inhibitory activity. Substitutions of other basic amino acids for histidine at the P2 position caused a great loss in potency, possibly due to disruption of a hydrogen bond as suggested by molecular modeling. Studies on the plasma renins of four nonhuman species suggest that the isoleucine-histidine segment at the P2'P3' position is important to defining the human specificity of the substrate. This work suggests a number of properties important to the design of potent renin inhibitors, and demonstrates the usefulness of three-dimensional models in the interpretation of structure-activity data. PMID:3302256

  1. 3-D models and structural analysis of analogue rock avalanche deposits: a kinematic analysis of the propagation mechanism

    NASA Astrophysics Data System (ADS)

    Longchamp, C.; Abellan, A.; Jaboyedoff, M.; Manzella, I.

    2015-11-01

    Rock avalanches are extremely destructive and uncontrollable events that involve a great volume of material (> 106 m3), several complex processes and they are difficult to witness. For this reason the study of these phenomena using analogue modelling and the accurate analysis of deposit structures and features of laboratory data and historic events become of great importance in the understanding of their behavior. The main objective of this research is to analyze rock avalanche dynamics by means of a detailed structural analysis of the deposits coming from data of 3-D measurements of mass movements of different magnitudes, from decimeter level scale laboratory experiments to well-studied rock avalanches of several square kilometers magnitude. Laboratory experiments were performed on a tilting plane on which a certain amount of a well-defined granular material is released, propagates and finally stops on a horizontal surface. The 3-D geometrical model of the deposit is then obtained using either a scan made with a 3-D digitizer (Konica Minolta vivid 9i) either using a photogrammetric method called Structure-from-Motion (SfM) which requires taking several pictures from different point of view of the object to be modeled. In order to emphasize and better detect the fault structures present in the deposits, we applied a median filter with different moving windows sizes (from 3 × 3 to 9 × 9 nearest neighbors) to the 3-D datasets and a gradient operator along the direction of propagation. The application of these filters on the datasets results in: (1) a precise mapping of the longitudinal and transversal displacement features observed at the surface of the deposits; and (2) a more accurate interpretation of the relative movements along the deposit (i.e. normal, strike-slip, inverse faults) by using cross-sections. Results shows how the use of filtering techniques reveal disguised features in the original point cloud and that similar displacement patterns are observable both in the laboratory simulation and in the real scale avalanche, regardless the size of the avalanche. Furthermore, we observed how different structural features including transversal fractures and folding patterns tend to show a constant wavelength proportional to the size of the avalanche event.

  2. Bispidin-9,9-diol Analogues of Cisplatin, Carboplatin, and Oxaliplatin: Synthesis, Structures, and Cytotoxicity.

    PubMed

    Cui, Huiling; Goddard, Richard; Pörschke, Klaus-Richard; Hamacher, Alexandra; Kassack, Matthias U

    2016-03-21

    3,7-Diallyl-bispidin-9-one (6) (bispidin-9-one = 3,7-diazabicyclo[3.3.1]nonan-9-one) is converted to N-unsubstituted spiro[bispidin-9,2'-[1,3]dioxolane] (12; 35%). The ketal crystallizes in the forms of anhydrous 12a and the dihydrate 12b. The molecules in anhydrous 12a are linked to each other, forming N1-H1···N2-H2···N1* hydrogen-bond chiral helices of alternating chirality. In the dihydrate 12b, the ketal molecules are connected to a central string of water molecules by O3-H···O1 and O4-H···N1 hydrogen bonds, but not to themselves. Reaction of 12 with (1,5-hexadiene)PtCl2 affords almost quantitatively spiro[bispidin-9,2'-[1,3]dioxolane]PtCl2 (13). Cleavage of the ketal to retrieve the ketone produces the geminal diol (bispidin-9,9-diol)PtCl2 (14; 85%). Compound 14 reacts with Ag2cbdca (cbdca = 1,1-cyclobutanedicarboxylate) to give the dihydrate (bispidin-9,9-diol)Pt(cbdca)·2H2O (15b), which can be dehydrated to obtain anhydrous (bispidin-9,9-diol)Pt(cbdca) (15a). Similarly, anhydrous (bispidin-9,9-diol)Pt(oxalate) (16) is obtained. Crystal structures of 14 and 15b reveal association by various forms of O-H···O, O-H···Cl, N-H···Cl, and N-H···O hydrogen bonds. Biological studies showed a moderate cytotoxic activity of the bispidin-9,9-diol complexes 14-16, compared to the 9,9-unsubstituted bispidine complexes. No unspecific cytotoxicity of 14-16 up to 316 μM was found against the noncancer cell line HEK293. PMID:26918619

  3. A cyclic CCK8 analogue selective for the cholecystokinin type A receptor: design, synthesis, NMR structure and binding measurements.

    PubMed

    De Luca, Stefania; Ragone, Raffaele; Bracco, Chiara; Digilio, Giuseppe; Aloj, Luigi; Tesauro, Diego; Saviano, Michele; Pedone, Carlo; Morelli, Giancarlo

    2003-11-01

    A cyclic CCK8 analogue, cyclo(29,34)[Dpr(29),Lys(34)]-CCK8 (Dpr=L-2,3-diaminopropionic acid), has been designed on the basis of the NMR structure of the bimolecular complex between the N-terminal fragment of the CCK(A) receptor and its natural ligand CCK8. The conformational features of cyclo(29,34)[Dpr(29),Lys(34)]-CCK8 have been determined by NMR spectroscopy in aqueous solution and in water containing DPC-d(38) micelles (DPC=dodecylphosphocholine). The structure of the cyclic peptide in aqueous solution is found to be in a relaxed conformation, with the backbone and Dpr29 side chain atoms making a planar ring and the N-terminal tripeptide extending approximately along the plane of this ring. In DPC/water, the cyclic peptide adopts a "boat-shaped" conformation, which is more compact than that found in aqueous solution. The cyclic constraint between the Dpr29 side chain and the CCK8 carboxyl terminus (Lys34) introduces a restriction in the backbone conformational freedom. However, the interaction of cyclo(29,34)[Dpr(29),Lys(34)]-CCK8 with the micelles still plays an important role in the stabilisation of the bioactive conformation. A careful comparison of the NMR structure of the cyclic peptide in a DPC micelle aqueous solution with the structure of the rationally designed model underlines that the turn-like conformation in the Trp30-Met31 region is preserved, such that the Trp30 and Met31 side chains can adopt the proper spatial orientation to interact with the CCK(A) receptor. The binding properties of cyclo(29,34)[Dpr(29),Lys(34)]-CCK8 to the N-terminal receptor fragment have been investigated by fluorescence spectroscopy in a micellar environment. Estimates of the apparent dissociation constant, K(d), were in the range of 70-150 nM, with a mean value of 120+/-27 nM. Preliminary nuclear medicine studies on cell lines transfected with the CCK(A) receptor indicate that the sulfated-Tyr derivative of cyclo(29,34)[Dpr(29),Lys(34)]-CCK8 displaces the natural ligand with an IC(50) value of 15 microM. PMID:14613109

  4. Titan's Organic Aerosols : Molecular Composition And Structure Inferred From Systematic Pyrolysis Gas Chromatography Mass Spectrometry Analysis of Analogues

    NASA Astrophysics Data System (ADS)

    Morisson, Marietta; Szopa, Cyril; Buch, Arnaud; Carrasco, Nathalie; Gautier, Thomas

    2015-04-01

    In spite of numerous studies carried out to characterize the chemical composition of laboratory analogues of Titan aerosols (tholins), their molecular composition as well as their structuration are still little known. If Pyrolysis gas chromatography mass spectrometry (Pyr-GCMS) has been used for years to give clues about this composition, the highly disparate results obtained show that they can be attributed to the analytical conditions used, to differences in the nature of the analogues studied, or both. In order to have a better description of Titan's tholins molecular composition, we led a systematic analysis of these materials by pyr-GCMS, exploring the analytical parameters to estimate the biases this technique can induce. With this aim, we used the PAMPRE experiment, a capacitively coupled RF cold plasma reactor (Szopa et al. 2006), to synthetize tholins with 2%, 5% and 10% of CH4 in N2. The three samples were systematically pyrolyzed in the temperature range 200-600°C with a 100°C step. The evolved gases were then injected into a GC-MS device for molecular identification. This systematic pyr-GC-MS analysis had two major objectives: (i) optimizing all the analytical parameters for the detection of a wide range of compounds and thus a characterization of the tholins composition as comprehensive as possible, and (ii) highlighting the role of the CH4 ratio on the tholins molecular structure. About a hundred of molecules have been identified in the pyrolysis products. Although an identical major pattern of nitriles and ethylene appears clearly for the three samples, some discriminant signatures were highlighted. The samples mainly differ by the number of released compounds. The results show especially an increase in the hydrocarbonaceous chains when the CH4 ratio increases. At the opposite, the formation of poly-nitrogenous compounds seems to be easier for lower CH4 ratios. We also performed a semi-quantitative study on the best represented chemical family in our chromatograms - namely nitriles: the existence of a relation between the quantity of a released compound and its molecular mass is consistent with the quantification of nitriles in the PAMPRE gas phase done by Gautier et al., 2011. Moreover, numerous species are present both in tholins and in the gas phase. That allowed us to make out potential precursors of the solid organic particles. From all these results, we conclude that the optimal pyrolysis temperature for a GC-MS analysis of our tholins is 600°C. This temperature choice results from the best compromise between the number of released compounds, the quality of the signal and the appearance of pyrolysis artefacts. Lastly, thanks to a review of pyr-GCMS studies carried out on Titan tholins since the first work of Khare et al. (1981), we compared all the previous analyses between them and with our own results in order to better understand the differences. References B. N. Khare et al., Icarus, vol. 48, no. 2, pp. 290-297, Nov. 1981. C. Szopa et al., Planet. Space Sci., vol. 54, no. 4, pp. 394-404, Apr. 2006. T. Gautier et al., Icarus, vol. 213, no. 2, pp. 625-635, Jun. 2011.

  5. Structure of beta-crystallite assemblies formed by Alzheimer beta-amyloid protein analogues: analysis by x-ray diffraction.

    PubMed Central

    Inouye, H.; Fraser, P. E.; Kirschner, D. A.

    1993-01-01

    To elucidate the relation between amyloid fibril formation in Alzheimer disease and the primary structure of the beta/A4 protein, which is the major component of the amyloid, we have been investigating the ability of peptides sharing sequences with beta/A4 to form fibrils in vitro. In previous studies we focused on the macroscopic morphology of the assemblies formed by synthetic peptides corresponding in sequence to different regions of this protein. In the present study we analyze the x-ray diffraction patterns obtained from these assemblies. All specimens showed wide angle reflections that could be indexed by an orthogonal lattice of beta-crystallites having unit cell dimensions a = 9.4 A, b = 7 A, and c = 10 A, where a refers to hydrogen bonding direction, b to polypeptide chain direction, and c to intersheet direction. Given the amino acid sequence of beta/A4 as NH2-DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIAT-COOH, we found that, based on their orientation and assembly, the analogues could be classified into three groups: Group A, residues 19-28, 13-28, 12-28, 11-28, 9-28, 1-28, 1-38, 1-40, 6-25, 11-25 and 34-42; Group B, residues 18-28, 17-28, and 15-28; and Group C, residues 22-35 and 26-33. For Groups A and C, the sharpest reflections were (h00), indicating that the assemblies were fibrillar, i.e., elongated in a single direction. Lateral alignment of the crystallites in Group A account for its cross-beta pattern, in which the hydrogen bonding (H-bonding) direction is the fiber (rotation) axis. By comparison, the beta-crystallites of Group C had no preferential orientation, thus giving circular scattering. For Group B, the sharpest reflections were (h0l) on the meridian, indicating that the assemblies were plate-like, i.e., extended in two directions. A series of equatorial Bragg reflections having a 40 A period indicated regular stacking of the plates, and the rotation axis was normal to the surface of the plates. Of the Group A peptides, the analogues 11-28 and 6-25 showed intensity maxima on the equator as well as on higher layer lines, indicating that the beta-crystallites are highly ordered relative to one another in the axial, H-bonding direction. This sampling of the layer lines by a larger period (60 A) suggests that the beta-crystallites are arrayed either in cylindrical or small restricted crystalline lattices. Consistent with its electron microscopic images, we modeled the structure as a tube with five or six f,-crystallites constituting the wall and with the individual crystallite, which either rotates freely or is restricted, made of five or fewer beta-pleated sheets. For the Group B peptides, the electron density projection along the b-axis was calculated from the observed intensities using phase combinations from fl-keratin.Amino acid side-chain positions were apparent and, when refined as 4-A-diameter spheres, led to a substantial decrease in the R-factors.For peptide 18-28 the electron density peaks, which are thought to correspond to side chains, were centered 3.3 A from the peptide backbone, whereas for peptides 17-28 and 15-28, these peaks were centered 1 A or more further from the backbone. Peaks having high electron density faced peaks having lower density, suggesting a favorable stereochemical arrangement of the residues. Thus, our analysis of the fiber x-ray patterns from beta/A4 peptides shows the organization of the beta-crystallites that form the wall of the amyloid fibrils as well as possible side-chain interactions. Images FIGURE 1 PMID:8457674

  6. Combined Quantum Chemistry and Photoelectron Spectroscopy Study of the Electronic Structure and Reduction Potentials of Rubredoxin Redox Site Analogues

    SciTech Connect

    Niu, Shuqiang; Wang, Xue B.; Nichols, J. A.; Wang, Lai S.; Ichiye, Toshiko

    2003-04-24

    Iron-sulfur proteins are an important class of electron carriers in a wide variety of biological reactions. Determining the intrinsic contribution of the metal site to the redox potential is crucial in understanding how the protein environment influences the overall redox properties of the Fe-S proteins. Here we combine density functional theory and coupled cluster methods with photodetachment spectroscopy to study the electronic structures and gas-phase redox potentials of the [Fe(SCH3)(4)](2-/-/0) and [Fe(SCH3)(3)](-/0) analogues of the rubredoxin redox site. The calculations show that oxidations of [Fe(SCH3)(4)](2-) and [Fe(SCH3)(4)](-) involve mainly the Fe 3d and S 3p orbitals, respectively. The calculated adiabatic and vertical detachment energies are in good agreement with the experiment for [Fe(SCH3)(3)](-) and [Fe(SCH3)(4)](-). The current results further confirm the "inverted level scheme" for the high-spin [1Fe] systems. The redox couple, [Fe(SCH3)(4)](- /2), which is the one found in rubredoxin, but cannot be accessed experimentally in the gas phase, was investigated using a thermodynamic cycle that relates it to the [Fe(SCH3)(3)](-/0) couple and the ligand association reaction, [Fe(SCH3)(3)](0/-) + SCH3- --> [Fe(SCH3)(4)](-/2-). The calculated reduction energy of [Fe(SCH3)(4)](-) (1.7 eV) compares well with the value (1.6 eV) estimated from the calculated bond energies and the experimental detachment energy of [Fe(SCH3)(3)](-). Thus, this thermodynamic cycle method can be used to estimate metal-ligand bonding energies and determine intrinsic reduction potentials from photodetachment experiments when the reduced forms are not stable in the gas phase.

  7. Structure-Activity Relationships at the Monoamine Transporters for a Novel Series of Modafinil (2-[(diphenylmethyl)sulfinyl]acetamide) Analogues.

    PubMed

    Cao, Jianjing; Prisinzano, Thomas E; Okunola, Oluyomi M; Kopajtic, Theresa; Shook, Matthew; Katz, Jonathan L; Newman, Amy Hauck

    2010-10-10

    A series of modafinil (1) analogues was synthesized wherein 1) para-halo-substitutents were added to the aryl rings, 2) the sulfoxide function was removed, and 3) the primary amide group was replaced with secondary and tertiary amides and amines to investigate the effects of these chemical modifications on DAT, SERT and NET binding. In addition, the locomotor-stimulant effects in mice of ()-modafinil (1), its R- and S-enantiomers and its para-chloro sulfinylacetamide analogue (5c) were compared to those of cocaine. PMID:21344069

  8. Polyamine analogues targeting epigenetic gene regulation

    PubMed Central

    Huang, Yi; Marton, Laurence J.; Woster, Patrick M.; Casero, Robert A.

    2013-01-01

    Over the past three decades the metabolism and functions of the polyamines have been actively pursued as targets for antineoplastic therapy. Interactions between cationic polyamines and negatively charged nucleic acids play a pivotal role in DNA stabilization and RNA processing that may affect gene expression, translation and protein activity. Our growing understanding of the unique roles that the polyamines play in chromatin regulation, and the discovery of novel proteins homologous with specific regulatory enzymes in polyamine metabolism, have led to our interest in exploring chromatin remodelling enzymes as potential therapeutic targets for specific polyamine analogues. One of our initial efforts focused on utilizing the strong affinity that the polyamines have for chromatin to create a backbone structure, which could be combined with active-site-directed inhibitor moieties of HDACs (histone deacetylases). Specific PAHAs (polyaminohydroxamic acids) and PABAs (polyaminobenzamides) polyamine analogues have demonstrated potent inhibition of the HDACs, re-expression of p21 and significant inhibition of tumour growth. A second means of targeting the chromatin-remodelling enzymes with polyamine analogues was facilitated by the recent identification of flavin-dependent LSD1 (lysine-specific demethylase 1). The existence of this enzyme demonstrated that histone lysine methylation is a dynamic process similar to other histone post-translational modifications. LSD1 specifically catalyses demethylation of mono- and di-methyl Lys4 of histone 3, key positive chromatin marks associated with transcriptional activation. Structural and catalytic similarities between LSD1 and polyamine oxidases facilitated the identification of biguanide, bisguanidine and oligoamine polyamine analogues that are potent inhibitors of LSD1. Cellular inhibition of LSD1 by these unique compounds led to the re-activation of multiple epigenetically silenced genes important in tumorigenesis. The use of these novel polyamine-based HDAC or LSD1 inhibitors represents a highly promising and novel approach to cancer prevention and therapy. PMID:20095972

  9. Analogues of diverse structure are unable to differentiate native melatonin receptors in the chicken retina, sheep pars tuberalis and Xenopus melanophores.

    PubMed Central

    Pickering, H.; Sword, S.; Vonhoff, S.; Jones, R.; Sugden, D.

    1996-01-01

    1. The pineal hormone melatonin exerts its biological effects through specific, high affinity G-protein coupled receptors. Recently, three melatonin receptor subtypes (Mel1a, Mel1b and Mel1c) have been cloned. Neither the cloned subtypes, nor the native receptors have yet been compared in a detailed pharmacological analysis. 2. The present study examined the structure-activity relationships of a series of 21 melatonin analogues, by comparing their potency on the pigment aggregation response in Xenopus laevis melanophores with their affinity in radioligand binding competition studies in chicken retina and sheep pars tuberalis (PT), two tissues in which melatonin is known to mediate a biological response. 3. All but four of the analogues were full melatonin receptor agonists producing a concentration-related redistribution of pigment granules in cultured Xenopus melanophores. The remaining analogues produced little pigment aggregation at 10 microM. 4. Saturation studies with 2-[125I]-iodomelatonin identified a single binding site in the chicken retina and sheep PT membranes, with a KD of 36.6 +/- 2.8 and 37.3 +/- 4.3 pM, and a maximal number of binding sites (Bmax) of 16.6 +/- 0.5, and 40.1 +/- 1.7 fmol mg-1 protein, respectively. 5. Comparison of the potency/affinity of the analogues for the binding sites gave a highly significant correlation in each case, retina/melanophore, r = 0.97 (P < 0.001, n = 17), PT/melanophore, r = 0.97 (P < 0.001, n = 17) and PT/retina, r = 0.98 (P < 0.001, n = 21). 6. Despite their large range in affinity and structural diversity these melatonin agonists were unable to distinguish between melatonin receptors in the chicken retina, sheep pars tuberalis and Xenopus melanophores. Images Figure 1 PMID:8886424

  10. Synthesis and high-throughput characterization of structural analogues of molecular glassformers: 1,3,5-trisarylbenzenes.

    PubMed

    Liu, Tianyi; Cheng, Kevin; Salami-Ranjbaran, Elmira; Gao, Feng; Glor, Ethan C; Li, Mu; Walsh, Patrick J; Fakhraai, Zahra

    2015-10-14

    We report the synthesis and characterization of an analogous series of small organic molecules derived from a well-known glass former, 1,3-bis(1-naphthyl)-5-(2-naphthyl)benzene (α,α,β-TNB). Synthesized molecules include α,α,β-TNB, 3,5-di(naphthalen-1-yl)-1-phenylbenzene (α,α-P), 9-(3,5-di(naphthalen-1-yl)phenyl)anthracene (α,α-A), 9,9'-(5-(naphthalen-2-yl)-1,3-phenylene)dianthracene (β-AA) and 3,3',5,5'-tetra(naphthalen-1-yl)-1,1'-biphenyl (α,α,α,α-TNBP). The design of molecules was based on increasing molecular weight with varied π-π interactions in one or more substituents. The synthesis is based on Suzuki cross-coupling of 1-bromo-3-chloro-5-iodobenzene with arylboronic acids, which allows attachment of various substituents to tailor the chemical structure. The bulk compounds were characterized using NMR spectroscopy and differential scanning calorimetry (DSC). Thin films of these compounds were produced using physical vapor deposition and were subsequently annealed above the glass transition temperatures (Tg). For each molecular glass, cooling rate-dependent glass transition temperature measurements (CR-Tg) were performed using ellipsometry as a high-throughput method to characterize thin film properties. CR-Tg allows rapid characterization of glassy properties, such as Tg, apparent thermal expansion coefficients, apparent activation energy at Tg and fragility. DSC measurements confirmed the general trend that increasing molecular weight leads to increasing melting point (Tm) and Tg. Furthermore, CR-Tg provided evidence that the introduction of stronger π-interacting substituents in the chosen set of structural analogues increases fragility and decreases the ability to form glasses, such that β-AA has the largest fragility and highest tendency to crystallize among all the compounds. These strong interactions also significantly elevate Tg and promote more harmonic intermolecular potentials, as observed by decreasing value of the apparent thermal expansion coefficient. PMID:26280737

  11. Structures of ceftazidime and its transition-state analogue in complex with AmpC beta-lactamase: Implications for resistance mutations and inhibitor design

    SciTech Connect

    Powers, R.A.; Caselli, E.; Focia, P.J.; Prati, F.; Shoichet, B.K.

    2010-03-08

    Third-generation cephalosporins are widely used {beta}-lactam antibiotics that resist hydrolysis by {beta}-lactamases. Recently, mutant {beta}-lactamases that rapidly inactivate these drugs have emerged. To investigate why third-generation cephalosporins are relatively stable to wild-type class C {beta}-lactamases and how mutant enzymes might overcome this, the structures of the class C {beta}-lactamase AmpC in complex with the third-generation cephalosporin ceftazidime and with a transition-state analogue of ceftazidime were determined by X-ray crystallography to 2.0 and 2.3 {angstrom} resolution, respectively. Comparison of the acyl-enzyme structures of ceftazidime and loracarbef, a {beta}-lactam substrate, reveals that the conformation of ceftazidime in the active site differs from that of substrates. Comparison of the structures of the acyl-enzyme intermediate and the transition-state analogue suggests that ceftazidime blocks formation of the tetrahedral transition state, explaining why it is an inhibitor of AmpC. Ceftazidime cannot adopt a conformation competent for catalysis due to steric clashes that would occur with conserved residues Val211 and Tyr221. The X-ray crystal structure of the mutant {beta}-lactamase GC1, which has improved activity against third-generation cephalosporins, suggests that a tandem tripeptide insertion in the {Omega} loop, which contains Val211, has caused a shift of this residue and also of Tyr221 that would allow ceftazidime and other third-generation cephalosporins to adopt a more catalytically competent conformation. These structural differences may explain the extended spectrum activity of GC1 against this class of cephalosporins. In addition, the complexed structure of the transition-state analogue inhibitor (K{sub i} 20 nM) with AmpC reveals potential opportunities for further inhibitor design.

  12. Purine Analogues as Kinase Inhibitors: A Review.

    PubMed

    Sharma, Sahil; Mehndiratta, Samir; Kumar, Sunil; Singh, Jagjeet; Bedi, Preet M S; Nepali, Kunal

    2015-01-01

    Protein kinases constitute one of the largest and most functionally diverse gene families that regulate key cell functions. In past several years, kinase inhibition has emerged as potential anti-cancer drug target. Purine is a priveleged heterocyclic nucleus which exists in the chemical architecture of various bioactive compounds. Numerous reports on the use of purine analogues in the treatment of acute leukemias (thiopurines, pentostatin), as antiviral (acyclovir, penciclovir, ganciclovir), as immunosuppressive (azathioprine), as antitumor (vidarabine), as bronchodilator (theophylline) have been revealed. In the past decade, purine analogues have emerged as significantly potent kinase inhibitors. A fair amount of research has been done and several patents have also been published highlighting the kinase inhibitory action of purines. Caffeine, 2-aminopurine, purvalanol-A, seleciclib, FSBA, adenosine thiol analogue possessing purine as the basic moiety fall under this category. In view of the use of purines for the inhibition of kinases, there is need for compilation of data specifying the prominence of purines in the treatment of cancer through this mechanism. The structure of the potent compounds, their IC50 values, models used and the enzymes/ receptors/ targets involved have been presented in this review. The present compilation covers the patents published entailing the purines as kinase inhibitors and the purine drugs employed in chemotherapy. PMID:26081925

  13. Modeling of the binding mode of a non-covalent inhibitor of the 20S proteasome. Application to structure-based analogue design.

    PubMed

    Furet, P; Imbach, P; Frst, P; Lang, M; Noorani, M; Zimmermann, J; Garca-Echeverria, C

    2001-05-21

    The 2-aminobenzvlstatine derivative I is a 20S proteasome inhibitor of a novel chemical type identified by high throughput screening. The compound specifically inhibits the chymotrypsin-like catalytic activity of the human proteasome with an IC50 value in the micromolar range. Using the crystal structure of the yeast proteasome, we modeled the structure of the human proteasome in complex with 1. As one of the first applications of the model in our oncology programme targeting the proteasome, we designed an analogue of the inhibitor having enhanced stacking/hydrophobic interactions with the enzyme. One order of magnitude in inhibitory potency was gained. PMID:11392546

  14. Structure-Based Design, Synthesis, Evaluation And Crystal Structures of Transition State Analogue Inhibitors of Inosine Monophosphate Cyclohydrolase

    SciTech Connect

    Xu, L.; Chong, Y.; Hwang, I.; D'Onofrio, A.; Amore, K.; Beardsley, G.P.; Li, C.; Olson, A.J.; Boger, D.L.; Wilson, I.A.; /Skaggs Inst. Chem. Biol. /Scripps Res. Inst. /Yale U.

    2007-07-13

    The inosine monophosphate cyclohydrolase (IMPCH) component (residues 1-199) of the bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase (AICAR Tfase, residues 200-593)/IMPCH (ATIC) catalyzes the final step in the de novo purine biosynthesis pathway that produces IMP. As a potential target for antineoplastic intervention, we designed IMPCH inhibitors, 1,5-dihydroimidazo[4,5-c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide (heterocycle, 1), the corresponding nucleoside (2), and the nucleoside monophosphate (nucleotide) (3), as mimics of the tetrahedral intermediate in the cyclization reaction. All compounds are competitive inhibitors against IMPCH (K(i) values = 0.13-0.23 microm) with the simple heterocycle 1 exhibiting the most potent inhibition (K(i) = 0.13 microm). Crystal structures of bifunctional ATIC in complex with nucleoside 2 and nucleotide 3 revealed IMPCH binding modes similar to that of the IMPCH feedback inhibitor, xanthosine 5'-monophosphate. Surprisingly, the simpler heterocycle 1 had a completely different IMPCH binding mode and was relocated to the phosphate binding pocket that was identified from previous xanthosine 5'-monophosphate structures. The aromatic imidazole ring interacts with a helix dipole, similar to the interaction with the phosphate moiety of 3. The crystal structures not only revealed the mechanism of inhibition of these compounds, but they now serve as a platform for future inhibitor improvements. Importantly, the nucleoside-complexed structure supports the notion that inhibitors lacking a negatively charged phosphate can still inhibit IMPCH activity with comparable potency to phosphate-containing inhibitors. Provocatively, the nucleotide inhibitor 3 also binds to the AICAR Tfase domain of ATIC, which now provides a lead compound for the design of inhibitors that simultaneously target both active sites of this bifunctional enzyme.

  15. Germananes: Germanium Graphane Analogues

    NASA Astrophysics Data System (ADS)

    Goldberger, Joshua

    2014-03-01

    Graphene's success has shown that it is not only possible to create stable, single-atom thick sheets from a crystalline solid, but that these materials have fundamentally different properties than the parent material. Our interest focuses on the synthesis and properties of Group IV graphane analogues. We have synthesized for the first time, mm-scale crystals of a hydrogen-terminated germanium multilayered graphane analogue (germanane, GeH) from the topochemical deintercalation of CaGe2. This layered van der Waals solid is analogous to multilayered graphane. The surface layer of GeH only slowly oxidizes in air over the span of five months, while the underlying layers are resilient to oxidation. We demonstrate that it is possible to covalently terminate the external surface with organic substituents to tune the electronic structure, and enhance the stability. These materials represent a new class of covalently terminated graphane analogues having great potential for a wide range of optoelectronic and sensing applications, especially since theory predicts a direct band gap of 1.53 eV and an electron mobility of 18,000 cm2/Vs which is five times higher than that of bulk Ge.

  16. The high-resolution crystal structure of phosphatidylinositol 4-kinase II? and the crystal structure of phosphatidylinositol 4-kinase II? containing a nucleoside analogue provide a structural basis for isoform-specific inhibitor design.

    PubMed

    Klima, Martin; Baumlova, Adriana; Chalupska, Dominika; H?ebabeck, Hubert; Dejmek, Milan; Nencka, Radim; Boura, Evzen

    2015-07-01

    Phosphatidylinositol 4-phosphate (PI4P) is the most abundant monophosphoinositide in eukaryotic cells. Humans have four phosphatidylinositol 4-kinases (PI4Ks) that synthesize PI4P, among which are PI4K II? and PI4K II?. In this study, two crystal structures are presented: the structure of human PI4K II? and the structure of PI4K II? containing a nucleoside analogue. The former, a complex with ATP, is the first high-resolution (1.9?) structure of a PI4K. These structures reveal new details such as high conformational heterogeneity of the lateral hydrophobic pocket of the C-lobe and together provide a structural basis for isoform-specific inhibitor design. PMID:26143926

  17. Erythrocyte membrane modifying agents and the inhibition of Plasmodium falciparum growth: structure-activity relationships for betulinic acid analogues.

    PubMed

    Ziegler, Hanne L; Franzyk, Henrik; Sairafianpour, Majid; Tabatabai, Mehrnoush; Tehrani, Mahboubeh D; Bagherzadeh, Karim; Hgerstrand, Henry; Staerk, Dan; Jaroszewski, Jerzy W

    2004-01-01

    The natural triterpene betulinic acid and its analogues (betulinic aldehyde, lupeol, betulin, methyl betulinate and betulinic acid amide) caused concentration-dependent alterations of erythrocyte membrane shape towards stomatocytes or echinocytes according to their hydrogen bonding properties. Thus, the analogues with a functional group having a capacity of donating a hydrogen bond (COOH, CH(2)OH, CONH(2)) caused formation of echinocytes, whereas those lacking this ability (CH(3), CHO, COOCH(3)) induced formation of stomatocytes. Both kinds of erythrocyte alterations were prohibitive with respect to Plasmodium falciparum invasion and growth; all compounds were inhibitory with IC(50) values in the range 7-28 microM, and the growth inhibition correlated well with the extent of membrane curvature changes assessed by transmission electron microscopy. Erythrocytes pre-loaded with betulinic acid or its analogues and extensively washed in order to remove excess of the chemicals could not serve as hosts for P. falciparum parasites. Betulinic acid and congeners can be responsible for in vitro antiplasmodial activity of plant extracts, as shown for Zataria multiflora Boiss. (Labiatae) and Zizyphus vulgaris Lam. (Rhamnaceae). The activity is evidently due to the incorporation of the compounds into the lipid bilayer of erythrocytes, and may be caused by modifications of cholesterol-rich membrane rafts, recently shown to play an important role in parasite vacuolization. The established link between erythrocyte membrane modifications and antiplasmodial activity may provide a novel target for potential antimalarial drugs. PMID:14697777

  18. Raman spectroscopic characterisations and analytical discrimination between caffeine and demethylated analogues of pharmaceutical relevance

    NASA Astrophysics Data System (ADS)

    Edwards, H. G. M.; Munshi, T.; Anstis, M.

    2005-05-01

    The FT Raman spectrum of caffeine was analysed along with that of its demethylated analogues, theobromine and theophylline. The similar but not identical structures of these three compounds allowed a more detailed assignment of the Raman bands. Noticeable differences in the Raman spectra of these compounds were apparent and key marker bands have been identified for the spectroscopic identification of these three compounds.

  19. Analysis of PUGNAc and NAG-thiazoline as transition state analogues for human O-GlcNAcase: mechanistic and structural insights into inhibitor selectivity and transition state poise.

    PubMed

    Whitworth, Garrett E; Macauley, Matthew S; Stubbs, Keith A; Dennis, Rebecca J; Taylor, Edward J; Davies, Gideon J; Greig, Ian R; Vocadlo, David J

    2007-01-24

    O-GlcNAcase catalyzes the cleavage of beta-O-linked 2-acetamido-2-deoxy-beta-d-glucopyranoside (O-GlcNAc) from serine and threonine residues of post-translationally modified proteins. Two potent inhibitors of this enzyme are O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc) and 1,2-dideoxy-2'-methyl-alpha-d-glucopyranoso[2,1-d]-Delta2'-thiazoline (NAG-thiazoline). Derivatives of these inhibitors differ in their selectivity for human O-GlcNAcase over the functionally related human lysosomal beta-hexosamindases, with PUGNAc derivatives showing modest selectivities and NAG-thiazoline derivatives showing high selectivities. The molecular basis for this difference in selectivities is addressed as is how well these inhibitors mimic the O-GlcNAcase-stabilized transition state (TS). Using a series of substrates, ground state (GS) inhibitors, and transition state mimics having analogous structural variations, we describe linear free energy relationships of log(KM/kcat) versus log(KI) for PUGNAc and NAG-thiazoline. These relationships suggest that PUGNAc is a poor transition state analogue, while NAG-thiazoline is revealed as a transition state mimic. Comparative X-ray crystallographic analyses of enzyme-inhibitor complexes reveal subtle molecular differences accounting for the differences in selectivities between these two inhibitors and illustrate key molecular interactions. Computational modeling of species along the reaction coordinate, as well as PUGNAc and NAG-thiazoline, provide insight into the features of NAG-thiazoline that resemble the transition state and reveal where PUGNAc fails to capture significant binding energy. These studies also point to late transition state poise for the O-GlcNAcase catalyzed reaction with significant nucleophilic participation and little involvement of the leaving group. The potency of NAG-thiazoline, its transition state mimicry, and its lack of traditional transition state-like design features suggest that potent rationally designed glycosidase inhibitors can be developed that exploit variation in transition state poise. PMID:17227027

  20. Preliminary results of a multi-scale structural analisys in an analogue carbonate reservoir (Hyblean Plateau, Sicily, Italy)

    NASA Astrophysics Data System (ADS)

    Cilona, Antonino; Agosta, Fabrizio; Criscenti, Alessandro; Dipasquale, Mario; Giunta, Giuseppe; Napoli, Giuseppe; Occhipinti, Rosario; Renda, Pietro; Tondi, Emanuele

    2010-05-01

    With the aim of studying the multi-scale fault architecture and permeability in hydrocarbon-rich porous carbonate rocks, we are currently involved in a project focused on the structural analysis of fractured and faulted platform-to-ramp carbonates cropping out in the Hyblean Plateau (Sicily, Italy). The Hyblean Plateau is part of the Maghrebian foreland and forms the northern portion of the African plate. The plateau is a NE-oriented structural high crosscut by a large-scale N10-20E oriented strike-slip fault system, named Scicli-Ragusa, which was affected by right-lateral kinematics during the Upper Miocene-Lower Pliocene. Some authors documented a recent activity of the Scicli-Ragusa fault system, during the Quaternary, characterized by left-lateral kinematics. The portion of the Hyblean Plateau crosscut by this fault system represents an excellent example of an outcropping analogue of a fractured carbonate reservoir. By taking advantage of the several oil shows located along the Scicli-Ragusa fault system, we combine stratigraphic-structural analyses, both at outcrop and microscopic scales, to assess the structural control exerted by faults and fractures on hydrocarbon migration and storage. The field work focused on the geological mapping, at 1:10.000 scale, on detailed stratigraphic characterization of the outcropping layered carbonates (Ragusa Fm.) and on traditional faults and fractures analysis. Sample collection was also performed in order to conduct, in the laboratory, optical microscope and image analyses. The Oligo-Miocenic Ragusa Fm. is comprised of two main members: i) the lower Leonardo Member, which is characterised by well-cemented carbonate packstones intercalated with marl-rich levels; ii) the upper Irminio Member, characterised by an alternation of well-cemented and poorly-cemented grainstones/packstones. According to both orientations and kinematics, we grouped the fault segments of the Scicli-Ragusa fault system into three major sets: (i) NNE-striking faults with predominant right-lateral kinematics, (ii) ENE-striking faults with left-lateral kinematics, and (iii) NE-striking faults characterized by normal slip. Conversely, based on the fault attributes we subdivided the outcropping faults into four main categories: (i) Major faults, comprised of well-developed fault cores (made up of cataclastic rocks and main slip surfaces) flanked by thicker fault damage zones, which are up to 18 km-long and have throws in the order of 100's of meters. (ii) Medium faults containing thin and discontinuous fault cores of brecciated and cataclastic fault rocks and through-going slip surfaces encompassed within the fault damage zones, which are long up to several 100's of meters and have throws up to 10's of meters. (iii) Small faults made up of isolated and discontinuous fault cores of faults breccias and through-going slip surfaces, which are up to a few m-long and have throws in order of several 10's of cm and a few meters. (iv) Incipient faults consist, predominantly, of sheared pre-existing fractures confined within the individual carbonate beds; the maximum throw < 10 cm. The meso-structural analysis performed to define the background deformation allowed us to identify mainly three different typology of structures: i) joints, ii) stylolites, and iii) shear bands. On the basis of their abutting relationships first originated bed-parallel stylolites and then two coeval sets of bed perpendicular joints. Shear bands nucleated by shearing of previously formed bed-parallel and bed-perpendicular structures. Another important data came out from preliminary microscope analysis carried out within mines of tar rich carbonates. Here, shear bands within porous layers behaved as a seal for oil migration whereas joints, localized in well cemented layers, acted as conduct for hydrocarbons. Finally, as planned work, we are going to combine fault architecture data with petrophysical analyses conducted on samples belonging to different structural domains in order to define hydraulic behaviours of the studied faults.

  1. Optoelectronic Smart Structure Interface - A key development for practical smart structures

    NASA Astrophysics Data System (ADS)

    Measures, Raymond M.; Alavie, Tino; Liu, Kexing; Melle, Serge

    1993-03-01

    The development of an Optoelectronic Smart Structure Interface (OSSI) will be required for the practical implementation of Smart Structure Technology. Such an interface will permit an extremely user-friendly interconnection to any Smart Structure component permitting the optical signals from an embedded optical fiber sensor array to be transmitted from the structure in a form most acceptable for that specific application. We have developed a simple, passive, fast response wavelength demodulation system for intracore Bragg grating sensors and have demonstrated real time strain measurements. Currently, we are exploring the use of this wavelength demodulation system with Bragg grating tuned fiber laser sensors and intend to show that such a system can form the basis of an OSSI.

  2. Phytoplankton community structure defined by key environmental variables in Tagus estuary, Portugal.

    PubMed

    Brogueira, Maria Jos; Oliveira, Maria do Rosrio; Cabeadas, Graa

    2007-12-01

    In this work, we analyze environmental (physical and chemical) and biological (phytoplankton) data obtained along Tagus estuary during three surveys, carried out in productive period (May/June/July) at ebb tide. The main objective of this study was to identify the key environmental factors affecting phytoplankton structure in the estuary. BIOENV analysis revealed that, in study period, temperature, salinity, silicate and total phosphorus were the variables that best explained the phytoplankton spatial pattern in the estuary (Spearman correlation, rho=0.803). A generalized linear model (GLM) also identified salinity, silicate and phosphate as having a high explanatory power (63%) of phytoplankton abundance. These selected nutrients appear to be consistent with the requirements of the dominant phytoplankton group, Baccilariophyceae. Apparently, phytoplankton community is adapted to fluctuations in light intensity, as suspended particulate matter did not come out as a key factor in shaping phytoplankton structure along Tagus estuary. PMID:17884159

  3. One-step separation of nine structural analogues from Poria cocos (Schw.) Wolf. via tandem high-speed counter-current chromatography.

    PubMed

    Zeng, Hualiang; Liu, Qi; Yu, Jingang; Jiang, Xinyu; Wu, Zhiliang; Wang, Meiling; Chen, Miao; Chen, Xiaoqing

    2015-11-01

    A novel one-step separation strategy-tandem high-speed counter-current chromatography (HSCCC) was developed with a six-port valve serving as the switch interface. Nine structural analogues including three isomers were successfully isolated from Poria cocos (Schw.) Wolf. by one step. Compared with conventional HSCCC, peak resolution of target compounds was effectively improved in tandem one. Purities of isolated compounds were all over 90% as determined by HPLC. Their structures were then identified via UV, MS and (1)H NMR, and eventually assigned as poricoic acid B (1), poricoic acid A (2), 3β,16α-dihydroxylanosta-7, 9(11), 24-trien-21-oic acid (3), dehydrotumulosic acid (4), polyporenic acid C (5), 3-epi-dehydrotumulosic acid (6), 3-o-acetyl-16α-hydroxydehydrotrametenolic acid (7), dehydropachymic acid (8) and dehydrotrametenolic acid (9) respectively. The results indicated that tandem HSCCC can effectively improve peak resolution of target compounds, and can be a good candidate for HSCCC separation of structural analogues. PMID:26435185

  4. Antitrypanosomal and antileishmanial activities of flavonoids and their analogues: in vitro, in vivo, structure-activity relationship, and quantitative structure-activity relationship studies.

    PubMed

    Tasdemir, Deniz; Kaiser, Marcel; Brun, Reto; Yardley, Vanessa; Schmidt, Thomas J; Tosun, Fatma; Redi, Peter

    2006-04-01

    Trypanosomiasis and leishmaniasis are important parasitic diseases affecting millions of people in Africa, Asia, and South America. In a previous study, we identified several flavonoid glycosides as antiprotozoal principles from a Turkish plant. Here we surveyed a large set of flavonoid aglycones and glycosides, as well as a panel of other related compounds of phenolic and phenylpropanoid nature, for their in vitro activities against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani. The cytotoxicities of more than 100 compounds for mammalian L6 cells were also assessed and compared to their antiparasitic activities. Several compounds were investigated in vivo for their antileishmanial and antitrypanosomal efficacies in mouse models. Overall, the best in vitro trypanocidal activity for T. brucei rhodesiense was exerted by 7,8-dihydroxyflavone (50% inhibitory concentration [IC50], 68 ng/ml), followed by 3-hydroxyflavone, rhamnetin, and 7,8,3',4'-tetrahydroxyflavone (IC50s, 0.5 microg/ml) and catechol (IC50, 0.8 microg/ml). The activity against T. cruzi was moderate, and only chrysin dimethylether and 3-hydroxydaidzein had IC50s less than 5.0 microg/ml. The majority of the metabolites tested possessed remarkable leishmanicidal potential. Fisetin, 3-hydroxyflavone, luteolin, and quercetin were the most potent, giving IC50s of 0.6, 0.7, 0.8, and 1.0 microg/ml, respectively. 7,8-Dihydroxyflavone and quercetin appeared to ameliorate parasitic infections in mouse models. Generally, the test compounds lacked cytotoxicity in vitro and in vivo. By screening a large number of flavonoids and analogues, we were able to establish some general trends with respect to the structure-activity relationship, but it was not possible to draw clear and detailed quantitative structure-activity relationships for any of the bioactivities by two different approaches. However, our results can help in directing the rational design of 7,8-dihydroxyflavone and quercetin derivatives as potent and effective antiprotozoal agents. PMID:16569852

  5. Lactam-stabilized helical analogues of the analgesic ?-conotoxin KIIIA

    PubMed Central

    Khoo, Keith K.; Wilson, Michael J.; Smith, Brian J.; Zhang, Min-Min; Gulyas, Joszef; Yoshikami, Doju; Rivier, Jean E.; Bulaj, Grzegorz; Norton, Raymond S.

    2011-01-01

    ?-Conotoxin KIIIA (?-KIIIA) blocks mammalian voltage-gated sodium channels (VGSCs) and is a potent analgesic following systemic administration in mice. Previous structure-activity studies of ?-KIIIA identified a helical pharmacophore for VGSC blockade. This suggested a route for designing truncated analogues of ?-KIIIA by incorporating the key residues into an ?-helical scaffold. As (i, i+4) lactam bridges constitute a proven approach for stabilizing ?-helices, we designed and synthesized six truncated analogues of ?-KIIIA containing single lactam bridges at various locations. The helicity of these lactam analogues was analysed by NMR spectroscopy, and their activities were tested against mammalian VGSC subtypes NaV1.1 through 1.7. Two of the analogues, Ac-cyclo9/13[Asp9,Lys13]KIIIA714 and Ac-cyclo9/13[Lys9,Asp13]KIIIA714, displayed M activity against VGSC subtypes NaV1.2 and NaV1.6; importantly, the subtype selectivity profile for these peptides matched that of ?-KIIIA. Our study highlights structure-activity relationships within these helical mimetics and provides a basis for the design of additional truncated peptides as potential analgesics. PMID:21962108

  6. OptZyme: Computational Enzyme Redesign Using Transition State Analogues

    PubMed Central

    Grisewood, Matthew J.; Gifford, Nathanael P.; Pantazes, Robert J.; Li, Ye; Cirino, Patrick C.; Janik, Michael J.; Maranas, Costas D.

    2013-01-01

    OptZyme is a new computational procedure for designing improved enzymatic activity (i.e., kcat or kcat/KM) with a novel substrate. The key concept is to use transition state analogue compounds, which are known for many reactions, as proxies for the typically unknown transition state structures. Mutations that minimize the interaction energy of the enzyme with its transition state analogue, rather than with its substrate, are identified that lower the transition state formation energy barrier. Using Escherichia coli ?-glucuronidase as a benchmark system, we confirm that KM correlates (R2?=?0.960) with the computed interaction energy between the enzyme and the para-nitrophenyl- ?, D-glucuronide substrate, kcat/KM correlates (R2?=?0.864) with the interaction energy of the transition state analogue, 1,5-glucarolactone, and kcat correlates (R2?=?0.854) with a weighted combination of interaction energies with the substrate and transition state analogue. OptZyme is subsequently used to identify mutants with improved KM, kcat, and kcat/KM for a new substrate, para-nitrophenyl- ?, D-galactoside. Differences between the three libraries reveal structural differences that underpin improving KM, kcat, or kcat/KM. Mutants predicted to enhance the activity for para-nitrophenyl- ?, D-galactoside directly or indirectly create hydrogen bonds with the altered sugar ring conformation or its substituents, namely H162S, L361G, W549R, and N550S. PMID:24116038

  7. Strong Nonadditivity as a Key StructureActivity Relationship Feature: Distinguishing Structural Changes from Assay Artifacts

    PubMed Central

    2015-01-01

    Nonadditivity in proteinligand affinity data represents highly instructive structureactivity relationship (SAR) features that indicate structural changes and have the potential to guide rational drug design. At the same time, nonadditivity is a challenge for both basic SAR analysis as well as many ligand-based data analysis techniques such as Free-Wilson Analysis and Matched Molecular Pair analysis, since linear substituent contribution models inherently assume additivity and thus do not work in such cases. While structural causes for nonadditivity have been analyzed anecdotally, no systematic approaches to interpret and use nonadditivity prospectively have been developed yet. In this contribution, we lay the statistical framework for systematic analysis of nonadditivity in a SAR series. First, we develop a general metric to quantify nonadditivity. Then, we demonstrate the non-negligible impact of experimental uncertainty that creates apparent nonadditivity, and we introduce techniques to handle experimental uncertainty. Finally, we analyze public SAR data sets for strong nonadditivity and use recourse to the original publications and available X-ray structures to find structural explanations for the nonadditivity observed. We find that all cases of strong nonadditivity (??pKi and ??pIC50 > 2.0 log units) with sufficient structural information to generate reasonable hypothesis involve changes in binding mode. With the appropriate statistical basis, nonadditivity analysis offers a variety of new attempts for various areas in computer-aided drug design, including the validation of scoring functions and free energy perturbation approaches, binding pocket classification, and novel features in SAR analysis tools. PMID:25760829

  8. Concise synthesis of ricciocarpin A and discovery of a more potent analogue.

    PubMed

    Michrowska, Anna; List, Benjamin

    2009-06-01

    Cascade reactions enable the rapid build-up of molecular complexity from relatively simple starting materials. Both rapid construction and the ability to prepare related structures are crucial to the study of biological activities. Here, we report an efficient, highly enantioselective and diastereoselective total synthesis of ricciocarpin A. The key feature of the synthesis is a one-pot, three-step, organocatalytic reductive Michael-Tishchenko cascade. The conciseness and flexibility of this approach not only resulted in the synthesis of the natural product, but also of its antipode and four other structural analogues. A preliminary biological evaluation of these compounds identified an analogue with significantly improved molluscicidal activity. PMID:21378852

  9. Crystal structure of Streptococcus pneumoniae pneumolysin provides key insights into early steps of pore formation

    PubMed Central

    Lawrence, Sara L.; Feil, Susanne C.; Morton, Craig J.; Farrand, Allison J.; Mulhern, Terrence D.; Gorman, Michael A.; Wade, Kristin R.; Tweten, Rodney K.; Parker, Michael W.

    2015-01-01

    Pore-forming proteins are weapons often used by bacterial pathogens to breach the membrane barrier of target cells. Despite their critical role in infection important structural aspects of the mechanism of how these proteins assemble into pores remain unknown. Streptococcus pneumoniae is the worlds leading cause of pneumonia, meningitis, bacteremia and otitis media. Pneumolysin (PLY) is a major virulence factor of S. pneumoniae and a target for both small molecule drug development and vaccines. PLY is a member of the cholesterol-dependent cytolysins (CDCs), a family of pore-forming toxins that form gigantic pores in cell membranes. Here we present the structure of PLY determined by X-ray crystallography and, in solution, by small-angle X-ray scattering. The crystal structure reveals PLY assembles as a linear oligomer that provides key structural insights into the poorly understood early monomer-monomer interactions of CDCs at the membrane surface. PMID:26403197

  10. Crystal structure of Streptococcus pneumoniae pneumolysin provides key insights into early steps of pore formation.

    PubMed

    Lawrence, Sara L; Feil, Susanne C; Morton, Craig J; Farrand, Allison J; Mulhern, Terrence D; Gorman, Michael A; Wade, Kristin R; Tweten, Rodney K; Parker, Michael W

    2015-01-01

    Pore-forming proteins are weapons often used by bacterial pathogens to breach the membrane barrier of target cells. Despite their critical role in infection important structural aspects of the mechanism of how these proteins assemble into pores remain unknown. Streptococcus pneumoniae is the world's leading cause of pneumonia, meningitis, bacteremia and otitis media. Pneumolysin (PLY) is a major virulence factor of S. pneumoniae and a target for both small molecule drug development and vaccines. PLY is a member of the cholesterol-dependent cytolysins (CDCs), a family of pore-forming toxins that form gigantic pores in cell membranes. Here we present the structure of PLY determined by X-ray crystallography and, in solution, by small-angle X-ray scattering. The crystal structure reveals PLY assembles as a linear oligomer that provides key structural insights into the poorly understood early monomer-monomer interactions of CDCs at the membrane surface. PMID:26403197

  11. Synthesis of cyclic N 1-pentylinosine phosphate, a new structurally reduced cADPR analogue with calcium-mobilizing activity on PC12 cells

    PubMed Central

    Borbone, Nicola; Pinto, Brunella; Secondo, Agnese; Costantino, Valeria; Tedeschi, Valentina; Piccialli, Vincenzo; Piccialli, Gennaro

    2015-01-01

    Summary Cyclic N 1-pentylinosine monophosphate (cpIMP), a novel simplified inosine derivative of cyclic ADP-ribose (cADPR) in which the N 1-pentyl chain and the monophosphate group replace the northern ribose and the pyrophosphate moieties, respectively, was synthesized. The role played by the position of the phosphate group in the key cyclization step, which consists in the formation of a phosphodiester bond, was thoroughly investigated. We have also examined the influence of the phosphate bridge on the ability of cpIMP to mobilize Ca2+ in PC12 neuronal cells in comparison with the pyrophosphate bridge present in the cyclic N 1-pentylinosine diphosphate analogue (cpIDP) previously synthesized in our laboratories. The preliminary biological tests indicated that cpIMP and cpIDP induce a rapid increase of intracellular Ca2+ concentration in PC12 neuronal cells. PMID:26877790

  12. Comparison of three development approaches for Stationary Phase Optimised Selectivity Liquid Chromatography based screening methods Part II: A group of structural analogues (PDE-5 inhibitors in food supplements).

    PubMed

    Deconinck, E; Ghijs, L; Kamugisha, A; Courselle, P

    2016-02-01

    Three approaches for the development of a screening method to detect adulterated dietary supplements, based on Stationary Phase Optimised Selectivity Liquid Chromatography were compared for their easiness/speed of development and the performance of the optimal method obtained. This comparison was performed for a heterogeneous group of molecules, i.e. slimming agents (Part I) and a group of structural analogues, i.e. PDE-5 inhibitors (Part II). The first approach makes use of primary runs at one isocratic level, the second of primary runs in gradient mode and the third of primary runs at three isocratic levels to calculate the optimal combination of segments of stationary phases. In each approach the selection of the stationary phase was followed by a gradient optimisation. For the PDE-5 inhibitors, the group of structural analogues, only the method obtained with the third approach was able to differentiate between all the molecules in the development set. Although not all molecules are baseline separated, the method allows the identification of the selected adulterants in dietary supplements using only diode array detection. Though, due to the mobile phases used, the method could also be coupled to mass spectrometry. The method was validated for its selectivity following the guidelines as described for the screening of pesticide residues and residues of veterinary medicines in food. PMID:26653459

  13. The crystal structure of an isopenicillin N synthase complex with an ethereal substrate analogue reveals water in the oxygen binding site.

    PubMed

    Clifton, Ian J; Ge, Wei; Adlington, Robert M; Baldwin, Jack E; Rutledge, Peter J

    2013-08-19

    Isopenicillin N synthase (IPNS) is a non-heme iron oxidase central to the biosynthesis of ?-lactam antibiotics. IPNS converts the tripeptide ?-(L-?-aminoadipoyl)-L-cysteinyl-D-valine (ACV) to isopenicillin N while reducing molecular oxygen to water. The substrate analogue ?-(L-?-aminoadipoyl)-L-cysteinyl-O-methyl-D-threonine (ACmT) is not turned over by IPNS. Epimeric ?-(L-?-aminoadipoyl)-L-cysteinyl-O-methyl-D-allo-threonine (ACmaT) is converted to a bioactive penam product. ACmT and ACmaT differ from each other only in the stereochemistry at the ?-carbon atom of their third residue. These substrates both contain a methyl ether in place of the isopropyl group of ACV. We report an X-ray crystal structure for the anaerobic IPNS:Fe(II):ACmT complex. This structure reveals an additional water molecule bound to the active site metal, held by hydrogen-bonding to the ether oxygen atom of the substrate analogue. PMID:23860486

  14. One pot synthesis, structural and spectral analysis of some symmetrical curcumin analogues catalyzed by calcium oxide under microwave irradiation

    NASA Astrophysics Data System (ADS)

    Elavarasan, S.; Bhakiaraj, D.; Chellakili, B.; Elavarasan, T.; Gopalakrishnan, M.

    2012-11-01

    A series of sixteen number of curcumin analogues have been synthesized under microwave irradiation using calcium oxide as a catalyst. The synthesized compounds have been characterized using FT-IR, MS, elemental analysis, 1H and 13C NMR spectroscopic techniques. The UV-Vis absorption studies for these compounds have been studied in order to provide the electronic transitions taking place in the molecule. When compared to the curcumin ((1E,4Z,6E)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-trien-3-one), the absorption maxima, ?max for all the synthesized curcumin analogues with a variety of substituents gets blue shifted i.e., hypsochromic shift was observed. This shift may be assigned to the change of dipole moment within the solvated molecule. Theoretical calculations regarding the optimization of the synthesized molecules, electronic properties like highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) and mapped electron density surface diagrams were done. The geometrical energy, dipole moments and heat of formation values have also been calculated using the ArgusLab package by AM1 semi-empirical method.

  15. Structurally modified analogues of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) as future antidiabetic agents.

    PubMed

    Green, Brian D; Gault, Victor A; O'harte, Finbarr P M; Flatt, Peter R

    2004-01-01

    Glucagon-like peptide-1(7-36)amide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal insulin-releasing hormones involved in the regulation of postprandial nutrient homeostasis. These two incretin hormones are glucose-dependent stimulators of pancreatic beta-cell function, exhibiting a spectrum of secondary extrapancreatic activities, which favour the efficient control of blood glucose homeostasis. Such actions of GLP-1 and GIP have generated considerable interest in their possible exploitation as novel agents for the treatment of type 2 diabetes. Despite the many attributes of GLP-1 and GIP as possible future antidiabetic agents, their rapid degradation in the circulation by dipeptidyl peptidase IV (DPP IV) to inactive truncated forms GLP-1(9-36)amide and GIP(3-42), severely limits their therapeutic usefulness. This review will consider recent developments in the design and effectiveness of synthetic DPP IV-resistant analogues of GLP-1 and GIP. Consideration will be given to the effects of N-terminal modification and amino acid substitution of GLP-1 and GIP either side of the DPP IV cleavage site on (i) susceptibility to enzymatic degradation, (ii) binding to native hormone receptor, (iii) ability to elevate intracellular cyclic AMP, (iv) potency as insulin secretagogues, and (v) antihyperglycaemic activity in type 2 diabetes. It will be shown that structural modification can produce a varied set of biological activities, ranging from more efficacious analogues to those which antagonise the activity of the native hormone. The antidiabetic properties of the best GLP-1 and GIP analogues indeed promise to provide the basis for novel, effective and long-acting drugs for type 2 diabetes therapy. This approach is currently being pursued actively by the pharmaceutical industry. PMID:15579061

  16. An optimized structure on FPGA of key point description in SIFT algorithm

    NASA Astrophysics Data System (ADS)

    Xu, Chenyu; Peng, Jinlong; Zhu, En; Zou, Yuxin

    2015-12-01

    SIFT algorithm is one of the most significant and effective algorithms to describe the features of image in the field of image matching. To implement SIFT algorithm to hardware environment is apparently considerable and difficult. In this paper, we mainly discuss the realization of Key Point Description in SIFT algorithm, along with Matching process. In Key Point Description, we have proposed a new method of generating histograms, to avoid the rotation of adjacent regions and insure the rotational invariance. In Matching, we replace conventional Euclidean distance with Hamming distance. The results of the experiments fully prove that the structure we propose is real-time, accurate, and efficient. Future work is still needed to improve its performance in harsher conditions.

  17. Effect of inherited structures on strike-slip plate boundaries: insight from analogue modelling of the central Levant Fracture System, Lebanon

    NASA Astrophysics Data System (ADS)

    Ghalayini, Ramadan; Daniel, Jean-Marc; Homberg, Catherine; Nader, Fadi

    2015-04-01

    Analogue sandbox modeling is a tool to simulate deformation style and structural evolution of sedimentary basins. The initial goal is to test what is the effect of inherited and crustal structures on the propagation, evolution, and final geometry of major strike-slip faults at the boundary between two tectonic plates. For this purpose, we have undertaken a series of analogue models to validate and reproduce the structures of the Levant Fracture System, a major NNE-SSW sinistral strike-slip fault forming the boundary between the Arabian and African plates. Onshore observations and recent high quality 3D seismic data in the Levant Basin offshore Lebanon demonstrated that Mesozoic ENE striking normal faults were reactivated into dextral strike-slip faults during the Late Miocene till present day activity of the plate boundary which shows a major restraining bend in Lebanon with a ~ 30°clockwise rotation in its trend. Experimental parameters consisted of a silicone layer at the base simulating the ductile crust, overlain by intercalated quartz sand and glass sand layers. Pre-existing structures were simulated by creating a graben in the silicone below the sand at an oblique (>60°) angle to the main throughgoing strike-slip fault. The latter contains a small stepover at depth to create transpression during sinistral strike-slip movement and consequently result in mountain building similarly to modern day Lebanon. Strike-slip movement and compression were regulated by steady-speed computer-controlled engines and the model was scanned using a CT-scanner continuously while deforming to have a final 4D model of the system. Results showed that existing normal faults were reactivated into dextral strike-slip faults as the sinistral movement between the two plates accumulated. Notably, the resulting restraining bend is asymmetric and segmented into two different compartments with differing geometries. One compartment shows a box fold anticline, while the second shows an asymmetric anticline. Thus, analogue modeling has validated observation in seismic data and onshore geology whereby Mount Lebanon and adjacent folds exhibit similar compartmentalization and geometric dissimilarities along the Levant Fracture System. We suggest that the presence of inherited structures will affect to a certain extent the geometry of restraining bends and control the evolution of large strike-slip faults passing through.

  18. Asymmetric Total Synthesis of (+)- and ent-(−)-Yatakemycin and Duocarmycin SA: Evaluation of Yatakemycin Key Partial Structures and its Unnatural Enantiomer

    PubMed Central

    Tichenor, Mark S.; Trzupek, John D.; Kastrinsky, David B.; Shiga, Futoshi; Hwang, Inkyu; Boger, Dale L.

    2008-01-01

    Complementary to studies that provided the first yatakemycin total synthesis resulting in its structure revision and absolute stereochemistry assignment, a second generation asymmetric total synthesis is disclosed herein. Since the individual yatakemycin subunits are identical to those of duocarmycin SA (alkylation subunit) or CC-1065 (central and right-hand subunits), the studies also provide an improvement in our earlier total synthesis of CC-1065 and, as detailed herein, have been extended to an asymmetric total synthesis of (+)-duocarmycin SA. Further extensions of the studies provided key yatakemycin partial structures and analogues for comparative assessments. This included the definition of the DNA selectivity (adenine central to a five base-pair AT sequence, eg. 5′-AAAAA), efficiency, relative rate, and reversibility of ent-(−)-yatakemycin and its comparison with the natural enantiomer (identical selectivity and efficiency), structural characterization of the adenine N3 adduct confirming the nature of the DNA reaction, and comparisons of the cytotoxic activity of the natural product (L1210 IC50 = 5 pM) with its unnatural enantiomer (IC50 = 5 pM) and a series of key partial structures including those that probe the role of the C-terminus thiomethyl ester. The only distinguishing features between the enantiomers is that ent-(−)-yatakemycin alkylates DNA at a slower rate (krel = 0.13) and is reversible, whereas (+)-yatakemycin is not. Nonetheless, even ent-(−)-yatakemycin alkylates DNA at a faster rate and with a greater thermodynamic stability than (+)-duocarmycin SA illustrating the unique characteristics of such “sandwiched” agents. PMID:17147378

  19. Issues of geologically-focused situational awareness in robotic planetary missions: Lessons from an analogue mission at Mistastin Lake impact structure, Labrador, Canada

    NASA Astrophysics Data System (ADS)

    Antonenko, I.; Osinski, G. R.; Battler, M.; Beauchamp, M.; Cupelli, L.; Chanou, A.; Francis, R.; Mader, M. M.; Marion, C.; McCullough, E.; Pickersgill, A. E.; Preston, L. J.; Shankar, B.; Unrau, T.; Veillette, D.

    2013-07-01

    Remote robotic data provides different information than that obtained from immersion in the field. This significantly affects the geological situational awareness experienced by members of a mission control science team. In order to optimize science return from planetary robotic missions, these limitations must be understood and their effects mitigated to fully leverage the field experience of scientists at mission control.Results from a 13-day analogue deployment at the Mistastin Lake impact structure in Labrador, Canada suggest that scale, relief, geological detail, and time are intertwined issues that impact the mission control science team's effectiveness in interpreting the geology of an area. These issues are evaluated and several mitigation options are suggested. Scale was found to be difficult to interpret without the reference of known objects, even when numerical scale data were available. For this reason, embedding intuitive scale-indicating features into image data is recommended. Since relief is not conveyed in 2D images, both 3D data and observations from multiple angles are required. Furthermore, the 3D data must be observed in animation or as anaglyphs, since without such assistance much of the relief information in 3D data is not communicated. Geological detail may also be missed due to the time required to collect, analyze, and request data.We also suggest that these issues can be addressed, in part, by an improved understanding of the operational time costs and benefits of scientific data collection. Robotic activities operate on inherently slow time-scales. This fact needs to be embraced and accommodated. Instead of focusing too quickly on the details of a target of interest, thereby potentially minimizing science return, time should be allocated at first to more broad data collection at that target, including preliminary surveys, multiple observations from various vantage points, and progressively smaller scale of focus. This operational model more closely follows techniques employed by field geologists and is fundamental to the geologic interpretation of an area. Even so, an operational time cost/benefit analyses should be carefully considered in each situation, to determine when such comprehensive data collection would maximize the science return.Finally, it should be recognized that analogue deployments cannot faithfully model the time scales of robotic planetary missions. Analogue missions are limited by the difficulty and expense of fieldwork. Thus, analogue deployments should focus on smaller aspects of robotic missions and test components in a modular way (e.g., dropping communications constraints, limiting mission scope, focusing on a specific problem, spreading the mission over several field seasons, etc.).

  20. Structure-binding relationships for the interaction between a vancomycin monoclonal antibody Fab fragment and a library of vancomycin analogues and tracers.

    PubMed

    Adamczyk, M; Grote, J; Moore, J A; Rege, S D; Yu, Z

    1999-01-01

    A series of vancomycin analogues and tracers were synthesized, and their binding interactions with an anti-vancomycin Fab fragment were evaluated under mass transport limiting conditions using surface plasmon resonance detection. Differences observed in binding interactions were utilized to define the vancomycin structural elements critical for antibody recognition. Major structural regions of vancomycin shown to play an important role in anti-vancomycin Fab fragment recognition include two sugar moieties and one chlorinated phenyl ring. The N-methylleucyl residue, the carboxy terminal residue, and residues in the peptide-binding region of vancomycin have minimal impact on the anti-vancomycin Fab fragment/vancomycin binding interaction. The selection of an antibody with such binding properties plays a critical role in the development of a vancomycin immunoassay that employs stable calibrators and controls. PMID:10077465

  1. Synthesis and biological properties of novel brefeldin A analogues.

    PubMed

    Seehafer, Kai; Rominger, Frank; Helmchen, Gnter; Langhans, Markus; Robinson, David G; zata, Ba?ak; Brgger, Britta; Strating, Jeroen R P M; van Kuppeveld, Frank J M; Klein, Christian D

    2013-07-25

    New brefeldin A (1) analogues were obtained by introducing a variety of substituents at C15. Most of the analogues exhibited significant biological activity. (15R)-Trifluoromethyl-nor-brefeldin A (3), (15R)-vinyl-nor-brefeldin A (5), their epimers 4 and 6 as well as (15S)-ethyl-nor-brefeldin A (2) were prepared from the key building blocks 12 or 24 by Julia-Kocienski olefination with tetrazolyl sulfones and subsequent macrolactonization. The vinyl derivative 5 allowed analogues to be synthesized by hydroboration and Suzuki-Miyaura coupling. The following biological properties were assessed: (a) inhibition of cell growth of human cancer cells (NCI), (b) induction of morphological changes of the Golgi apparatus of plant and mammalian cells, and (c) influence on the replication of the enterovirus CVB3. Furthermore, conformational aspects were studied by X-ray crystal structure analysis and molecular mechanics calculations, including docking of the analogues into the brefeldin A binding site of an Arf1/Sec7-complex. PMID:23805957

  2. New Insights into the Design of Inhibitors of Human S-Adenosylmethionine Decarboxylase: Studies of Adenine C[superscript 8] Substitution in Structural Analogues of S-Adenosylmethionine

    SciTech Connect

    McCloskey, Diane E.; Bale, Shridhar; Secrist, III, John A.; Tiwari, Anita; Moss, III, Thomas H.; Valiyaveettil, Jacob; Brooks, Wesley H.; Guida, Wayne C.; Pegg, Anthony E.; Ealick, Steven E.

    2009-04-02

    S-Adenosylmethionine decarboxylase (AdoMetDC) is a critical enzyme in the polyamine biosynthetic pathway and depends on a pyruvoyl group for the decarboxylation process. The crystal structures of the enzyme with various inhibitors at the active site have shown that the adenine base of the ligands adopts an unusual syn conformation when bound to the enzyme. To determine whether compounds that favor the syn conformation in solution would be more potent AdoMetDC inhibitors, several series of AdoMet substrate analogues with a variety of substituents at the 8-position of adenine were synthesized and analyzed for their ability to inhibit hAdoMetDC. The biochemical analysis indicated that an 8-methyl substituent resulted in more potent inhibitors, yet most other 8-substitutions provided no benefit over the parent compound. To understand these results, we used computational modeling and X-ray crystallography to study C{sup 8}-substituted adenine analogues bound in the active site.

  3. Scale-integrated observations of morphological biosignatures and associated relict structures: Addressing the practicalities of in situ astrobiology using martian analogue "field" specimens and space instrumentation

    NASA Astrophysics Data System (ADS)

    Pullan, D.; Cockell, C. S.; Pafs-Net

    We investigate how morphological biosignatures 1 could be identified with an array of viable instruments of choice in the framework of robotic planetary surface operations For purposes of the study a modest number of geological hand specimens from our archive of planetary analogues were selected on the basis of feature morphology scale and analogy Three morphological criteria were considered preserved microbial filaments 2 crypto-chasmoendoliths 3 and relict sedimentatry structures 4 The materials originate from a variety of topical martian analogue localities on Earth including impact craters high latitude deserts ancient epochs i e Early Archaean and hydrothermal deposits Instrumentation and techniques available to us included flight spare assets from the Beagle2 deployable package aka the PAW panoramic camera microscope M o ssbauer spectrometer X-ray spectrometer soil sampling Mole aka Planetary Underground Tool PLUTO and rock corer In addition selected commercial equipment served as emulators of potential future instruments including a multi-spectral imager Nuance system a micro-Raman spectrometer Bruker NIR non-confocal and Renishaw VNIR VIS Raman microscopes and a bespoke in situ X-Ray diffractometer Basic requirements for identifying morphological biosignatures are scale-integrated imaging spatial and spectral characterization of host material by analytical means and accessibility to features sample preparation We introduce a scaling philosophy that defines practical working distances for

  4. Structure-activity relationship (SAR) studies of benzoxazinones, their degradation products, and analogues. Phytotoxicity on problematic weeds Avena fatua L. and Lolium rigidum Gaud.

    PubMed

    Macas, Francisco A; Marn, David; Oliveros-Bastidas, Alberto; Castellano, Diego; Simonet, Ana M; Molinillo, Jos M G

    2006-02-22

    Avena fatua L. (wild oat) and Lolium rigidum Gaud. (rigid ryegrass) are highly problematic weeds affecting a wide variety of cereal crops worldwide. The fact that both of these weeds have developed resistance to several herbicide groups made them optimal candidates as target organisms for ongoing research about the potential application of allelochemicals and analogue compounds as natural herbicide models. Benzoxazinones, a family of natural allelochemicals present in corn, wheat, and rye, including 2,4-dihydroxy-(2H)-1,4-benzoxazin-3(4H)-one and 2,4-dihydroxy-7-methoxy-(2H)-1,4-benzoxazin-3(4H)-one, together with some degradation products, found in crop soils as well as in other systems, and some synthetic analogues of them were tested on wild oat and rigid ryegrass seeds; the results were statistically treated, and some structure-activity relationships, useful in further development of natural herbicide models, were elucidated. The most active compounds were the synthetic benzoxazinone 2-acetoxy-(2H)-1,4-benzoxazin-3(4H)-one and the degradation product 2-aminophenoxazin-3-one, with highly significant inhibition on the development of both weeds. The ecological role of these compounds is discussed by considering both degradability and phytotoxicity. The bioactivity of aminophenoxazines has been correlated by their aqueous solubility-lipophilicity predicted by means of computational methods. PMID:16478215

  5. Synthesis and structure of an open-cage thiafullerene C69S: reactivity differences of an open-cage C70 tetraketone relative to its C60 analogue.

    PubMed

    Zhang, Rui; Futagoishi, Tsukasa; Murata, Michihisa; Wakamiya, Atsushi; Murata, Yasujiro

    2014-06-11

    An open-cage C70 fullerene with a 13-membered ring-opening and a bis(hemiacetal) moiety was synthesized by the reaction of the corresponding open-cage C70 diketone with nucleophilic oxidizing agents. The size of the cage opening could be expanded by a subsequent dehydration reaction. Reaction of the thus obtained open-cage C70 tetraketone with elemental sulfur in the presence of tetrakis(dimethylamino)ethylene resulted in the formation of the first example of an open-cage C69S thiafullerene with a 12-membered ring-opening. The formation of this sulfur-containing heterofullerene reflects a significantly different chemical reactivity for the open-cage C70 tetraketone relative to its C60 analogue. The structures of all novel compounds were unambiguously determined by single crystal X-ray diffraction analyses, in addition to which the electrochemical properties of the thiafullerene C69S were examined and compared with those of the corresponding C70 analogue. PMID:24884230

  6. Test assessment of RC structures in marine environment: the Geiger Key Bridge

    NASA Astrophysics Data System (ADS)

    Loreto, G.; Di Benedetti, M.; Nanni, A.

    2012-04-01

    Reinforced concrete marine structures are highly vulnerable to corrosion due to chloride ion attack; the severity of the attack being dependent on, among other factors, the prevailing climatic condition. The aggressiveness of the warm marine environment of Florida has led to the premature deterioration of numerous bridges and building along the coastline. This paper describes a methodology for structural assessment of concrete bridges while incorporating analysis uncertainty. The procedure includes the use of visual, electrochemical and non-destructive methods in order to define the cause and the level of concrete deterioration. A probabilistic mechanistic model is used to generate the distribution of the time to corrosion initiation based on statistical models of the governing parameters obtained from field data. The proposed methodology is applied to predict the time to corrosion initiation and predict the residual service life of the reinforcing steel in the concrete girders of the Geiger Bridge in Key West, FL.

  7. Synthesis and structure-activity relationships of azamacrocyclic C-X-C chemokine receptor 4 antagonists: analogues containing a single azamacrocyclic ring are potent inhibitors of T-cell tropic (X4) HIV-1 replication.

    PubMed

    Bridger, Gary J; Skerlj, Renato T; Hernandez-Abad, Pedro E; Bogucki, David E; Wang, Zhongren; Zhou, Yuanxi; Nan, Susan; Boehringer, Eva M; Wilson, Trevor; Crawford, Jason; Metz, Markus; Hatse, Sigrid; Princen, Katrien; De Clercq, Erik; Schols, Dominique

    2010-02-11

    Bis-tetraazamacrocycles such as the bicyclam AMD3100 (1) are a class of potent and selective anti-HIV-1 agents that inhibit virus replication by binding to the chemokine receptor CXCR4, the coreceptor for entry of X4 viruses. By sequential replacement and/or deletion of the amino groups within the azamacrocyclic ring systems, we have determined the minimum structural features required for potent antiviral activity in this class of compounds. All eight amino groups are not required for activity, the critical amino groups on a per ring basis are nonidentical, and the overall charge at physiological pH can be reduced without compromising potency. This approach led to the identification of several single ring azamacrocyclic analogues such as AMD3465 (3d), 36, and 40, which exhibit EC(50)'s against the cytopathic effects of HIV-1 of 9.0, 1.0, and 4.0 nM, respectively, antiviral potencies that are comparable to 1 (EC(50) against HIV-1 of 4.0 nM). More importantly, however, the key structural elements of 1 required for antiviral activity may facilitate the design of nonmacrocyclic CXCR4 antagonists suitable for HIV treatment via oral administration. PMID:20043638

  8. Initial synthesis and structure of an all-ferrous analogue of the fully reduced [Fe4S4]0 cluster of the nitrogenase iron protein.

    PubMed

    Scott, Thomas A; Berlinguette, Curtis P; Holm, Richard H; Zhou, Hong-Cai

    2005-07-12

    The synthetic cubane-type iron-sulfur clusters [Fe(4)S(4)(SR)(4)](z) form a four-member electron transfer series (z = 3-, 2-, 1-, and 0), all members of which except that with z = 0 have been isolated and characterized. They serve as accurate analogues of protein-bound [Fe(4)S(4)(SCys)(4)](z) redox centers, which, in terms of core oxidation states, exhibit the redox couples [Fe(4)S(4)](3+/2+) and [Fe(4)S(4)](2+/1+). Clusters with the all-ferrous core [Fe(4)S(4)](0) have never been isolated because of their oxidative sensitivity. Recent work on the Fe protein of Azotobacter vinelandii nitrogenase has demonstrated the formation of the all-ferrous state upon reaction with a strong reductant. Treatment of the cyanide cluster [Fe(4)S(4)(CN)(4)](3-) with K[Ph(2)CO] in acetonitrile/tetrahydrofuran affords the all-ferrous cluster [Fe(4)S(4)(CN)(4)](4-), isolated as the Bu(4)N(+) salt. The x-ray structure demonstrates retention of a cubane-type structure with idealized D(2)(d) symmetry. The Mössbauer spectrum unambiguously demonstrates the [Fe(4)S(4)](0) oxidation state. Bond distances, core volumes, (57)Fe isomer shifts, and visible absorption spectra make evident the high degree of structural and electronic similarity with the fully reduced Fe protein. The attribute of cyanide ligation causes positive [Fe(4)S(4)](2+/1+) and [Fe(4)S(4)](1+/0) redox potential shifts, facilitating the initial isolation of an analogue of the [Fe(4)S(4)](0) protein site. PMID:15985547

  9. Geometry and field dependence of the formation of magnetic antivortices in pound-key-like structures

    NASA Astrophysics Data System (ADS)

    Asmat-Uceda, Martin; Li, Lin; Haldar, Arabinda; Shaw, Brian; Buchanan, Kristen S.

    2015-05-01

    In this work, we assess the effects of field history and structure shape on the formation of magnetic antivortices. The magnetic reversal process was investigated for a series of patterned micron-sized permalloy pound-key structures with varying degrees of asymmetry using magneto-optical Kerr effect hysteresis measurements combined with magnetic force microscopy. The largest number of antivortices was observed in the structures with the highest level of structure asymmetry, which also show an intermediate state in the hysteresis loop. A significant enhancement of the antivortex formation ratefrom 5% to almost 80%was achieved by adjusting the structure dimensions. Images of the magnetic states obtained at various points in the hysteresis loop show that the highest rate of antivortex formation occurs near the coercive field, also the nucleation field, and that the antivortex formation is also sensitive to the angle of the applied field, where the highest antivortex formation rate is observed when the field is aligned along the structure diagonal. A comparison of the experimental results with micromagnetic simulations shows that the areas with lower shape anisotropy lead the reversal in the formation step and the upper field limit for the antivortex stability is related to the reversal of the regions with higher shape anisotropy, although the simulations suggest that the annihilation mechanism will change to one that involves domain wall propagation when the smallest structure dimensions are below 60 nm. These results demonstrate how shape anisotropy can be used to promote the formation of isolated magnetic antivortices, which will facilitate future investigations of this topological magnetic state.

  10. B38: an all-boron fullerene analogue

    NASA Astrophysics Data System (ADS)

    Lv, Jian; Wang, Yanchao; Zhu, Li; Ma, Yanming

    2014-09-01

    Fullerene-like structures formed by elements other than carbon have long been sought. Finding all-boron (B) fullerene-like structures is challenging due to the geometrical frustration arising from competitions among various structural motifs. We report here the prediction of a B38 fullerene analogue found through first-principles swarm structure searching calculations. The structure is highly symmetric and consists of 56 triangles and four hexagons, which provide an optimal void in the center of the cage. Energetically, it is more favorable than the planar and tubular structures, and possesses an unusually high chemical stability: a large energy gap (~2.25 eV) and a high double aromaticity, superior to those of most aromatic quasi-planar B12 and double-ring B20 clusters. Our findings represent a key step forward towards to the understanding of structures of medium-sized B clusters and map out the experimental direction of the synthesis of an all-B fullerene analogue.Fullerene-like structures formed by elements other than carbon have long been sought. Finding all-boron (B) fullerene-like structures is challenging due to the geometrical frustration arising from competitions among various structural motifs. We report here the prediction of a B38 fullerene analogue found through first-principles swarm structure searching calculations. The structure is highly symmetric and consists of 56 triangles and four hexagons, which provide an optimal void in the center of the cage. Energetically, it is more favorable than the planar and tubular structures, and possesses an unusually high chemical stability: a large energy gap (~2.25 eV) and a high double aromaticity, superior to those of most aromatic quasi-planar B12 and double-ring B20 clusters. Our findings represent a key step forward towards to the understanding of structures of medium-sized B clusters and map out the experimental direction of the synthesis of an all-B fullerene analogue. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr01846j

  11. The structure of vanin 1: a key enzyme linking metabolic disease and inflammation.

    PubMed

    Boersma, Ykelien L; Newman, Janet; Adams, Timothy E; Cowieson, Nathan; Krippner, Guy; Bozaoglu, Kiymet; Peat, Thomas S

    2014-12-01

    Although part of the coenzyme A pathway, vanin 1 (also known as pantetheinase) sits on the cell surface of many cell types as an ectoenzyme, catalyzing the breakdown of pantetheine to pantothenic acid (vitamin B5) and cysteamine, a strong reducing agent. Vanin 1 was initially discovered as a protein involved in the homing of leukocytes to the thymus. Numerous studies have shown that vanin 1 is involved in inflammation, and more recent studies have shown a key role in metabolic disease. Here, the X-ray crystal structure of human vanin 1 at 2.25? resolution is presented, which is the first reported structure from the vanin family, as well as a crystal structure of vanin 1 bound to a specific inhibitor. These structures illuminate how vanin 1 can mediate its biological roles by way of both enzymatic activity and protein-protein interactions. Furthermore, it sheds light on how the enzymatic activity is regulated by a novel allosteric mechanism at a domain interface. PMID:25478849

  12. Antibacterial and antimutagenic activities of novel zerumbone analogues.

    PubMed

    Santosh Kumar, S C; Srinivas, P; Negi, P S; Bettadaiah, B K

    2013-11-15

    Zerumbone, the key constituent of Zingiber zerumbet Smith, is a very important bioactive phytochemical. Two new compounds viz. azazerumbone 1 and azazerumbone 2 were synthesised by ZnCl2-catalysed Beckmann rearrangement of the zerumbone oxime. The structure elucidation of these analogues of zerumbone was carried out by 1D ((1)H NMR and (13)C NMR) and 2D-NMR (COSY, HSQC and NOESY) spectral analysis. Studies on the antibacterial activity established that azazerumbone 2 had better activity than zerumbone. Among the tested bacteria, Bacillus cereus was the most sensitive and Yersinia enterocolitica was found to be the most resistant. These compounds exhibited strong protection against sodium azide induced mutagenicity of Salmonella typhimurium strains TA 98 and TA 1531. Azazerumbone 2 showed better antibacterial and antimutagenic activity than azazerumbone 1. The antibacterial and antimutagenic activities exhibited by zerumbone and its analogues demonstrate their potential for use as nutraceuticals and in food preservation. PMID:23790891

  13. 1.45 A resolution crystal structure of recombinant PNP in complex with a pM multisubstrate analogue inhibitor bearing one feature of the postulated transition state

    SciTech Connect

    Chojnowski, Grzegorz; International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw ; Breer, Katarzyna; Narczyk, Marta; Wielgus-Kutrowska, Beata; Czapinska, Honorata; Hashimoto, Mariko; Hikishima, Sadao; Yokomatsu, Tsutomu; Bochtler, Matthias; Schools of Chemistry and Biosciences, Park Place, CF10 3AT Cardiff; Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstr. 108, 01309 Dresden ; Girstun, Agnieszka; Staron, Krzysztof; Bzowska, Agnieszka

    2010-01-01

    Low molecular mass purine nucleoside phosphorylases (PNPs, E.C. 2.4.2.1) are homotrimeric enzymes that are tightly inhibited by immucillins. Due to the positive charge on the ribose like part (iminoribitol moiety) and protonation of the N7 atom of the purine ring, immucillins are believed to act as transition state analogues. Over a wide range of concentrations, immucillins bind with strong negative cooperativity to PNPs, so that only every third binding site of the enzyme is occupied (third-of-the-sites binding). 9-(5',5'-difluoro-5'-phosphonopentyl)-9-deazaguanine (DFPP-DG) shares with immucillins the protonation of the N7, but not the positive charge on the ribose like part of the molecule. We have previously shown that DFPP-DG interacts with PNPs with subnanomolar inhibition constant. Here, we report additional biochemical experiments to demonstrate that the inhibitor can be bound with the same K{sub d} ({approx}190 pM) to all three substrate binding sites of the trimeric PNP, and a crystal structure of PNP in complex with DFPP-DG at 1.45 A resolution, the highest resolution published for PNPs so far. The crystals contain the full PNP homotrimer in the asymmetric unit. DFPP-DG molecules are bound in superimposable manner and with full occupancies to all three PNP subunits. Thus the postulated third-of-the-sites binding of immucillins should be rather attribute to the second feature of the transition state, ribooxocarbenium ion character of the ligand or to the coexistence of both features characteristic for the transition state. The DFPP-DG/PNP complex structure confirms the earlier observations, that the loop from Pro57 to Gly66 covering the phosphate-binding site cannot be stabilized by phosphonate analogues. The loop from Glu250 to Gln266 covering the base-binding site is organized by the interactions of Asn243 with the Hoogsteen edge of the purine base of analogues bearing one feature of the postulated transition state (protonated N7 position).

  14. Structural comparison of complexes of methotrexate analogues with Lactobacillus casei dihydrofolate reductase by two-dimensional /sup 1/H NMR at 500 MHz

    SciTech Connect

    Hammond, S.J.; Birdsall, B.; Feeney, J.; Searle, M.S.; Roberts, G.C.K.; Cheung, H.T.A.

    1987-12-29

    The authors have used two-dimensional (2D) NMR methods to examine complexes of Lactobacillus casei dihydrofolate reductase and methotrexate (MTX) analogues having structural modifications of the benzoyl ring and also the glutamic acid moiety. Assignments of the /sup 1/H signals in the spectra of the various complexes were made by comparison of their 2D spectra with those complexes containing methotrexate where we have previously assigned resonances from 32 of the 162 amino acid residues. In the complexes formed with the dihalomethotrexate analogues, the glutamic acid and pteridine ring moieties were shown to bind to the enzyme in a manner similar to that found in the methotrexate-enzyme complex. Perturbations in /sup 1/H chemical shifts of protons in Phe-49, Leu-54, and Leu-27 and the methotrexate H7 and NMe protons were observed in the different complexes and were accounted for by changes in orientation of the benzoyl ring in the various complexes. Binding of oxidized or reduced coenzyme to the binary complexes did not result in different shifts for Leu-27, Leu-54, or Leu-19 protons, and thus, the orientation of the benzoyl ring of the methotrexate analogues is not perturbed greatly by the presence of either oxidized or reduced coenzyme. In the complex with the ..gamma..-monoamide analog, the /sup 1/H signals of assigned residues in the protein had almost identical shifts with the corresponding protons in the methotrexate-enzyme complex for all residues except His-28 and, to a lesser extent, Leu-27. This indicates that while the His-28 interaction with the MTX ..gamma..-CO/sub 2//sup -/ is no longer present in this complex with the ..gamma..-amide, there has not been a major change in the overall structure of the two complexes. This behavior contrasts to that of the ..cap alpha..-amide complex where /sup 1/H signals from protons in several amino acid residues are different compared with their values in the complex formed with methotrexate.

  15. Structure Reassignment and Synthesis of Jenamidines A1/A2, Synthesis of (+)-NP25302, and Formal Synthesis of SB-311009 Analogues

    PubMed Central

    Duvall, Jeremy R.; Wu, Fanghui; Snider, Barry B.

    2008-01-01

    The proposed structures of jenamidines A, B, and C (1?3) were revised to jenamidines A1/A2, B1/B2, and C (8-10). Jenamidines A1/A2 (8) were synthesized from activated proline derivative 43 by conversion to 26 in two steps and 50% overall yield. Acylation of 26 with acid chloride 38d gave 39d, which was deprotected with TFA and then mild base to give 8 in 45% yield from 26. (?)-trans-2,5-Dimethylproline ethyl ester (49) was prepared by the enantioselective Michael reaction of ethyl 2-nitropropionate (51) and methyl vinyl ketone (50) using modified dihydroquinine 60 as the catalyst. Further elaboration converted 49 to natural (+)-NP25302 (12). A Wittig reaction of proline NCA (76) with ylide 79 gave 72 as a 9/1 E/Z mixture in 27% yield completing a one step formal synthesis of SB-311009 analogues. PMID:17064037

  16. Drug design by machine learning: the use of inductive logic programming to model the structure-activity relationships of trimethoprim analogues binding to dihydrofolate reductase.

    PubMed Central

    King, R D; Muggleton, S; Lewis, R A; Sternberg, M J

    1992-01-01

    The machine learning program GOLEM from the field of inductive logic programming was applied to the drug design problem of modeling structure-activity relationships. The training data for the program were 44 trimethoprim analogues and their observed inhibition of Escherichia coli dihydrofolate reductase. A further 11 compounds were used as unseen test data. GOLEM obtained rules that were statistically more accurate on the training data and also better on the test data than a Hansch linear regression model. Importantly machine learning yields understandable rules that characterized the chemistry of favored inhibitors in terms of polarity, flexibility, and hydrogen-bonding character. These rules agree with the stereochemistry of the interaction observed crystallographically. Images PMID:1454814

  17. Bivalent Tin Analogues of Carbenes

    NASA Astrophysics Data System (ADS)

    Shiryaev, Vladimir I.; Mironov, Vladimir F.

    1983-02-01

    The structure and certain chemical and physicochemical properties of bivalent tin compounds (stannylenes) are examined and the electronic, structural and chemical similarity between these compounds and carbenes and their analogues bivalent compounds of Group IVB elements is demonstrated. The possibilities of stannylenes in the synthesis of organotin (IV) compounds as well as complexes in which stannylenes are electron-donating ligands, like carbenes, are analysed. The bibliography includes 457 references.

  18. eIF2B: recent structural and functional insights into a key regulator of translation.

    PubMed

    Wortham, Noel C; Proud, Christopher G

    2015-12-01

    The eukaryotic translation initiation factor (eIF) eIF2B is a key regulator of mRNA translation, being the guanine nt exchange factor (GEF) responsible for the recycling of the heterotrimeric G-protein, eIF2, which is required to allow translation initiation to occur. Unusually for a GEF, eIF2B is a multi-subunit protein, comprising five different subunits termed α through ε in order of increasing size. eIF2B is subject to tight regulation in the cell and may also serve additional functions. Here we review recent insights into the subunit organization of the mammalian eIF2B complex, gained both from structural studies of the complex and from studies of mutations of eIF2B that result in the neurological disorder leukoencephalopathy with vanishing white matter (VWM). We will also discuss recent data from yeast demonstrating a novel function of the eIF2B complex key for translational regulation. PMID:26614666

  19. Structure of the key species in the enzymatic oxidation of methane to methanol.

    PubMed

    Banerjee, Rahul; Proshlyakov, Yegor; Lipscomb, John D; Proshlyakov, Denis A

    2015-02-19

    Methane monooxygenase (MMO) catalyses the O2-dependent conversion of methane to methanol in methanotrophic bacteria, thereby preventing the atmospheric egress of approximately one billion tons of this potent greenhouse gas annually. The key reaction cycle intermediate of the soluble form of MMO (sMMO) is termed compound Q (Q). Q contains a unique dinuclear Fe(IV) cluster that reacts with methane to break an exceptionally strong 105kcalmol(-1) C-H bond and insert one oxygen atom. No other biological oxidant, except that found in the particulate form of MMO, is capable of such catalysis. The structure of Q remains controversial despite numerous spectroscopic, computational and synthetic model studies. A definitive structural assignment can be made from resonance Raman vibrational spectroscopy but, despite efforts over the past two decades, no vibrational spectrum of Q has yet been obtained. Here we report the core structures of Q and the following product complex, compound T, using time-resolved resonance Raman spectroscopy (TR(3)). TR(3) permits fingerprinting of intermediates by their unique vibrational signatures through extended signal averaging for short-lived species. We report unambiguous evidence that Q possesses a bis-?-oxo diamond core structure and show that both bridging oxygens originate from O2. This observation strongly supports a homolytic mechanism for O-O bond cleavage. We also show that T retains a single oxygen atom from O2 as a bridging ligand, while the other oxygen atom is incorporated into the product. Capture of the extreme oxidizing potential of Q is of great contemporary interest for bioremediation and the development of synthetic approaches to methane-based alternative fuels and chemical industry feedstocks. Insight into the formation and reactivity of Q from the structure reported here is an important step towards harnessing this potential. PMID:25607364

  20. Synthesis of new praziquantel analogues: potential candidates for the treatment of schistosomiasis.

    PubMed

    Sadhu, Partha Sarathi; Kumar, Singam Naveen; Chandrasekharam, Malapaka; Pica-Mattoccia, Livia; Cioli, Donato; Rao, Vaidya Jayathirtha

    2012-01-15

    An efficient synthesis of antischistosomal drug praziquantel and analogues was achieved and the synthetic route designed was to afford structurally diverse analogues for better structure-activity relationship understanding. Total of nineteen PZQ analogues with structural variations at amide, piperazine and aromatic moieties have been synthesized and fully characterized. Among all the new analogues tested for antischistosomal activity, one dimethoxy tetrahydroisoquinoline analogue and two tetrahydro-?-carboline analogues exhibited moderate activity against adult Schistosoma mansoni. Tetrahydro-?-carboline analogues showed moderate activity whereas the presence of p-trifluoromethylbenzoyl and p-toluenesulphonyl moieties resulted in complete suppression of antischistosomal activity. PMID:22217873

  1. Potassium as a key modulator of tropical woody vegetation structure and function

    NASA Astrophysics Data System (ADS)

    Lloyd, Jonathan

    2015-04-01

    Sampling a range of tropical vegetation types across Africa, Australia and South America we find - other things being equal - lower soil and plant potassium concentrations in savanna as opposed to forest species. There is also a trend- similarly observed in cross-continental comparisons, for foliar [K] to increase with declining precipitation. Moreover, when considered in a multivariate context with mean annual precipitation and soil plant available water storage capacity as covariates, soil exchangeable K turns to be an excellent predictor of stand-level canopy areas across vegetation types, providing drastically improved predictions as compared to models considering just precipitation or soil water storage potential alone This underlying basis of an important role for potassium as a modulator of tropical vegetation structure and function will be considered in terms of its role in plant water relations as well as in relation to recent key findings implicating potassium to have an important role in many root-shoot signalling pathways.

  2. Mutational analysis of the Notch2 negative regulatory region identifies key structural elements for mechanical stability

    PubMed Central

    Stephenson, Natalie L.; Avis, Johanna M.

    2015-01-01

    The Notch signalling pathway is fundamental to cell differentiation in developing and self-renewing tissues. Notch is activated upon ligand-induced conformational change of the Notch negative regulatory region (NRR), unmasking a key proteolytic site (S2) and facilitating downstream events. The favoured model requires endocytosis of a tightly bound ligand to transmit force to the NRR region, sufficient to cause a structural change that exposes the S2 site. We have previously shown, using atomic force microscopy and molecular dynamics simulations, that application of force to the N-terminus of the Notch2 NRR facilitates metalloprotease cleavage at an early stage in the unfolding process. Here, mutations are made within the heterodimerization (HD) domain of the NRR that are known to cause constitutive activation of Notch1 whilst having no effect on the chemical stability of Notch2. Comparison of the mechanical stability and simulated forced unfolding of recombinant Notch2 NRR proteins demonstrates a reduced stability following mutation and identifies two critical structural elements of the NRR in its response to force the linker region between Lin12-Notch repeats LNRA and LNRB and the ?3 helix within the HD domain both of which mask the S2 cleavage site prior to Notch activation. In two mutated proteins, the LNRC:HD domain interaction is also reduced in stability. The observed changes to mechanical stability following these HD domain mutations highlight key regions of the Notch2 NRR that are important for mechanical, but not chemical, stability. This research could also help determine the fundamental differences in the NRRs of Notch1 and Notch2. PMID:26288744

  3. Glutamate Provides a Key Structural Contact Between Reticulon-4 (Nogo-66) and Phosphocholine

    PubMed Central

    Alhoshani, Ali; Vithayathil, Rosemarie; Bandong, Jonathan; Chrunyk, Katherine M.; Moreno, Gabriel O.; Weiss, Gregory A.; Cocco, Melanie J.

    2014-01-01

    Human reticulon 4 (RTN-4) has been identified as the neurite outgrowth inhibitor (Nogo). This protein contains a span of 66 amino acids (Nogo-66) flanked by two membrane helices at the C-terminus. We previously determined the NMR structure of Nogo-66 in a native-like environment and defined the regions of Nogo-66 expected to be membrane embedded. We hypothesize that aromatic groups and a negative charge hyperconserved among RTNs (Glu26) drive the remarkably strong association of Nogo-66 with a phosphocholine surface. Glu26 is an isolated charge with no counterion provided by nearby protein groups. We modeled the docking of dodecylphosphocholine (DPC) with Nogo-66 and found that a lipid choline group could form a stable salt bridge with Glu26 and serve as a membrane anchor point. To test the role of the Glu26 anion in binding choline, we mutated this residue to alanine and assessed the structural consequences, association with lipid and affinity for the Nogo receptor. In an aqueous environment, Nogo-66 Glu26Ala is more helical than WT and binds the Nogo receptor with higher affinity. Thus, we can conclude that in the absence of a neutralizing positive charge provided by lipid, the glutamate anion is destabilizing to the Nogo-66 fold. Although the Nogo-66 Glu26Ala free energy of transfer from water into lipid is similar to that of WT, NMR data reveal a dramatic loss of tertiary structure for the mutant in DPC micelles. These data show that Glu26 has a key role in defining the structure of Nogo-66 on a phosphocholine surface. PMID:24863057

  4. Utility of Remote Sensing, Robotic Precursor Data and a Focused Science Hypothesis for a Follow-On Human Exploration Lunar Analogue Mission at the Mistastin Lake (Kamestastin) Impact Structure

    NASA Astrophysics Data System (ADS)

    Tornabene, L. L.; Osinski, G. R.; Mader, M. M.; Chanou, A.; Francis, R.; Joliff, B. L.; Marion, C.; McCullough, E.; Pickersgill, A.; Sapers, H.; Souders, K.; Sylvester, P.; Young, K.; Zanetti, M.; Krash Operations; Science Team

    2012-03-01

    Here we summarize how remote sensing, robotic precursor data and a focused science hypothesis augmented the results from a lunar analogue mission to the Mistastin impact structure in Labrador, Canada. Join me as we go on a magical tour of this crater.

  5. Emulating exhalative chemistry: synthesis and structural characterization of ilinskite, Na[Cu5O2](SeO3)2Cl3, and its K-analogue

    NASA Astrophysics Data System (ADS)

    Kovrugin, Vadim M.; Siidra, Oleg I.; Colmont, Marie; Mentré, Olivier; Krivovichev, Sergey V.

    2015-08-01

    The K- and Na-synthetic analogues of the fumarolic mineral ilinskite have been synthesized by the chemical vapor transport (CVT) reactions method. The A[Cu5O2](SeO3)2Cl3 ( A + = K+, Na+) compounds crystallize in the orthorhombic space group Pnma: a = 18.1691(6) Å, b = 6.4483(2) Å, c = 10.5684(4) Å, V = 1238.19(7) Å3, R 1 = 0.018 for 1957 unique reflections with F > 4σ F for K[Cu5O2](SeO3)2Cl3 ( KI), and a = 17.7489(18) Å, b = 6.4412(6) Å, c = 10.4880(12) Å, V = 1199.0(2) Å3, R 1 = 0.049 for 1300 unique reflections with F > 4σ F for Na[Cu5O2](SeO3)2Cl3 ( NaI). The crystal structures of KI and NaI are based upon the [O2Cu5]6+ sheets consisting of corner-sharing (OCu4)6+ tetrahedra. The Na-for-K substitution results in the significant expansion of the interlayer space and changes in local coordination of some of the Cu2+ cations. The A + cation coordination changes from fivefold (for Na+) to ninefold (for K+). The CVT reactions method provides a unique opportunity to model physicochemical conditions existing in fumarolic environments and may be used not only to model exhalative processes, but also to predict possible mineral phases that may form in fumaroles. In particular, the K analogue of ilinskite is not known in nature, whereas it may well form from volcanic gases in a K-rich local geochemical environment.

  6. The unsaturated acyclic nucleoside analogues bearing a sterically constrained (Z)-4'-benzamido-2'-butenyl moiety: Synthesis, X-ray crystal structure study, cytostatic and antiviral activity evaluations.

    PubMed

    Benci, Kresimir; Wittine, Karlo; Radan, Malajka; Cetina, Mario; Sedi?, Mirela; Kraljevi? Paveli?, Sandra; Paveli?, Kresimir; Clercq, Erik De; Mintas, Mladen

    2010-09-01

    A series of the novel acyclic unsaturated pyrimidine (1-12) and adenine (13) nucleoside analogues bearing conformationally restricted (Z)-2'-butenyl moiety were synthesized and evaluated for their antiviral and cytostatic activity potency against malignant tumor cell lines and normal human fibroblast (WI38). The N-1 and/or N-3 acyclic side chain substitution in pyrimidine ring in N-3 substituted 5-trifluoromethyluracil derivative (11), N-1, N-3 disubstituted 5-fluorouracil derivative (12) and adenine derivative (13) was deduced from their (1)H and (13)C NMR spectra and confirmed by single crystal X-ray structure analysis. The X-ray crystal structure analysis 11-13 revealed also supramolecular self-assemblies, in which infinite chains or dimers built two- and three-dimensional networks. The results of the in vitro cytostatic activity evaluations of 1-13 indicate that the majority of the compounds tested exhibited a non-specific and moderate antiproliferative effect at the highest concentration (100 microM). Of all evaluated compounds on the cell lines tested only the N-1 4''-fluoro-substituted-benzamide uracil derivative (7) showed rather marked and selective inhibitory activity against the growth of MCF-7 cells at a concentration of 2.7 microM and no cytotoxic effect on normal fibroblasts WI38. This compound can be therefore considered as a potential antitumor lead compound for further synthetic structure modification. PMID:20696582

  7. Fluorescence, CD, attenuated total reflectance (ATR) FTIR, and sup 13 C NMR characterization of the structure and dynamics of synthetic melittin and melittin analogues in lipid environments

    SciTech Connect

    Weaver, A.J.; Prendergast, F.G. ); Kemple, M.D. ); Brauner, J.W.; Mendelsohn, R. )

    1992-02-11

    The structure and dynamics of synthetic melittin (MLT) and MLT analogues bound to monomyristoylphosphatidylcholine micelles, dimyristoylphosphatidylcholine vesicles, and diacylphosphatidylcholine films have been investigated by fluorescence, CD, attenuated total reflectance (ATR) FTIR, and {sup 13}C NMR spectroscopy. All of these methods provide information about peptide secondary structure and/or about the environment of the single tryptophan side chain in these lipid environments. ATR-FTIR data provide additional information about the orientation of helical peptide segments with respect to the bilayer plane. Steady-state fluorescence anisotropy, fluorescence lifetime, and {sup 13}C NMR relaxation data are used in concert to provide quantitative information about the dynamics of a single {sup 13}C{alpha}-labeled glycine incorporated into each of the MLT peptides at position 12. The cumulative structural and dynamic data are consistent with a model wherein the N-terminal {alpha}-helical segment of these peptides is oriented perpendicular to the bilayer plane. Correlation times for the lysolipid-peptide complexes provide evidence for binding of a single peptide monomer per micelle. A model for the membranolytic action of MLT and MLT-like peptides is proposed.

  8. Efficient synthesis and biological activity of Psammaplin A and its analogues as antitumor agents.

    PubMed

    Hong, Suckchang; Shin, Yoonho; Jung, Myunggi; Ha, Min Woo; Park, Yohan; Lee, Yeon-Ju; Shin, Jongheon; Oh, Ki Bong; Lee, Sang Kook; Park, Hyeung-geun

    2015-01-01

    We describe a new concise method for the synthesis of psammaplin A and its analogues, and antitumor activity of psammaplin A analogues. Psammaplin A was obtained with 41% yield in 5 steps from 3-bromo-4-hydroxybenzaldahyde and ethyl acetoacetate via Knoevenagel condensation and ?-nitrosation as key steps. Twenty eight analogues of psammaplin A were prepared employing the new synthetic approach. Structure-activity relationship study against cytotoxicity reveal that the free oxime group and disulfide functional group were responsible for high cytotoxicity. Also the bromotyrosine component was relatively tolerable and hydrophobic aromatic groups preserved the cytotoxicity. The cytotoxicity of aromatic group is dependent on the size and spatial geometry. Among them, five compounds showed comparable cytotoxicity to psammaplin A. Compound 30 exhibited potential HDAC inhibitory activity and in vivo antitumor activity. PMID:25884112

  9. Natural analogues of nuclear waste glass corrosion.

    SciTech Connect

    Abrajano, T.A. Jr.; Ebert, W.L.; Luo, J.S.

    1999-01-06

    This report reviews and summarizes studies performed to characterize the products and processes involved in the corrosion of natural glasses. Studies are also reviewed and evaluated on how well the corrosion of natural glasses in natural environments serves as an analogue for the corrosion of high-level radioactive waste glasses in an engineered geologic disposal system. A wide range of natural and experimental corrosion studies has been performed on three major groups of natural glasses: tektite, obsidian, and basalt. Studies of the corrosion of natural glass attempt to characterize both the nature of alteration products and the reaction kinetics. Information available on natural glass was then compared to corresponding information on the corrosion of nuclear waste glasses, specifically to resolve two key questions: (1) whether one or more natural glasses behave similarly to nuclear waste glasses in laboratory tests, and (2) how these similarities can be used to support projections of the long-term corrosion of nuclear waste glasses. The corrosion behavior of basaltic glasses was most similar to that of nuclear waste glasses, but the corrosion of tektite and obsidian glasses involves certain processes that also occur during the corrosion of nuclear waste glasses. The reactions and processes that control basalt glass dissolution are similar to those that are important in nuclear waste glass dissolution. The key reaction of the overall corrosion mechanism is network hydrolysis, which eventually breaks down the glass network structure that remains after the initial ion-exchange and diffusion processes. This review also highlights some unresolved issues related to the application of an analogue approach to predicting long-term behavior of nuclear waste glass corrosion, such as discrepancies between experimental and field-based estimates of kinetic parameters for basaltic glasses.

  10. Structures of the hydrolase domain of zebrafish 10-formyltetrahydrofolate dehydrogenase and its complexes reveal a complete set of key residues for hydrolysis and product inhibition

    PubMed Central

    Lin, Chien-Chih; Chuankhayan, Phimonphan; Chang, Wen-Ni; Kao, Tseng-Ting; Guan, Hong-Hsiang; Fun, Hoong-Kun; Nakagawa, Atsushi; Fu, Tzu-Fun; Chen, Chun-Jung

    2015-01-01

    10-Formyltetrahydrofolate dehydrogenase (FDH), which is composed of a small N-terminal domain (Nt-FDH) and a large C-terminal domain, is an abundant folate enzyme in the liver and converts 10-formyltetrahydrofolate (10-FTHF) to tetrahydrofolate (THF) and CO2. Nt-FDH alone possesses a hydrolase activity, which converts 10-FTHF to THF and formate in the presence of ?-mercaptoethanol. To elucidate the catalytic mechanism of Nt-FDH, crystal structures of apo-form zNt-FDH from zebrafish and its complexes with the substrate analogue 10-formyl-5,8-dideazafolate (10-FDDF) and with the products THF and formate have been determined. The structures reveal that the conformations of three loops (residues 8690, 135143 and 200203) are altered upon ligand (10-FDDF or THF) binding in the active site. The orientations and geometries of key residues, including Phe89, His106, Arg114, Asp142 and Tyr200, are adjusted for substrate binding and product release during catalysis. Among them, Tyr200 is especially crucial for product release. An additional potential THF binding site is identified in the cavity between two zNt-FDH molecules, which might contribute to the properties of product inhibition and THF storage reported for FDH. Together with mutagenesis studies and activity assays, the structures of zNt-FDH and its complexes provide a coherent picture of the active site and a potential THF binding site of zNt-FDH along with the substrate and product specificity, lending new insights into the molecular mechanism underlying the enzymatic properties of Nt-FDH. PMID:25849409

  11. Structural Revisions of a Class of Natural Products: Scaffolds of Aglycon Analogues of Fusicoccins and Cotylenins Isolated from Fungi.

    PubMed

    Tang, Ying; Xue, Yongbo; Du, Guang; Wang, Jianping; Liu, Junjun; Sun, Bin; Li, Xiao-Nian; Yao, Guangmin; Luo, Zengwei; Zhang, Yonghui

    2016-03-14

    The reisolation and structural revision of brassicicene D is described, and inspired us to reassign the core skeletons of brassicicenes C-H, J and K, ranging from dicyclopenta[a,d]cyclooctane to tricyclo[9.2.1.0(3,7) ]tetradecane using quantum-chemical predictions and experimental validation strategies. Three novel, highly modified fusicoccanes, brassicicenes L-N, were also isolated from the fungus Alternaria brassicicola, and their structures were unequivocally established by spectroscopic data, ECD calculations, and crystallography. The reassigned structures represent the first class of bridgehead double-bond-containing natural products with a bicyclo[6.2.1]undecane carbon skeleton. Furthermore, their stabilities were first predicted with olefin strain energy calculations. Collectively, these findings extend our view of the application of computational predictions and biosynthetic logic-based structure elucidation to address problems related to the structure and stability of natural products. PMID:26916098

  12. Novobiocin Analogues That Inhibit the MAPK Pathway.

    PubMed

    Hall, Jessica A; Seedarala, Sahithi; Zhao, Huiping; Garg, Gaurav; Ghosh, Suman; Blagg, Brian S J

    2016-02-11

    Heat shock protein 90 (Hsp90) inhibition by modulation of its N- or C-terminal binding site has become an attractive strategy for the development of anticancer chemotherapeutics. The first Hsp90 C-terminus inhibitor, novobiocin, manifested a relatively high IC50 value of ?700 ?M. Therefore, investigation of the novobiocin scaffold has led to analogues with improved antiproliferative activity (nanomolar concentrations) against several cancer cell lines. During these studies, novobiocin analogues that do not inhibit Hsp90 were identified; however, these analogues demonstrated potent antiproliferative activity. Compound 2, a novobiocin analogue, was identified as a MAPK pathway signaling disruptor that lacked Hsp90 inhibitory activity. In addition, structural modifications of compound 2 were identified that segregated Hsp90 inhibition from MAPK signaling disruption. These studies indicate that compound 2 represents a novel scaffold for disruption of MAPK pathway signaling and may serve as a useful structure for the generation of new anticancer agents. PMID:26745854

  13. Synthesis, crystal structure, high-temperature behavior and magnetic properties of CoBiO(AsO4), a Co analogue of paganoite

    NASA Astrophysics Data System (ADS)

    Aliev, Almaz; Kozin, Michael S.; Colmont, Marie; Siidra, Oleg I.; Krivovichev, Sergey V.; Mentré, Olivier

    2015-09-01

    Single crystals and powder samples of Co analogue of paganoite CoBiO(AsO4) have been obtained by high-temperature solid-state reactions. Crystal structure [triclinic, , a = 5.2380(3), b = 6.8286(4), c = 7.6150(4) Å, α = 111.631(2), β = 108.376(2), γ = 108.388(2)°, V = 209.55(2) Å3] has been refined to R 1 = 0.018 on the basis of 1524 unique observed reflections. CoBiO(AsO4) is isotypic to paganoite, NiBiO(AsO4). The crystal structure can be described as based upon [OCoBi]3+ chains of edge-sharing (OBi2Co2) tetrahedra linked via (AsO4) groups. Differential thermal analysis reveals no phase decomposition till 850 °C, when the compound starts to melt. A small endothermic peak is observed near 330 °C. Thermal expansion has been studied by high-temperature powder X-ray diffraction. Thermal expansion coefficients ( α a = 10.1 × 10-6, α b = 12.6 × 10-6, α c = 10.5 × 10-6 K-1) indicate a relatively isotropic behavior with the less intense expansion direction parallel to the direction of the chains of oxocentered tetrahedra. Magnetic susceptibility of CoBiO(AsO4) reveals the presence of an antiferromagnetic ordering at T N = 15.4 K.

  14. STRUCTURE-ACTIVITY STUDY OF PARACETAMOL ANALOGUES: INHIBITION OF REPLICATIVE DNA SYNTHESIS IN V79 CHINESE HAMSTER CELLS

    EPA Science Inventory

    Experimental and theoretical evidence pertaining to cytotoxic and genotoxic activity of paracetamol in biological systems was used to formulate a simple mechanistic hypothesis to explain the relative inhibition of replicative DNA synthesis by a series of 19 structurally similar p...

  15. Study of structure and orientation of mesentericin Y105, a bacteriocin from Gram-positive Leuconostoc mesenteroides, and its Trp-substituted analogues in phospholipid environments.

    PubMed

    Castano, Sabine; Desbat, Bernard; Delfour, Antoine; Dumas, Jean Marie; da Silva, Alexandra; Dufourcq, Jean

    2005-02-01

    Mesentericin Y105 (Mes-Y105) is a bacteriocin secreted by Leuconostoc mesenteroides which is particularly active on Listeria. It is constituted by 37 residues and reticulated by one disulfide bridge. It has two W residues, W18 and W37, which can be studied by fluorescence. Two single substituted W/F analogues were synthesized (Mes-Y105/W18 and Mes-Y105/W37) to differentiate the local environment around each W and to study their changes in the presence of lipid vesicles. Fluorescence experiments show that, for the pure Trp-analogues, W18 and W37 are fully exposed to solvent whatever pH and buffer conditions. In the presence of lipid vesicles, both became buried. Lipid affinities were estimated: they are weak for zwitterionic phospholipids but an order of magnitude higher for negatively charged phosphatidylserine (PS) and phosphatidylglycerol (PG) lipids. On negatively charged PG lipids, Mes-Y105 and Mes-Y105/W37 display comparable lipid affinities. A decrease in lipid affinity is observed for Mes-Y105/W18 compared to Mes-Y105, which means that W37 would seem to be required for increased lipid selectivity. In the lipid-bound state W18 is strongly dehydrated, probably embedded into the acyl chains, while W37 stands more at the interface. Mes-Y105 was also studied by polarization modulation infrared reflection absorption spectroscopy (PMIRRAS), alone and in various phospholipid environments, to obtain structural information and to assess lipid perturbations. At nanomolar concentrations close to those required for anti-Listeria activity, Mes-Y105 forms films at the air/water interface and inserts into negatively charged lipid monolayers. In situ infrared data show that Mes-Y105 binding only affects the polar head group vibrations while the lipid order of the acyl chains remains unaffected. The PMIRRAS show that Mes-Y105 folds into an N-terminal antiparallel beta-sheet followed by an alpha-helix, both structures being tilted (40 degrees) compared to the normal at the interface, which is in agreement with the thickness estimated by Brewster angle microscopy (BAM). All these data support the proposal of a new model for Mes-Y105 at the membrane interface. PMID:15670734

  16. Crystal structures and hydrogen bonding in the morpholinium salts of four phen-oxy-acetic acid analogues.

    PubMed

    Smith, Graham; Lynch, Daniel E

    2015-11-01

    The anhydrous salts morpholinium (tetra-hydro-2-H-1,4-oxazin-4-ium) phen-oxy-acetate, C4H10NO(+)·C8H7O3 (-), (I), morpholinium (4-fluoro-phen-oxy)acetate, C4H10NO(+)·C8H6 FO3 (-), (II), and isomeric morpholinium (3,5-di-chloro-phen-oxy)acetate (3,5-D), (III), and morpholinium (2,4-di-chloro-phen-oxy)acetic acid (2,4-D), C4H10NO(+)·C8H5Cl2O3 (-), (IV), have been determined and their hydrogen-bonded structures are described. In the crystals of (I), (III) and (IV), one of the the aminium H atoms is involved in a three-centre asymmetric cation-anion N-H⋯O,O' R 1 (2)(4) hydrogen-bonding inter-action with the two carboxyl O-atom acceptors of the anion. With the structure of (II), the primary N-H⋯O inter-action is linear. In the structures of (I), (II) and (III), the second N-H⋯Ocarbox-yl hydrogen bond generates one-dimensional chain structures extending in all cases along [100]. With (IV), the ion pairs are linked though inversion-related N-H⋯O hydrogen bonds [graph set R 4 (2)(8)], giving a cyclic hetero-tetra-meric structure. PMID:26594518

  17. Crystal structures and hydrogen bonding in the morpholinium salts of four phenoxyacetic acid analogues

    PubMed Central

    Smith, Graham; Lynch, Daniel E.

    2015-01-01

    The anhydrous salts morpholinium (tetrahydro-2-H-1,4-oxazin-4-ium) phenoxyacetate, C4H10NO+C8H7O3 ?, (I), morpholinium (4-fluorophenoxy)acetate, C4H10NO+C8H6?FO3 ?, (II), and isomeric morpholinium (3,5-dichlorophenoxy)acetate (3,5-D), (III), and morpholinium (2,4-dichlorophenoxy)acetic acid (2,4-D), C4H10NO+C8H5Cl2O3 ?, (IV), have been determined and their hydrogen-bonded structures are described. In the crystals of (I), (III) and (IV), one of the the aminium H atoms is involved in a three-centre asymmetric cationanion NH?O,O? R 1 2(4) hydrogen-bonding interaction with the two carboxyl O-atom acceptors of the anion. With the structure of (II), the primary NH?O interaction is linear. In the structures of (I), (II) and (III), the second NH?Ocarboxyl hydrogen bond generates one-dimensional chain structures extending in all cases along [100]. With (IV), the ion pairs are linked though inversion-related NH?O hydrogen bonds [graph set R 4 2(8)], giving a cyclic heterotetrameric structure. PMID:26594518

  18. A cytotoxic principle of Tamarindus indica, di-n-butyl malate and the structure-activity relationship of its analogues.

    PubMed

    Kobayashi, A; Adenan, M I; Kajiyama, S; Kanzaki, H; Kawazu, K

    1996-01-01

    Bioassay-guided fractionation of the methanolic extract of Tamarindus indica fruits led to the isolation of L-(-)-di-n-butyl malate which exhibited a pronounced cytotoxic activity against sea urchin embryo cells. In order to study structure-activity relationships, close-structure relatives of di-n-butyl malate were synthesized using D-(+)- and L-(-)-malic acid as starting materials, and their cytotoxic activities were examined for the sea urchin embryo assay. L-(-)-Di-n-pentyl malate was the most effective inhibitor to the development of the fertilized eggs. Significant inhibitory activity was not seen in the esters of D-(-)-isomer. PMID:8639230

  19. Improving the hydrogen-adsorption properties of a hydroxy-modified MIL-53(Al) structural analogue by lithium doping.

    PubMed

    Himsl, Dieter; Wallacher, Dirk; Hartmann, Martin

    2009-01-01

    Lithium makes the difference: A simple strategy for the synthesis of lithium-doped porous metal-organic frameworks (MOFs) is developed (see structure; C black, O red, AlO(6) blue octahedra), thus paving the way for the facile preparation of lithium-doped MOFs. Moreover, the significant increase in hydrogen adsorption predicted by theoretical calculations is observed. PMID:19455533

  20. Augmenting the activity of antifungal agents against aspergilli using structural analogues of benzoic acid as chemosensitizing agents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids were increased against strains of Aspergillus flavus, A. fumigatus and A. terreus, causative agents of human aspergillosis, by addition of a methyl, methoxyl or a chloro group at position 4 of the aromatic ri...

  1. New Kagome metal Sc?Mn?Al?Si? and its gallium-doped analogues: synthesis, crystal structure, and physical properties.

    PubMed

    He, Hua; Miiller, Wojciech; Aronson, Meigan C

    2014-09-01

    We report the synthesis, crystal structure, and basic properties of the new intermetallic compound Sc3Mn3Al7Si5. The structure of the compound was established by single-crystal X-ray diffraction, and it crystallizes with a hexagonal structure (Sc3Ni11Si4 type) with Mn atoms forming the Kagome nets. The dc magnetic susceptibility measurements reveal a Curie-Weiss moment of ~0.51 ?(B)/Mn; however, no magnetic order is found for temperatures as low as 1.8 K. Electrical resistivity and heat capacity measurements show that this compound is definitively metallic, with a relatively large specific heat Sommerfeld coefficient, indicating strong electronic correlations. Intriguingly, these features have revealed Sc3Mn3Al7Si5 as a possible quantum spin liquid. With chemical and lattice disorder introduced by doping, a spin liquid to spin glass transition is observed in the highest Ga-doped compounds. The roles of the geometrically frustrated structure and Mn-ligand hybridization in the magnetism of the title compounds are also discussed. PMID:25144523

  2. Augmenting the activity of antifungal agents against aspergilli using structural analogues of benzoic acid as chemosensitizing agents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Several benzoic acid analogs showed antifungal activity against strains of Aspergillus flavus, A. fumigatus and A. terreus, causative agents of human aspergillosis. Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids increased by addition of a methyl, methoxyl...

  3. Direct exfoliation of carbon allotropes with structural analogues of self-assembled nanostructures and their photovoltaic applications.

    PubMed

    Lee, Woochul; Lee, Dong-Woo; Lee, Myongsoo; Hong, Jong-In

    2014-12-01

    Aromatic amphiphiles were self-assembled into 2-D nanosheets and 1-D nanofibers by systematically varying the volume fraction of the hydrophilic coils, which enabled the direct exfoliation of carbon allotropes with high quality and quantity. A 2-D nanosheet structure was introduced as the hole transporting layer for improving the performance of organic photovoltaic devices. PMID:25325079

  4. KEY, LOCK, and LOCKSMITH: complementary hydropathic map predictions of drug structure from a known receptor-receptor structure from known drugs.

    PubMed

    Kellogg, G E; Abraham, D J

    1992-12-01

    Three new routines (LOCK, KEY and LOCKSMITH) for the program HINT (hydrophobic interactions) are described and demonstrated. The KEY routine uses receptor structure to model the hydropathic profile of the ideal substrate for the receptor. The LOCK routine uses substrate or drug structure to model the hydropathic character of the receptor. LOCKSMITH is an algorithm designed to highlight the significant hydropathic features from a collection of agents. Ten allosteric modifiers of hemoglobin that have been characterized biologically and with X-ray diffraction to determine their protein binding sites/conformations illustrate the KEY and LOCKSMITH routines: The LOCKSMITH composite map correctly identifies the structural features and conformation of the more active modifiers. In addition, many hydropathic features of the "ideal" drug predicted by the KEY map overlap with actual structural features of the most active hemoglobin allosteric modifiers. PMID:1476993

  5. Evaluation of Cancer Preventive Activity and Structure-Activity Relationships of 3-Demethylubiquinone Q2, Isolated from the Ascidian Aplidium glabrum, and its Synthetic Analogues

    PubMed Central

    Fedorov, Sergey N.; Radchenko, Oleg S.; Shubina, Larisa K.; Balaneva, Nadezhda N.; Bode, Ann M.; Stonik, Valentin A.; Dong, Zigang

    2006-01-01

    Purpose 3-Demethylubiquinone Q2 (1) was isolated from the ascidian Aplidium glabrum. The cancer preventive properties and the structure-activity relationship for 3-demethylubiquinone Q2 (1) and 12 of its synthetic analogues (3–14) are reported. Methods Compounds 3–14, having one or several di- or triprenyl substitutions and quinone moieties with methoxyls in different positions, were synthesized. The cancer preventive properties of compounds 1 and 3–14 were tested in JB6 Cl41 mouse skin cells, using a variety of assessments, including the MTS assay, flow cytometry, and soft agar assay. Statistical nonparametric methods were used to confirm statistical significance. Results All quinones tested were shown to inhibit JB6 Cl41 cell transformation, to induce apoptosis, AP-1 and NF-κB activity, and to inhibit p53 activity. The most promising effects were indicated for compounds containing two isoprene units in a side chain and a methoxyl group at the para-position to a polyprenyl substitution. Conclusions Quinones 1 and 3–14 demonstrated cancer preventive activity in JB6 Cl41 cells, which may be attributed to the induction of p53-independent apoptosis. These activities depended on the length of side chains and on the positions of the methoxyl groups in the quinone part of the molecule. PMID:16320003

  6. Structure of Bacillus subtilis γ-glutamyltranspeptidase in complex with acivicin: diversity of the binding mode of a classical and electrophilic active-site-directed glutamate analogue

    SciTech Connect

    Ida, Tomoyo; Suzuki, Hideyuki; Fukuyama, Keiichi; Hiratake, Jun; Wada, Kei

    2014-02-01

    The binding modes of acivicin, a classical and an electrophilic active-site-directed glutamate analogue, to bacterial γ-glutamyltranspeptidases were found to be diverse. γ-Glutamyltranspeptidase (GGT) is an enzyme that plays a central role in glutathione metabolism, and acivicin is a classical inhibitor of GGT. Here, the structure of acivicin bound to Bacillus subtilis GGT determined by X-ray crystallography to 1.8 Å resolution is presented, in which it binds to the active site in a similar manner to that in Helicobacter pylori GGT, but in a different binding mode to that in Escherichia coli GGT. In B. subtilis GGT, acivicin is bound covalently through its C3 atom with sp{sup 2} hybridization to Thr403 O{sup γ}, the catalytic nucleophile of the enzyme. The results show that acivicin-binding sites are common, but the binding manners and orientations of its five-membered dihydroisoxazole ring are diverse in the binding pockets of GGTs.

  7. Stress- as well as suckling-induced prolactin release is blocked by a structural analogue of the putative hypophysiotrophic prolactin-releasing factor, salsolinol.

    PubMed

    Bodnár, I; Mravec, B; Kubovcakova, L; Tóth, E B; Fülöp, F; Fekete, M I K; Kvetnansky, R; Nagy, G M

    2004-03-01

    Prolactin is secreted from the anterior lobe of the pituitary gland in response both to suckling and to stress. We recently observed that 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), produced in the neurointermediate lobe of the pituitary gland, as well as in the medial basal hypothalamus, can selectively release prolactin from the anterior pituitary. Therefore, it has been proposed that salsolinol is a putative endogenous prolactin-releasing factor (PRF). Here, we report that one structural analogue of salsolinol, 1-methyl-3,4-dihydroisoquinoline (1MeDIQ), can block salsolinol-induced release of prolactin, but does not affect prolactin release in response to thyrotropin releasing hormone (TRH), alpha-methyl-p-tyrosine (alpha MpT) (an inhibitor of tyrosine hydroxylase), domperidone (a D(2) dopamine receptor antagonist), or 5-hydroxytryptophan (5-HTP), a precursor of serotonin). 1MeDIQ profoundly inhibited suckling-, immobilization-, as well as formalin-stress induced prolactin release without any influence on corticosterone secretion. The 1MeDIQ-induced reduction in prolactin response to immobilization stress was dose-dependent. These results suggest that salsolinol can play a pivotal role in the regulation of prolactin release induced by either physiological (suckling) or environmental (stress) stimuli. PMID:15049851

  8. Fluorous Analogue of Chloramine-T: Preparation, X-ray Structure Determination, and Use as an Oxidant for Radioiodination and s-Tetrazine Synthesis.

    PubMed

    Dzandzi, James P K; Beckford Vera, Denis R; Genady, Afaf R; Albu, Silvia A; Eltringham-Smith, Louise J; Capretta, Alfredo; Sheffield, William P; Valliant, John F

    2015-07-17

    A fluorous oxidant that can be used to introduce radioiodine into small molecules and proteins and generate iodinated tetrazines for bioorthogonal chemistry has been developed. The oxidant was prepared in 87% overall yield by combining a fluorous amine with tosyl chloride, followed by chlorination using aqueous sodium hypochlorite. A crystal structure of the oxidant, which is a fluorous analogue of chloramine-T, was obtained. The compound was shown to be stable for 7 days in EtOH and for longer than three months as a solid. The oxidant was effective at promoting the labeling of arylstannanes using [(125)I]NaI, where products were isolated in high specific activity in yields ranging from 46% to 86%. Similarly, iodinated biologically active proteins (e.g., thrombin) were successfully produced, as well as a radioiodinated tetrazine, through a concomitant oxidation-halodemetalation reaction. Because of its fluorous nature, unreacted oxidant and associated reaction byproducts can be removed quantitatively from reaction mixtures by passing solutions through fluorous solid phase extraction cartridges. This feature enables rapid and facile purification, which is critical when working with radionuclides and is similarly beneficial for general synthetic applications. PMID:26030355

  9. An Attempt to Infer the Electrophysiological Functions of Some Intracellular Structures in Cardiac Cells by an Electronic Analogue

    PubMed Central

    Challice, C. E.; Clark, T. A.

    1966-01-01

    A circuit which simulates the electrical conduction characteristics of the neuron has been modified by the addition of a feedback loop to simulate the electrical properties of some of the specialized tissues of the mammalian heart. It is suggested that there is similar electrical feedback in the muscle cells which is responsible for their electrical properties, and possible relationships between the feedback and observed structures are discussed. PMID:5903154

  10. Structure-activity relationships in a series of melatonin analogues with the low-density lipoprotein oxidation model.

    PubMed

    Gozzo, A; Lesieur, D; Duriez, P; Fruchart, J C; Teissier, E

    1999-06-01

    Despite an increasing number of publications concerning the antioxidant activity of melatonin, little is known about the structural features responsible for this kind of activity. To understand the role played by the different elements of melatonin structure in its antioxidant activity, we have designed and tested several compounds related to this molecule in the low-density lipoprotein peroxidation model. We present here the results of this study in terms of structure-activity relationships focusing on the influence of the acetamidoethyl side chain, the methoxy group, and the indole heterocycle. In this model, we found that changing the acyl residue generally resulted in more active products. We obtained particularly good results with the nonanoyl derivative which showed a level of activity comparable to that of phenols despite lacking a phenolic function. The presence of a methoxy group in position 5 generally had a beneficial influence on the activity, but when located in position 6, the effects were various. The substitution of a hydroxy for the methoxy group led to phenolic compounds endowed with very high antioxidant activity. Replacing the amide with a ketone function did not affect the activity while replacement with an amine group in some cases resulted in prooxidant compounds. Finally, we compared the efficacy of different aromatic rings. The indole heterocycle proved to be better than benzofurane and naphthalene rings. PMID:10401620

  11. Crystal Structure of Insulin-Regulated Aminopeptidase with Bound Substrate Analogue Provides Insight on Antigenic Epitope Precursor Recognition and Processing.

    PubMed

    Mpakali, Anastasia; Saridakis, Emmanuel; Harlos, Karl; Zhao, Yuguang; Papakyriakou, Athanasios; Kokkala, Paraskevi; Georgiadis, Dimitris; Stratikos, Efstratios

    2015-09-15

    Aminopeptidases that generate antigenic peptides influence immunodominance and adaptive cytotoxic immune responses. The mechanisms that allow these enzymes to efficiently process a vast number of different long peptide substrates are poorly understood. In this work, we report the structure of insulin-regulated aminopeptidase, an enzyme that prepares antigenic epitopes for cross-presentation in dendritic cells, in complex with an antigenic peptide precursor analog. Insulin-regulated aminopeptidase is found in a semiclosed conformation with an extended internal cavity with limited access to the solvent. The N-terminal moiety of the peptide is located at the active site, positioned optimally for catalysis, whereas the C-terminal moiety of the peptide is stabilized along the extended internal cavity lodged between domains II and IV. Hydrophobic interactions and shape complementarity enhance peptide affinity beyond the catalytic site and support a limited selectivity model for antigenic peptide selection that may underlie the generation of complex immunopeptidomes. PMID:26259583

  12. Water induces a structural conversion and accelerates the oxygenation of carboxylate-bridged non-heme diiron enzyme synthetic analogues.

    PubMed

    Zhao, Min; Song, Datong; Lippard, Stephen J

    2006-08-01

    Recently, we reported the synthesis of a carboxylate-rich non-heme diiron enzyme model compound [Fe2(mu-O2CAr(Tol))4(4-CNPy)2] (1), where (-)O(2)CAr(Tol) is 2,6-di-p-tolylbenzoate and 4-CNPy is 4-cyanopyridine (Yoon, S.; Lippard, S. J. J. Am. Chem. Soc. 2005, 127, 8386-8397). A metal-to-ligand charge-transfer band in the visible region of the optical absorption spectrum involving the nitrogen-donor ligand endowed this complex with a distinctive red color that facilitated analysis of its chemistry. Following this strategy, we prepared and characterized two related isomeric complexes, windmill (3) and paddlewheel (4) species having the formula [Fe2(O2CAr(Tol))4(4-AcPy)2], where 4-AcPy is 4-acetylpyridine. In anhydrous solvents, 1 and 4 adopt paddlewheel structures, but upon the addition of water, they convert to aquated forms, windmill structures having the composition [Fe2(mu-O2CAr(Tol))2(O2CAr(Tol))2(4-RPy)2(H2O)2]. This conversion is favored at low temperature and was studied by NMR spectroscopy. A kinetic analysis of the aquation reaction was undertaken by stopped-flow measurements between 198 and 223 K for both 1 and 4, which revealed a first-order dependence on both the diiron compound and water. The oxygenation rates for the water-containing complexes are much faster than those for the corresponding anhydrous complexes, being 20-fold faster for 4 and 10-fold more rapid for 1. The presence or absence of water had little effect on the activation enthalpies, suggesting that the loss of water may not be necessary prior to dioxygen binding in the transition state. PMID:16878942

  13. Structural Analysis of Peptide-Analogues of Human Zona Pellucida ZP1 Protein with Amyloidogenic Properties: Insights into Mammalian Zona Pellucida Formation

    PubMed Central

    Louros, Nikolaos N.; Iconomidou, Vassiliki A.; Giannelou, Polina; Hamodrakas, Stavros J.

    2013-01-01

    Zona pellucida (ZP) is an extracellular matrix surrounding and protecting mammalian and fish oocytes, which is responsible for sperm binding. Mammalian ZP consists of three to four glycoproteins, called ZP1, ZP2, ZP3, ZP4. These proteins polymerize into long interconnected filaments, through a common structural unit, known as the ZP domain, which consists of two domains, ZP-N and ZP-C. ZP is related in function to silkmoth chorion and in an evolutionary fashion to the teleostean fish chorion, also fibrous structures protecting the oocyte and embryo, that both have been proven to be functional amyloids. Two peptides were predicted as ‘aggregation-prone’ by our prediction tool, AMYLPRED, from the sequence of the human ZP1-N domain. Here, we present results from transmission electron microscopy, X-ray diffraction, Congo red staining and attenuated total reflectance Fourier-transform infrared spectroscopy (ATR FT-IR), of two synthetic peptide-analogues of these predicted ‘aggregation-prone’ parts of the human ZP1-N domain, that we consider crucial for ZP protein polymerization, showing that they both self-assemble into amyloid-like fibrils. Based on our experimental data, we propose that human ZP (hZP) might be considered as a novel, putative, natural protective amyloid, in close analogy to silkmoth and teleostean fish chorions. Experiments are in progress to verify this proposal. We also attempt to provide insights into ZP formation, proposing a possible model for hZP1-N domain polymerization. PMID:24069181

  14. A Mission Control Architecture for robotic lunar sample return as field tested in an analogue deployment to the sudbury impact structure

    NASA Astrophysics Data System (ADS)

    Moores, John E.; Francis, Raymond; Mader, Marianne; Osinski, G. R.; Barfoot, T.; Barry, N.; Basic, G.; Battler, M.; Beauchamp, M.; Blain, S.; Bondy, M.; Capitan, R.-D.; Chanou, A.; Clayton, J.; Cloutis, E.; Daly, M.; Dickinson, C.; Dong, H.; Flemming, R.; Furgale, P.; Gammel, J.; Gharfoor, N.; Hussein, M.; Grieve, R.; Henrys, H.; Jaziobedski, P.; Lambert, A.; Leung, K.; Marion, C.; McCullough, E.; McManus, C.; Neish, C. D.; Ng, H. K.; Ozaruk, A.; Pickersgill, A.; Preston, L. J.; Redman, D.; Sapers, H.; Shankar, B.; Singleton, A.; Souders, K.; Stenning, B.; Stooke, P.; Sylvester, P.; Tornabene, L.

    2012-12-01

    A Mission Control Architecture is presented for a Robotic Lunar Sample Return Mission which builds upon the experience of the landed missions of the NASA Mars Exploration Program. This architecture consists of four separate processes working in parallel at Mission Control and achieving buy-in for plans sequentially instead of simultaneously from all members of the team. These four processes were: science processing, science interpretation, planning and mission evaluation. science processing was responsible for creating products from data downlinked from the field and is organized by instrument. Science Interpretation was responsible for determining whether or not science goals are being met and what measurements need to be taken to satisfy these goals. The Planning process, responsible for scheduling and sequencing observations, and the Evaluation process that fostered inter-process communications, reporting and documentation assisted these processes. This organization is advantageous for its flexibility as shown by the ability of the structure to produce plans for the rover every two hours, for the rapidity with which Mission Control team members may be trained and for the relatively small size of each individual team. This architecture was tested in an analogue mission to the Sudbury impact structure from June 6-17, 2011. A rover was used which was capable of developing a network of locations that could be revisited using a teach and repeat method. This allowed the science team to process several different outcrops in parallel, downselecting at each stage to ensure that the samples selected for caching were the most representative of the site. Over the course of 10 days, 18 rock samples were collected from 5 different outcrops, 182 individual field activities - such as roving or acquiring an image mosaic or other data product - were completed within 43 command cycles, and the rover travelled over 2200 m. Data transfer from communications passes were filled to 74%. Sample triage was simulated to allow down-selection to 1 kg of material for return to Earth.

  15. Desferrithiocin Analogue Uranium Decorporation Agents

    PubMed Central

    Bergeron, Raymond J.; Wiegand, Jan; Singh, Shailendra

    2010-01-01

    Purpose Previous systematic structure-activity studies of the desferrithiocin (DFT) platform have allowed the design and synthesis of analogues and derivatives of DFT that retain the exceptional iron-clearing activity of the parent, while eliminating its adverse effects. We hypothesized that a similar approach could be adopted to identify DFT-related analogues that could effectively decorporate uranium. Materials and Methods The decorporation properties of nine DFT-related analogues were determined in a bile duct-cannulated rat model. Diethylenetriaminepentaacetic acid (DTPA) served as a positive control. Selected ligands also underwent multiple and delayed dosing regimens. Uranium excretion in urine and bile or stool was determined by inductively coupled plasma mass spectroscopy (ICP-MS); tissue levels of uranium were also assessed. Results The two best clinical candidates are (S)-4,5-dihydro-2-[2-hydroxy-4-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT-PE (9)], with a 57% reduction in kidney uranium levels on oral (p.o.) administration and (S)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-3'-(HO)-DADFT-PE (10)], with a 62% renal reduction on p.o. administration. The majority of the metal excretion promoted by these analogues is in the bile, thus further reducing kidney actinide exposure. Conclusions While 9 administered p.o. or subcutaneously (s.c.) immediately post-metal is an effective decorporation agent, withholding the dose (s.c.) until 4 h reduced the activity of the compound. Conversion of 9 to its isopropyl ester may circumvent this issue. PMID:19399680

  16. Structure-Activity Relationships of Neplanocin A Analogues as S-Adenosylhomocysteine Hydrolase Inhibitors and Their Antiviral and Antitumor Activities.

    PubMed

    Chandra, Girish; Moon, Yang Won; Lee, Yoonji; Jang, Ji Yong; Song, Jayoung; Nayak, Akshata; Oh, Kawon; Mulamoottil, Varughese A; Sahu, Pramod K; Kim, Gyudong; Chang, Tong-Shin; Noh, Minsoo; Lee, Sang Kook; Choi, Sun; Jeong, Lak Shin

    2015-06-25

    On the basis of the potent inhibitory activity of neplanocin A (1) against S-adenosylhomocysteine (AdoHcy) hydrolase, we analyzed the comprehensive structure-activity relationships by modifying the adenine and carbasugar moiety of 1 to find the pharmacophore in the active site of the enzyme. The introduction of 7-deazaadenine instead of adenine eliminated the inhibitory activity against the AdoHcy hydrolase, while 3-deazaadenine maintained the inhibitory activity of the enzyme, indicating that N-7 is essential for its role as a hydrogen bonding acceptor. The substitution of hydrogen at the 6'-position with fluorine increased the inhibitory activity of the enzyme. The one-carbon homologation at the 5'-position generally decreased the inhibitory activity of the enzyme, indicating that steric repulsion exists. A molecular docking study also supported these experimental data. In this study, 6'-fluoroneplanocin A (2) was the most potent inhibitor of AdoHcy hydrolase (IC50 = 0.24 ?M). It showed a potent anti-VSV activity (EC50 = 0.43 ?M) and potent anticancer activity in all the human tumor cell lines tested. PMID:26010585

  17. Structural analysis of metabolites of asiatic acid and its analogue madecassic acid in zebrafish using LC/IT-MSn.

    PubMed

    Xia, Binbin; Bai, Lu; Li, Xiaorong; Xiong, Jie; Xu, Pinxiang; Xue, Ming

    2015-01-01

    Although zebrafish has become a significant animal model for drug discovery and screening, drug metabolism in zebrafish remains largely unknown. Asiatic acid (AA) and madecassic acid (MA), two natural pentacyclic triterpenoids mainly obtained from Centella asiatica (L.) Urban, have been found to possess many pharmacological effects. This study is to probe the metabolic capability of zebrafish via investigation of the drug metabolism of AA and MA in zebrafish, using a sensitive LC/IT-MSn method. In addition, the main fragmentation pathways of AA and MA were reported for the first time. Nineteen metabolites of AA and MA were firstly identified after zebrafish was exposed to the drug, which all were the phase I metabolites and mainly formed from hydroxylation, dehydrogenation, hydroxylation and dehydrogenation, dihydroxylation and dehydrogenation, and dehydroxylation reaction. The results indicated that zebrafish possessed strong metabolic capacity, and the metabolites of AA and MA were formed via similar metabolic pathways and well matched with the known metabolic rules in vivo and in vitro, which supports the widely use of this system in drug metabolism research. This investigation would also contribute to the novel information on the structural elucidation, in vivo metabolites and metabolic mechanism of pentacyclic triterpenoids. PMID:25685908

  18. Mobilizing Communities around HIV Prevention for Youth: How Three Coalitions Applied Key Strategies to Bring about Structural Changes

    ERIC Educational Resources Information Center

    Chutuape, Kate S.; Willard, Nancy; Sanchez, Kenia; Straub, Diane M.; Ochoa, Tara N.; Howell, Kourtney; Rivera, Carmen; Ramos, Ibrahim; Ellen, Jonathan M.

    2010-01-01

    Increasingly, HIV prevention efforts must focus on altering features of the social and physical environment to reduce risks associated with HIV acquisition and transmission. Community coalitions provide a vehicle for bringing about sustainable structural changes. This article shares lessons and key strategies regarding how three community

  19. Mobilizing Communities around HIV Prevention for Youth: How Three Coalitions Applied Key Strategies to Bring about Structural Changes

    ERIC Educational Resources Information Center

    Chutuape, Kate S.; Willard, Nancy; Sanchez, Kenia; Straub, Diane M.; Ochoa, Tara N.; Howell, Kourtney; Rivera, Carmen; Ramos, Ibrahim; Ellen, Jonathan M.

    2010-01-01

    Increasingly, HIV prevention efforts must focus on altering features of the social and physical environment to reduce risks associated with HIV acquisition and transmission. Community coalitions provide a vehicle for bringing about sustainable structural changes. This article shares lessons and key strategies regarding how three community…

  20. Detection of sildenafil analogues in herbal products for erectile dysfunction.

    PubMed

    Oh, Sharon Sze-Yin; Zou, Peng; Low, Min-Yong; Koh, Hwee-Ling

    2006-11-01

    Sildenafil, the active ingredient in Viagra (Pfizer), is a prescription medicine used for erectile dysfunction. Compounds with chemical structures similar to that of sildenafil were isolated and purified during the analysis of some herbal products marketed for treatment of erectile dysfunction. Structural elucidation using liquid chromatography-diode array detection, infrared spectroscopy, liquid chromatography-tandem mass spectrometry, and nuclear magnetic resonance spectroscopy confirmed that the compounds were homosildenafil, hydroxyhomosildenafil, and acetildenafil. The implications of adulteration by compounds structurally related to prescription drugs are discussed. Unlike established drugs, the efficacy and safety of such analogues are largely unknown. This poses a great challenge for safety and health administrators to detect these modified structures and to regulate them. Consumers who use such adulterated products are at risk of developing serious adverse reactions, potentially leading to death. Greater collaboration and exchange of information between various health authorities, health professionals, academics, researchers, and industry, as well as public education, are key steps in the efforts to stem the growing trend of adulteration of herbal products by analogues of prescription drugs. PMID:16982533

  1. Stabilization of the potent odorant 2-acetyl-1-pyrroline and structural analogues by complexation with zinc halides.

    PubMed

    Fang, Ming-Chih; Cadwallader, Keith R

    2014-09-01

    2-Acetyl-1-pyrroline (2AP) and the structurally similar compounds 6-acetyl-2,3,4,5-tetrahydropyridine (ATHP, along with its tautomer 6-acetyl-1,2,3,4-tetrahydropyridine), 2-propionyl-1-pyrroline (2PP), and 2-acetyl-2-thiazoline (2A2T) are well-known potent odorants in various food products. However, due to the highly unstable nature of these compounds, especially 2AP and ATHP, they are scarcely used commercially in flavor formulations. A novel and attractive method for the stabilization of these potent odorants in dry powder form is presented. Coordination of 2AP, ATHP, 2PP, and 2A2T to zinc ions (ZnI2, ZnBr2, or ZnCl2) resulted in the formation in high yields of stable crystalline complexes, which upon hydration release the free odorant. Infrared spectroscopy was used to study the coordination complexes. 2AP contains donor atoms, which coordinate (with covalent character) through both the heterocyclic nitrogen and carbonyl oxygen atoms to the zinc ion. This is also the case for ATHP and 2PP, but not for 2A2T, because the sulfur group in 2A2T provides a third possible donor site. Stability studies showed that the 2AP-ZnI2 complex (with 14% loading) maintained >94% retention of 2AP after 3 months of storage at ambient temperature in a dry environment. Meanwhile, the ATHP-ZnI2 complex was similarly stable and retained 89% of the ATHP after 3 months of storage. This stabilization technology may enable the commercial use of this powerful aroma compound as a flavoring agent. PMID:25147956

  2. Design, Synthesis, and Evaluation of Irciniastatin Analogues: Simplification of the Tetrahydropyran Core and the C(11) Substituents.

    PubMed

    Liu, Qi; An, Chihui; TenDyke, Karen; Cheng, Hongsheng; Shen, Young Yongchun; Hoye, Adam T; Smith, Amos B

    2016-03-01

    The design, synthesis, and biological evaluation of irciniastatin A (1) analogues, achieved by removal of three synthetically challenging structural units, as well as by functional group manipulation of the C(11) substituent of both irciniastatins A and B (1 and 2), has been achieved. To this end, we first designed a convergent synthetic route toward the diminutive analogue (+)-C(8)-desmethoxy-C(11)-deoxy-C(12)-didesmethylirciniastatin (6). Key transformations include an acid-catalyzed 6-exo-tet pyran cyclization, a chiral Lewis acid mediated aldol reaction, and a facile amide union. The absolute configuration of 6 was confirmed via spectroscopic analysis (CD spectrum, HSQC, COSY, and ROESY NMR experiments). Structure-activity relationship (SAR) studies of 6 demonstrate that the absence of the three native structural units permits access to analogues possessing cytotoxic activity in the nanomolar range. Second, manipulation of the C(11) position, employing late-stage synthetic intermediates from our irciniastatin syntheses, provides an additional five analogues (7-11). Biological evaluation of these analogues indicates a high functional group tolerance at position C(11). PMID:26879056

  3. Planetary habitability: lessons learned from terrestrial analogues

    NASA Astrophysics Data System (ADS)

    Preston, Louisa J.; Dartnell, Lewis R.

    2014-01-01

    Terrestrial analogue studies underpin almost all planetary missions and their use is essential in the exploration of our Solar system and in assessing the habitability of other worlds. Their value relies on the similarity of the analogue to its target, either in terms of their mineralogical or geochemical context, or current physical or chemical environmental conditions. Such analogue sites offer critical ground-truthing for astrobiological studies on the habitability of different environmental parameter sets, the biological mechanisms for survival in extreme environments and the preservation potential and detectability of biosignatures. The 33 analogue sites discussed in this review have been selected on the basis of their congruence to particular extraterrestrial locations. Terrestrial field sites that have been used most often in the literature, as well as some lesser known ones which require greater study, are incorporated to inform on the astrobiological potential of Venus, Mars, Europa, Enceladus and Titan. For example, the possibility of an aerial habitable zone on Venus has been hypothesized based on studies of life at high-altitudes in the terrestrial atmosphere. We also demonstrate why many different terrestrial analogue sites are required to satisfactorily assess the habitability of the changing environmental conditions throughout Martian history, and recommend particular sites for different epochs or potential niches. Finally, habitable zones within the aqueous environments of the icy moons of Europa and Enceladus and potentially in the hydrocarbon lakes of Titan are discussed and suitable analogue sites proposed. It is clear from this review that a number of terrestrial analogue sites can be applied to multiple planetary bodies, thereby increasing their value for astrobiological exploration. For each analogue site considered here, we summarize the pertinent physiochemical environmental features they offer and critically assess the fidelity with which they emulate their intended target locale. We also outline key issues associated with the existing documentation of analogue research and the constraints this has on the efficiency of discoveries in this field. This review thus highlights the need for a global open access database for planetary analogues.

  4. Synthesis of isoxazolidine-containing uridine derivatives as caprazamycin analogues.

    PubMed

    Yamaguchi, Mayumi; Matsuda, Akira; Ichikawa, Satoshi

    2015-01-28

    Simplification of caprazamycins, which are promising antibacterial nucleoside natural products, was conducted by scaffold-hopping of the structurally complex diazepanone moiety to the isoxazolidine scaffold. The designed isoxazolidine-containing uridine derivatives were synthesized by an intramolecular 1,3-dipolar cycloaddition of alkenyl nitrone as a key step. The lactone-fused isoxazolidine intermediate was easily converted to the target compounds by sequential introduction of key substituents upon ring-opening the lactone moiety by nucleophilic substitution and electrophilic capping of the resulting primary alcohol. Several analogues exhibited good activity against H. influenzae ATCC 10211 (MIC 0.25-0.5 ?g mL(-1)) and moderate activity against vancomycin-resistant E. faecalis SR7914 (MIC 4-8 ?g mL(-1)). PMID:25428330

  5. Analogue Representations of Spatial Objects and Tranformations.

    ERIC Educational Resources Information Center

    Cooper, Lynn A.

    Considerable discussion and debate have been devoted to the extent and nature of structural or functional correspondence between internal representations and their external visual counterparts. An analogue representation or process is one in which the relational structure of external events is preserved in the corresponding internal…

  6. Liquid chromatography coupled to quadrupole-time of flight tandem mass spectrometry based quantitative structure-retention relationships of amino acid analogues derivatized via n-propyl chloroformate mediated reaction.

    PubMed

    Kritikos, Nikolaos; Tsantili-Kakoulidou, Anna; Loukas, Yannis L; Dotsikas, Yannis

    2015-07-17

    In the current study, quantitative structure-retention relationships (QSRR) were constructed based on data obtained by a LC-(ESI)-QTOF-MS/MS method for the determination of amino acid analogues, following their derivatization via chloroformate esters. Molecules were derivatized via n-propyl chloroformate/n-propanol mediated reaction. Derivatives were acquired through a liquid-liquid extraction procedure. Chromatographic separation is based on gradient elution using methanol/water mixtures from a 70/30% composition to an 85/15% final one, maintaining a constant rate of change. The group of examined molecules was diverse, including mainly ?-amino acids, yet also ?- and ?-amino acids, ?-amino acid analogues, decarboxylated and phosphorylated analogues and dipeptides. Projection to latent structures (PLS) method was selected for the formation of QSRRs, resulting in a total of three PLS models with high cross-validated coefficients of determination Q(2)Y. For this reason, molecular structures were previously described through the use of descriptors. Through stratified random sampling procedures, 57 compounds were split to a training set and a test set. Model creation was based on multiple criteria including principal component significance and eigenvalue, variable importance, form of residuals, etc. Validation was based on statistical metrics Rpred(2),QextF2(2),QextF3(2) for the test set and Roy's metrics rm(Av)(2) and rm(?)(2), assessing both predictive stability and internal validity. Based on aforementioned models, simplified equivalent were then created using a multi-linear regression (MLR) method. MLR models were also validated with the same metrics. The suggested models are considered useful for the estimation of retention times of amino acid analogues for a series of applications. PMID:26044385

  7. Effects of Oblique Extension and Inherited Structure Geometry on Transfer Zone Development in Continental Rifts: A 4D Analogue Modeling Approach

    NASA Astrophysics Data System (ADS)

    Zwaan, Frank; Schreurs, Guido

    2015-04-01

    INTRODUCTION Inherited structures in the crust form weak zones along which deformation will focus during rifting. Along-strike connection of rift segments may occur along transfer zones, as observed in East Africa. Previous studies have focused on numerical and analog modeling of transfer zones (e.g. Acocella et al., 1999, Allken et al., 2012). We elaborate upon those by investigating the effects of 1) oblique extension and 2) the geometry of linked and non-linked inherited structures on the development of transfer zones. A further improvement is the use of X-ray Computer Tomography (CT) for detailed internal analysis. METHODS The experimental set-up (see Schreurs & Colleta, 1998) contains two sidewalls with a base of compressed foam and plexiglass bars stacked in between. Decompressing this base results in distributed deformation of the overlying model materials. Deforming the model laterally with a mobile base plate produces the strike-slip components for oblique extension. Divergence velocities are in the order of 5 mm/h, translating to ca. 5 mm/Ma in nature, and 1 cm represents 10 km. A 2 cm thick layer of viscous silicone represents the ductile lower crust and a 2 cm quartz sand layer the brittle upper crust. Inherited structures are created with thin lines of silicon laid down on top of the basal silicone layer. Several models were run in a CT-scanner to reveal the 3D evolution of internal structures with time, hence 4D. RESULTS Localization of deformation along the pre-defined structures works well. The models show that the structural style changes with extension obliquity, from wide rift structures to narrower rifts with internal oblique-slip and finally strike-slip structures. Furthermore, rift offset is an important parameter influencing the occurrence of linkage: increasing rift offset decreases linkage as previously observed by Allken et al. (2012). However, increasing divergence obliquity promotes transfer zone formation, as does the presence of rift-connecting inherited zones, whose strike is at an angle of >15 with respect to the divergence direction. CT-analysis indicates that faulting initiated shortly after the start of the experiments, while structures become only clearly visible at the surface only after 1:30h (4% extension). Rift boundary fault angles tend to decrease from an initial 70 to ca. 55 after 4:00h (10% extension). Further CT-analysis will reveal the 3D evolution of the transform zones in more detail. REFERENCES Acocella, V., Faccenna, C., Funiciello, R., Rossetti, F., 1999. Sand-box modelling of basement-controlled transfer zones in extensional domains. Terra Nova, Vol. 11, No. 4, pp 149-156 Allken, V., Huismans, R. S., Thieulot, C., 2012. Factors controlling the mode of rift interaction in brittle-ductile coupled systems: A 3D numerical study, Geochem. Geophys. Geosyst. Vol. 13, Q05010 Schreurs, G., Colletta, B. (1998) Analogue modelling of faulting in zones of continental transpression and transtension. In: Holdsworth, R. E., Strachan R. A., Dewey, J. F., (eds.) 1998. Continental Transpressional and Transtensional Tectonics. Geological Society, London, Special Publications. No. 135, pp 59-79

  8. Application of the McMurry Coupling Reaction in the Synthesis of Tri- and Tetra-arylethylene Analogues as Potential Cancer Chemotherapeutic Agents

    PubMed Central

    Tanpure, Rajendra P.; Harkrider, Amanda R.; Strecker, Tracy E.; Hamel, Ernest; Trawick, Mary Lynn; Pinney, Kevin G.

    2010-01-01

    Structural redesign of selected non-steroidal estrogen receptor binding compounds has previously been successful in the discovery of new inhibitors of tubulin assembly. Accordingly, tetra-substituted alkene analogues (21-30) were designed based in part on combinations of the structural and electronic components of tamoxifen and combretastatin A-4 (CA4). The McMurry coupling reaction was used as the key synthetic step in the preparation of these tri- and tetra-arylethylene analogues. The structural assignment of E, Z isomers was determined on the basis of 2D-NOESY experiments. The ability of these compounds to inhibit tubulin polymerization and cell growth in selected human cancer cell lines was evaluated. Although the compounds were found to be less potent than CA4, these analogues significantly advance the known structure activity relationship associated with the colchicine binding site on ?-tubulin. PMID:19733085

  9. Structural biology of the IL-1 superfamily: Key cytokines in the regulation of immune and inflammatory responses

    PubMed Central

    Krumm, Brian; Xiang, Yan; Deng, Junpeng

    2014-01-01

    Interleukin-1 superfamily of cytokines (IL-1, IL-18, IL-33) play key roles in inflammation and regulating immunity. The mechanisms of agonism and antagonism in the IL-1 superfamily have been pursued by structural biologists for nearly 20 years. New insights into these mechanisms were recently provided by the crystal structures of the ternary complexes of IL-1β and its receptors. We will review here the structural biology related to receptor recognition by IL-1 superfamily cytokines and the regulation of its cytokine activities by antagonists. PMID:24677376

  10. Clearance and early hydrolysis of atrial natriuretic factor in vivo. Structural analysis of cleavage sites and design of an analogue that inhibits hormone cleavage.

    PubMed Central

    Condra, C L; Leidy, E A; Bunting, P; Colton, C D; Nutt, R F; Rosenblatt, M; Jacobs, J W

    1988-01-01

    This study examines the clearance and early hydrolysis of atrial natriuretic factor (ANF) in vivo. Radiolabeled ANF was cleared from the circulation of the rat with biphasic kinetics; the majority (90%) of ANF cleared with a t1/2 of 15 s, the remaining peptide was cleared with a t1/2 of 5 min. Microsequence analysis of ANF peptides recovered from the circulation of rats revealed five major degradation products of the intact hormone. The first cleavage occurred between amino acids 12 and 13 of the hormone and would inactivate ANF. Over time, additional fragments of the hormone were generated, including fragments of 6, 7, 21, and 24 amino acids in length. Whole body radioautography of rats injected with [123I]-ANF revealed the kidney as a predominant organ involved in clearance of ANF. Subsequent amino acid sequence analyses of radiolabeled ANF exposed to the kidney in vivo indicated that this organ generated four of the five major hydrolysis products observed in circulation, namely, the 6, 7, 16, and 21 amino acid fragments of the hormone. In an attempt to stabilize ANF in vivo, a synthetic analogue of the hormone was prepared that contained the amino acid analogue, aminoisobutyric acid, substituted at position 13. This analogue completely abolished the in vivo cleavage of ANF at this site. These studies demonstrate the usefulness of a protein chemistry approach in characterizing hormone metabolism in vivo and designing analogues with enhanced in vivo stability to cleavage. Images PMID:2966813

  11. Soil Surface Structure: A key factor for the degree of soil water repellency

    NASA Astrophysics Data System (ADS)

    Ahn, S.; Doerr, S. H.; Douglas, P.; Bryant, R.; Hamlett, C.; McHale, G.; Newton, M.; Shirtcliffe, N.

    2012-04-01

    Despite of considerable efforts, the degree of water repellency has not always been fully explained by chemical property of soil (termed hydrophobicity). That might be because the structure of a soil surface was not considered properly, which is another main factor determining the severity of soil water repellency. Surface structure has only recently been considered in soil science, whilst it has been paid attention for several decades in materials science due to its relevance to industrial applications. In this contribution, comparison of critical contact angles measured on different surface structures (made with glass beads, glass shards and beach sands) is presented and the effect of surface structure on manifestation of soil water repellency is discussed in terms of several different variables such as the individual particles shape, and areal and structural factors of the actual surface.

  12. Particle trapping: A key requisite of structure formation and stability of VlasovPoisson plasmas

    SciTech Connect

    Schamel, Hans

    2015-04-15

    Particle trapping is shown to control the existence of undamped coherent structures in VlasovPoisson plasmas and thereby affects the onset of plasma instability beyond the realm of linear Landau theory.

  13. Crystal structure and its bearing towards an understanding of key biological functions of EpCAM.

    PubMed

    Pavi?, Miha; Gun?ar, Gregor; Djinovi?-Carugo, Kristina; Lenar?i?, Brigita

    2014-01-01

    EpCAM (epithelial cell adhesion molecule), a stem and carcinoma cell marker, is a cell surface protein involved in homotypic cell-cell adhesion via intercellular oligomerization and proliferative signalling via proteolytic cleavage. Despite its use as a diagnostic marker and being a drug target, structural details of this conserved vertebrate-exclusive protein remain unknown. Here we present the crystal structure of a heart-shaped dimer of the extracellular part of human EpCAM. The structure represents a cis-dimer that would form at cell surfaces and may provide the necessary structural foundation for the proposed EpCAM intercellular trans-tetramerization mediated by a membrane-distal region. By combining biochemical, biological and structural data on EpCAM, we show how proteolytic processing at various sites could influence structural integrity, oligomeric state and associated functionality of the molecule. We also describe the epitopes of this therapeutically important protein and explain the antigenicity of its regions. PMID:25163760

  14. Impact melt-bearing breccias of the Mistastin Lake impact structure: A unique planetary analogue for ground-truthing proximal ejecta emplacement

    NASA Astrophysics Data System (ADS)

    Mader, M. M.; Osinski, G. R.

    2013-12-01

    Impact craters are the dominant geological landform on rocky planetary surfaces; however, relationships between specific craters and their ejecta are typically poorly constrained. With limited planetary samples, scientists look to terrestrial craters as analogues. Impact ejecta is defined here as any target material, regardless of its physical state, that is transported beyond the rim of the transient cavity [1]. The original transient cavity reaches its maximum size during the excavation stage of crater formation, before rim collapse begins in the modification stage [2]. In complex craters, during the modification stage, rocks around the periphery of the bowl-shaped transient crater collapse downward and inward to form a series of terraces along the outer margin of the crater structure [3]. Proximal impact ejecta, can therefore be found on the terraces of the modified rim of a complex crater, interior to the final crater rim [1]. Although typically poorly preserved on Earth due to post-impact erosional processes, impact ejecta have been identified in the terraced rim region of the Mistastin Lake impact structure, located in northern Labrador, Canada (5553'N; 6318'W) [4]. The Mistastin Lake impact structure is an intermediate-size, complex crater (28 km apparent crater diameter) formed by a meteorite impact ~36 Ma in crystalline target rocks. The original crater has been differentially eroded; however, a terraced rim and distinct central uplift are still observed [5]. The inner portion of the structure is covered by the Mistastin Lake and the surrounding area is locally covered by soil/glacial deposits and vegetation. Locally, allochthonous impactites overlying fractured target rocks are exposed along the lakeshore and along banks of radially cutting streams. They define a consistent stratigraphy, including, from bottom to top: monomict, lithic breccias, allochthonous polymict lithic breccias, and allochthonous impact melt rocks. Mistastin impact breccias range in matrix content, melt-fragment concentration, and contact relationships with adjacent impactites. Initial findings suggest differing origins for impact melt-bearing breccias from a single impact event. Three examples are highlighted: 1) Impact melt-bearing breccias, on an inner terrace, formed in boundary zones where hot impact melt flowed over cooler, ballistically emplaced polymict impact breccias. 2) Locally, a dyke of impact melt-bearing breccia suggests that this unit originated as hot lithic flow that moved laterally along the ground and then intruded as a fracture fill into target rocks. 3) A m-scale lens of melt-bearing breccia within the middle of a thick, 80m impact melt rock unit situated on an inner terrace, suggests that this lens may have originated from the crater floor and been incorporated into the melt pond during emplacement (i.e. movement of the melt from the crater floor to terrace shelf). In summary, the Mistastin Lake impact structure displays a multiple layered ejecta sequence that is consistent with, and requires, a multi-stage ejecta emplacement model as proposed by [1]. References: [1] Osinski et al. (2011) EPSL (310:167-181. [2] Melosh (1989) Oxford Univ. 245 pp. [3] French B. M. (1998) LPI Contribution 954,120pp. [4] Mader et al. (2011) 42nd LPSC, No.1608. [5] Mader et al. (2013) 43rd LPSC, No. 2517.

  15. Biophysical characterization of recombinant proteins: A key to higher structural genomics success

    PubMed Central

    Vedadi, Masoud; Arrowsmith, Cheryl H.; Allali-Hassani, Abdellah; Senisterra, Guillermo; Wasney, Gregory A.

    2010-01-01

    Hundreds of genomes have been successfully sequenced to date, and the data are publicly available. At the same time, the advances in large-scale expression and purification of recombinant proteins have paved the way for structural genomics efforts. Frequently, however, little is known about newly expressed proteins calling for large-scale protein characterization to better understand their biochemical roles and to enable structurefunction relationship studies. In the Structural Genomics Consortium (SGC), we have established a platform to characterize large numbers of purified proteins. This includes screening for ligands, enzyme assays, peptide arrays and peptide displacement in a 384-well format. In this review, we describe this platform in more detail and report on how our approach significantly increases the success rate for structure determination. Coupled with high-resolution X-ray crystallography and structure-guided methods, this platform can also be used toward the development of chemical probes through screening families of proteins against a variety of chemical series and focused chemical libraries. PMID:20466062

  16. Biophysical characterization of recombinant proteins: a key to higher structural genomics success.

    PubMed

    Vedadi, Masoud; Arrowsmith, Cheryl H; Allali-Hassani, Abdellah; Senisterra, Guillermo; Wasney, Gregory A

    2010-10-01

    Hundreds of genomes have been successfully sequenced to date, and the data are publicly available. At the same time, the advances in large-scale expression and purification of recombinant proteins have paved the way for structural genomics efforts. Frequently, however, little is known about newly expressed proteins calling for large-scale protein characterization to better understand their biochemical roles and to enable structure-function relationship studies. In the Structural Genomics Consortium (SGC), we have established a platform to characterize large numbers of purified proteins. This includes screening for ligands, enzyme assays, peptide arrays and peptide displacement in a 384-well format. In this review, we describe this platform in more detail and report on how our approach significantly increases the success rate for structure determination. Coupled with high-resolution X-ray crystallography and structure-guided methods, this platform can also be used toward the development of chemical probes through screening families of proteins against a variety of chemical series and focused chemical libraries. PMID:20466062

  17. Millennial Climatic Fluctuations Are Key to the Structure of Last Glacial Ecosystems

    PubMed Central

    Huntley, Brian; Allen, Judy R. M.; Collingham, Yvonne C.; Hickler, Thomas; Lister, Adrian M.; Singarayer, Joy; Stuart, Anthony J.; Sykes, Martin T.; Valdes, Paul J.

    2013-01-01

    Whereas fossil evidence indicates extensive treeless vegetation and diverse grazing megafauna in Europe and northern Asia during the last glacial, experiments combining vegetation models and climate models have to-date simulated widespread persistence of trees. Resolving this conflict is key to understanding both last glacial ecosystems and extinction of most of the mega-herbivores. Using a dynamic vegetation model (DVM) we explored the implications of the differing climatic conditions generated by a general circulation model (GCM) in normal and hosing experiments. Whilst the former approximate interstadial conditions, the latter, designed to mimic Heinrich Events, approximate stadial conditions. The hosing experiments gave simulated European vegetation much closer in composition to that inferred from fossil evidence than did the normal experiments. Given the short duration of interstadials, and the rate at which forest cover expanded during the late-glacial and early Holocene, our results demonstrate the importance of millennial variability in determining the character of last glacial ecosystems. PMID:23613985

  18. Millennial climatic fluctuations are key to the structure of last glacial ecosystems.

    PubMed

    Huntley, Brian; Allen, Judy R M; Collingham, Yvonne C; Hickler, Thomas; Lister, Adrian M; Singarayer, Joy; Stuart, Anthony J; Sykes, Martin T; Valdes, Paul J

    2013-01-01

    Whereas fossil evidence indicates extensive treeless vegetation and diverse grazing megafauna in Europe and northern Asia during the last glacial, experiments combining vegetation models and climate models have to-date simulated widespread persistence of trees. Resolving this conflict is key to understanding both last glacial ecosystems and extinction of most of the mega-herbivores. Using a dynamic vegetation model (DVM) we explored the implications of the differing climatic conditions generated by a general circulation model (GCM) in "normal" and "hosing" experiments. Whilst the former approximate interstadial conditions, the latter, designed to mimic Heinrich Events, approximate stadial conditions. The "hosing" experiments gave simulated European vegetation much closer in composition to that inferred from fossil evidence than did the "normal" experiments. Given the short duration of interstadials, and the rate at which forest cover expanded during the late-glacial and early Holocene, our results demonstrate the importance of millennial variability in determining the character of last glacial ecosystems. PMID:23613985

  19. Cell size as a key determinant of phytoplankton metabolism and community structure.

    PubMed

    Maran, Emilio

    2015-01-01

    Phytoplankton size structure controls the trophic organization of planktonic communities and their ability to export biogenic materials toward the ocean's interior. Our understanding of the mechanisms that drive the variability in phytoplankton size structure has been shaped by the assumption that the pace of metabolism decreases allometrically with increasing cell size. However, recent field and laboratory evidence indicates that biomass-specific production and growth rates are similar in both small and large cells but peak at intermediate cell sizes. The maximum nutrient uptake rate scales isometrically with cell volume and superisometrically with the minimum nutrient quota. The unimodal size scaling of phytoplankton growth arises from ataxonomic, size-dependent trade-off processes related to nutrient requirement, acquisition, and use. The superior ability of intermediate-size cells to exploit high nutrient concentrations explains their biomass dominance during blooms. Biogeographic patterns in phytoplankton size structure and growth rate are independent of temperature and driven mainly by changes in resource supply. PMID:25062405

  20. Learning to represent reward structure: a key to adapting to complex environments

    PubMed Central

    Nakahara, Hiroyuki; Hikosaka, Okihide

    2012-01-01

    Predicting outcomes is a critical ability of humans and animals. The dopamine reward prediction error hypothesis, the driving force behind the recent progress in neural value-based decision making, states that dopamine activity encodes the signals for learning in order to predict a reward, that is, the difference between the actual and predicted reward, called the reward prediction error. However, this hypothesis and its underlying assumptions limit the prediction and its error as reactively triggered by momentary environmental events. Reviewing the assumptions and some of the latest findings, we suggest that the internal state representation is learned to reflect the environmental reward structure, and we propose a new hypothesis the dopamine reward structural learning hypothesis in which dopamine activity encodes multiplex signals for learning in order to represent reward structure in the internal state, leading to better reward prediction. PMID:23069349

  1. The Genomic Threading Database: a comprehensive resource for structural annotations of the genomes from key organisms.

    PubMed

    McGuffin, Liam J; Street, Stefano A; Bryson, Kevin; Srensen, Sren-Aksel; Jones, David T

    2004-01-01

    Currently, the Genomic Threading Database (GTD) contains structural assignments for the proteins encoded within the genomes of nine eukaryotes and 101 prokaryotes. Structural annotations are carried out using a modified version of GenTHREADER, a reliable fold recognition method. The Gen THREADER annotation jobs are distributed across multiple clusters of processors using grid technology and the predictions are deposited in a relational database accessible via a web interface at http://bioinf.cs.ucl.ac.uk/GTD. Using this system, up to 84% of proteins encoded within a genome can be confidently assigned to known folds with 72% of the residues aligned. On average in the GTD, 64% of proteins encoded within a genome are confidently assigned to known folds and 58% of the residues are aligned to structures. PMID:14681393

  2. Cell Size as a Key Determinant of Phytoplankton Metabolism and Community Structure

    NASA Astrophysics Data System (ADS)

    Maran, Emilio

    2015-01-01

    Phytoplankton size structure controls the trophic organization of planktonic communities and their ability to export biogenic materials toward the ocean's interior. Our understanding of the mechanisms that drive the variability in phytoplankton size structure has been shaped by the assumption that the pace of metabolism decreases allometrically with increasing cell size. However, recent field and laboratory evidence indicates that biomass-specific production and growth rates are similar in both small and large cells but peak at intermediate cell sizes. The maximum nutrient uptake rate scales isometrically with cell volume and superisometrically with the minimum nutrient quota. The unimodal size scaling of phytoplankton growth arises from ataxonomic, size-dependent trade-off processes related to nutrient requirement, acquisition, and use. The superior ability of intermediate-size cells to exploit high nutrient concentrations explains their biomass dominance during blooms. Biogeographic patterns in phytoplankton size structure and growth rate are independent of temperature and driven mainly by changes in resource supply.

  3. Structure and Dynamics of Thin Ionomer Films: a Key to A Stable Fuel Cell Membrane.

    NASA Astrophysics Data System (ADS)

    Perahia, Dvora

    2000-03-01

    The technology for solid polymeric electrolytic membranes for a fuel cells, calls for the thinnest film which is electrochemically stable. At present, none supported polymeric solid state fuel cell membranes, thinner than 50 microns, fail mechanically during fuel cell operation. When approaching the thin film limits, interfacial effects become significant to structure dynamics and consequently, the stability of the membranes. Our work focuses on understanding the interfacial effects on thin per-fluorinated ionomer films, including interfacial effects on the thin films themselves and nanotubes-thin film complexes, mimicking the catalyst-ionomer complexes. In particular we investigated the dynamics and structure in 500 angstrom and less, films made by several perfluorinated ionomers, cast on a solid support. Both the films and their parent solutions were investigated with the goal of resolving the factors that affect the stability in the ultra thin regime. AFM/STM and X-ray and neutron reflectivity were used to investigate the thin films and small angle neutron scattering was utilized to the study of the solutions. Films were both spin-coated and self assembles from solutions on a model oxidized single crystal silicon wafer, treated with HF. When coated from molecular solutions, the films tend to dewet on a time scale of minutes to hours. With increasing concentrations, above the critical micellar concentration of the ionomers in water/alcohol, stable films on the order of 200-500 angstroms were formed. While self-assembled films were found to be stable at temperatures close to Tg of the ionomer, spin-coated ones partially dewet. The surface structure obtained, exhibit periodicity on different length scales, depending on the concentration of the polymer in the solution from which the film was assembled. In the ultra dilute regime, micelles were detected at the solid interface. Films formed from dilute solutions exhibit fractal nature with a fractal dimension varying between 2 and 3. Further increase of the solution concentration resulted in oriented domains. The unique surface structures are attributed to natural micellization processes, which arise from the nature of the polymer. A close look into the structure of the self assembled films, revealed stacked of cylinders, a structure which differs from the well established bulk structure. These thin micellar films were found to be extremely stable. With the dramatic increase of film stability we observed as micelles are formed, further studies to quantify the interfacial interactions are currently underway together with subsequent studies of the factors, which govern the solution structure.

  4. Synthesis of fluorinated indoles as RNA analogues.

    PubMed

    Bozilovi?, Jelena; Engels, Joachim W

    2007-01-01

    Nucleoside analogues are chemical means to investigate hydrogen bonds, base stacking, and solvation as the three predominant forces that are responsible for the stability of secondary structure of nucleic acids. To obtain deeper insight into the contributions of these interactions to RNA stability apart from the ones exerted by the predominant nucleosides we decided to synthesize some novel nucleic acid analogues where the nucleobases are replaced by fluoroindoles. Fluorinated indoles can be compared to fluorinated benzimidazoles to determine the role of nitrogen in five membered ring system. The synthesis of fluoroindole ribonucleosides is described here. PMID:18058498

  5. Synthesis and antifeeding activities of Tonghaosu analogues.

    PubMed

    Chen, Li; Xu, Han-Hong; Yin, Biao-Lin; Xiao, Chun; Hu, Tai-Shan; Wu, Yu-Lin

    2004-11-01

    Tonghaosu (1), a lead for a botanical antifeedant, and its 22 analogues were synthesized according to a previously reported concise and straightforward procedure. The structures of all new compounds were confirmed by NMR, IR, MS, and HREIMS or elemental analysis. Their insect antifeedant activities against the large white butterfly (Pieris brassicae L.) were examined, and six analogues (Z- and E-6h and Z-isomers of 6i-l), which contain 1,3-diyn or 3,4-methylenedioxyphenyl acetylene group, showed considerable antifeedant activity. Interestingly, Z-isomers of 6i-k are much more active than their corresponding E-isomers. PMID:15506807

  6. Synthesis of diosgenin analogues as potential anti-inflammatory agents.

    PubMed

    Singh, Monika; Hamid, A A; Maurya, Anil K; Prakash, Om; Khan, Feroz; Kumar, Anant; Aiyelaagbe, O O; Negi, Arvind S; Bawankule, Dnyaneshwar U

    2014-09-01

    We herein report the synthesis of diosgenin analogues from commercially available diosgenin as the starting material. The structures of newly synthesised compounds were confirmed by (1)H NMR, (13)C NMR and mass spectrometry. All analogues were evaluated for in-vitro anti-inflammatory profile against LPS-induced inflammation in primary peritoneal macrophages isolated from mice by quantification of pro-inflammatory (TNF-?, IL-6 and IL-1?) cytokines in cell culture supernatant using the ELISA technique followed by in-vitro cytotoxicity study. Among the synthesised analogues, analogue 15 [(E) 26-(3',4',5'-trimethoxybenzylidene)-furost-5en-3?-acetate)] showed significant anti-inflammatory activity by inhibiting LPS-induced pro-inflammatory cytokines in a dose-dependent manner without any cytotoxicity. Efficacy and safety of analogue 15 were further validated in an in-vivo system using LPS-induced sepsis model and acute oral toxicity in mice. Oral administration of analogue 15 inhibited the pro-inflammatory cytokines in serum, attenuated the liver and lung injury and reduced the mortality rate in sepsis mice. Acute oral toxicity study showed that analogue 15 is non-toxic at higher dose in BALB/c mice. Molecular docking study revealed the strong binding affinity of diosgenin analogues to the active site of the pro-inflammatory proteins. These findings suggested that analogue 15 may be a useful therapeutic candidate for the treatment of inflammatory diseases. PMID:24816230

  7. The German Teacher's Companion. Development and Structure of the German Language. Workbook and Key.

    ERIC Educational Resources Information Center

    Hosford, Helga

    This complete pedagogical reference grammar for German was designed as a textbook for advanced language teacher preparation, as a reference handbook on the structure of the German language, and for reference in German study. It systematically analyzes and describes the language's phonology, morphology, and syntax, and gives a brief survey of its…

  8. Unorganized Cognitive Structures of Illiterate as the Key Factor in Rural E-Learning Design

    ERIC Educational Resources Information Center

    Katre, Dinesh S.

    2006-01-01

    Cognitive Structures and Linguistic Sequential Memory or Memory of Serial Order are not very well developed among illiterate people contrary to educated people. It affects the comprehension of abstract ideas and the usability of the system. Therefore the cognitive limitations of illiterate must be considered for instructional design and user

  9. Comparing Religious Education in Canadian and Australian Catholic High Schools: Identifying Some Key Structural Issues

    ERIC Educational Resources Information Center

    Rymarz, Richard

    2013-01-01

    Religious education (RE) in Catholic high schools in Australia and Canada is compared by examining some of the underlying structural factors that shape the delivery of RE. It is argued that in Canadian Catholic schools RE is diminished by three factors that distinguish it from the Australian experience. These are: the level and history of

  10. Comparing Religious Education in Canadian and Australian Catholic High Schools: Identifying Some Key Structural Issues

    ERIC Educational Resources Information Center

    Rymarz, Richard

    2013-01-01

    Religious education (RE) in Catholic high schools in Australia and Canada is compared by examining some of the underlying structural factors that shape the delivery of RE. It is argued that in Canadian Catholic schools RE is diminished by three factors that distinguish it from the Australian experience. These are: the level and history of…

  11. Solanapyrone analogues from a Hawaiian fungicolous fungus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Four new solanayrone analogues (solanapyrones J-M; 1-4) have been isolated from an unidentified fungicolous fungus collected in Hawaii. The structures and relative configurations of these compounds were determined by analysis of ID NMR, 2D NMR, and MS data. Solanapyrone J(1) showed antifungal acti...

  12. Synthesis and Cytoxicity of Sempervirine and Analogues.

    PubMed

    Pan, Xiaohong; Yang, Chunying; Cleveland, John L; Bannister, Thomas D

    2016-03-01

    Sempervirine and analogues were synthesized using a route featuring Sonogashira and Larock Pd-catalyzed reactions. Structure-activity relationships were investigated using three human cancer cell lines. 10-Fluorosempervirine is the most potently cytotoxic member of the family yet described. PMID:26828413

  13. Key structure-activity relationships in the vanadium phosphorus oxide catalyst system

    SciTech Connect

    Thompson, M.R. ); Ebner, J.R. )

    1990-04-01

    The crystal structure of vanadyl pyrophosphate has been redetermined using single crystals obtained from a near solidified melt of a microcrystalline catalyst sample. Crystals that index as vanadyl pyrophosphate obtained from this melt are variable in color. Crystallographic refinement of the single crystal x-ray diffraction data indicates that structural differences among these materials can be described in terms of crystal defects associated with linear disorder of the vanadium atoms. The importance of the disorder is outlined in the context of its effect on the proposed surface topology parallel to (1,0,0). Models of the surface topology simply and intuitively account for the non-stoichometric surface atomic P/V ratio exhibited by selective catalysts of this phase. These models also point to the possible role of the excess phosphorus in providing site isolation of reactive centers at the surface. 33 refs., 7 figs.

  14. Defining Key Structural Determinants for the Pro-osteogenic Activity of Flavonoids.

    PubMed

    Swioklo, Stephen; Watson, Kimberly A; Williamson, Elizabeth M; Farrimond, Jonathan A; Putnam, Sophie E; Bicknell, Katrina A

    2015-11-25

    Epidemiological studies suggest that fruits and vegetables may play a role in promoting bone growth and preventing age-related bone loss, attributable, at least in part, to phytochemicals such as flavonoids stimulating osteoblastogenesis. Through systematically screening the effect of flavonoids on the osteogenic differentiation of human mesenchymal stem cells in vitro and correlating activity with chemical structure using comparative molecular field analysis, we have successfully identified important structural features that relate to their activity, as well as reliably predicted the activity of compounds with unknown activity. Contour maps emphasized the importance of electronegativity, steric bulk, and a 2-C-3-C double bond at the flavonoid C-ring, as well as overall electropositivity and reduced steric bulk at the flavonoid B-ring. These results support a role for certain flavonoids in promoting osteogenic differentiation, thus their potential for preventing skeletal deterioration, as well as providing a foundation for the lead optimization of novel bone anabolics. PMID:26517554

  15. Structure of the CRISPR Interference Complex CSM Reveals Key Similarities with Cascade

    PubMed Central

    Rouillon, Christophe; Zhou, Min; Zhang, Jing; Politis, Argyris; Beilsten-Edmands, Victoria; Cannone, Giuseppe; Graham, Shirley; Robinson, CarolV.; Spagnolo, Laura; White, MalcolmF.

    2013-01-01

    Summary The Clustered Regularly Interspaced Palindromic Repeats (CRISPR) system is an adaptive immune system in prokaryotes. Interference complexes encoded by CRISPR-associated (cas) genes utilize small RNAs for homology-directed detection and subsequent degradation of invading genetic elements, and they have been classified into three main types (IIII). Type III complexes share the Cas10 subunit but are subclassifed as type IIIA (CSM) and type IIIB (CMR), depending on their specificity for DNA or RNA targets, respectively. The role of CSM in limiting the spread of conjugative plasmids in Staphylococcus epidermidis was first described in2008. Here, we report a detailed investigation of the composition and structure of the CSM complex from the archaeon Sulfolobus solfataricus, using a combination of electron microscopy, mass spectrometry, and deep sequencing. This reveals a three-dimensional model for the CSM complex that includes a helical component strikingly reminiscent of the backbone structure of the type I (Cascade) family. PMID:24119402

  16. Bacillus licheniformis trehalose-6-phosphate hydrolase structures suggest keys to substrate specificity.

    PubMed

    Lin, Min Guan; Chi, Meng Chun; Naveen, Vankadari; Li, Yi Ching; Lin, Long Liu; Hsiao, Chwan Deng

    2016-01-01

    Trehalose-6-phosphate hydrolase (TreA) belongs to glycoside hydrolase family 13 (GH13) and catalyzes the hydrolysis of trehalose 6-phosphate (T6P) to yield glucose and glucose 6-phosphate. The products of this reaction can be further metabolized by the energy-generating glycolytic pathway. Here, crystal structures of Bacillus licheniformis TreA (BlTreA) and its R201Q mutant complexed with p-nitrophenyl-?-D-glucopyranoside (R201Q-pPNG) are presented at 2.0 and 2.05? resolution, respectively. The overall structure of BlTreA is similar to those of other GH13 family enzymes. However, detailed structural comparisons revealed that the catalytic site of BlTreA contains a long loop that adopts a different conformation from those of other GH13 family members. Unlike the homologous regions of Bacillus cereus oligo-1,6-glucosidase (BcOgl) and Erwinia rhapontici isomaltulose synthase (NX-5), the surface potential of the BlTreA active site exhibits a largely positive charge contributed by the four basic residues His281, His282, Lys284 and Lys292. Mutation of these residues resulted in significant decreases in the enzymatic activity of BlTreA. Strikingly, the (281)HHLK(284) motif and Lys292 play critical roles in substrate discrimination by BlTreA. PMID:26894535

  17. Structure and function of DsbA, a key bacterial oxidative folding catalyst.

    PubMed

    Shouldice, Stephen R; Heras, Begoa; Walden, Patricia M; Totsika, Makrina; Schembri, Mark A; Martin, Jennifer L

    2011-05-01

    Since its discovery in 1991, the bacterial periplasmic oxidative folding catalyst DsbA has been the focus of intense research. Early studies addressed why it is so oxidizing and how it is maintained in its less stable oxidized state. The crystal structure of Escherichia coli DsbA (EcDsbA) revealed that the oxidizing periplasmic enzyme is a distant evolutionary cousin of the reducing cytoplasmic enzyme thioredoxin. Recent significant developments have deepened our understanding of DsbA function, mechanism, and interactions: the structure of the partner membrane protein EcDsbB, including its complex with EcDsbA, proved a landmark in the field. Studies of DsbA machineries from bacteria other than E. coli K-12 have highlighted dramatic differences from the model organism, including a striking divergence in redox parameters and surface features. Several DsbA structures have provided the first clues to its interaction with substrates, and finally, evidence for a central role of DsbA in bacterial virulence has been demonstrated in a range of organisms. Here, we review current knowledge on DsbA, a bacterial periplasmic protein that introduces disulfide bonds into diverse substrate proteins and which may one day be the target of a new class of anti-virulence drugs to treat bacterial infection. PMID:21241169

  18. Longevity and thermo-rheological structure of old lithospheres : key constraints form surface and Moho topography.

    NASA Astrophysics Data System (ADS)

    François, Thomas; Burov, Evgueni

    2014-05-01

    Surface topography and Moho are the most robust observables that have been insufficiently exploited for containing the rheological and thermal structure and hence for understanding the longevity and eventual destruction of cratons and "tectons". Craton longevity has been often explained by their buoyancy and analysed by testing gravitational stability of cratonic mantle "keels" as a function of the hypothesized plate thickness and thermo-rheological structure. Destruction of some cratons (e.g. North China) and data indicating little if no buoyancy of some tectons (e.g., Arabian shield) suggest that buoyancy is not the only factor of their stability, and previous studies show that their mechanical strength is as important as buoyancy. The upper bounds on this strength are provided by flexural studies demonstrating that Te values (equivalent elastic thickness) in cratons are highest in the world and may probably reach 150 km. Yet, the sensitivity of common methods is poor for Te values above 80 km while the lower bounds on the strength and the equivalent elastic thickness of cratons are still matter of debate. How this strength is partitioned between crust and mantle, and which set of rheological parameters pertain, remain major unknowns. We show that smooth low topography and "frozen" heterogeneous crustal structure of cratons represent the missing constraints for understanding of craton longevity. The cratonic crust is characterized by isostatically misbalanced density heterogeneities, suggesting that the lithosphere has to be strong enough to keep them "frozen" through the time without producing major gravitational instabilities and topographic undulations. Hence, to constrain thermo-rheological properties of cratons one should first investigate the stability of their topography and internal structure (constrained from seismic and gravity data). Our thermo-mechanical numerical experiments accounting for free surface boundary condition demonstrate that craton stability cannot be warranted by crustal strength only, and that strong dry olivine mantle rheology and cold thick lithosphere are needed for craton survival. We find fairly robust lower-bound limits on their thermo-rheological structure. In particular, the minimal Te needed for long-term stability of continents (cratons or tectons) is approximately 70 km.

  19. The current structure of key actors involved in research on land and soil degradation

    NASA Astrophysics Data System (ADS)

    Escadafal, Richard; Barbero, Celia; Exbrayat, Williams; Marques, Maria Jose; Ruiz, Manuel; El Haddadi, Anass; Akhtar-Schuster, Mariam

    2013-04-01

    Land and soil conservation topics, the final mandate of the United Convention to Combat desertification in drylands, have been diagnosed as still suffering from a lack of guidance. On the contrary, climate change and biodiversity issues -the other two big subjects of the Rio Conventions- seem to progress and may benefit from the advice of international panels. Arguably the weakness of policy measures and hence the application of scientific knowledge by land users and stakeholders could be the expression of an inadequate research organization and a lack of ability to channel their findings. In order to better understand the size, breadth and depth of the scientific communities involved in providing advice to this convention and to other bodies, this study explores the corpus of international publications dealing with land and/or with soils. A database of several thousands records including a significant part of the literature published so far was performed using the Web of Science and other socio-economic databases such as FRANCIS and CAIRN. We extracted hidden information using bibliometric methods and data mining applied to these scientific publications to map the key actors (laboratories, teams, institutions) involved in research on land and on soils. Several filters were applied to the databases in combination with the word "desertification". The further use of Tetralogie software merges databases, analyses similarities and differences between keywords, disciplines, authors and regions and identifies obvious clusters. Assessing their commonalities and differences, the visualisation of links and gaps between scientists, organisations, policymakers and other stakeholders is possible. The interpretation of the 'clouds' of disciplines, keywords, and techniques will enhance the understanding of interconnections between them; ultimately this will allow diagnosing some of their strengths and weaknesses. This may help explain why land and soil degradation remains a serious global problem that lacks sufficient attention. We hope that this study will contribute to clarify the scientific landscape at stake to remediate possible weaknesses in the future.

  20. Structural Insights into Maize Viviparous14, a Key Enzyme in the Biosynthesis of the Phytohormone Abscisic Acid W

    SciTech Connect

    Messing, S.; Gabelli, S; Echeverria, I; Vogel, J; Guan, J; Tan, B; Klee, H; McCarty, D; Amzela, M

    2010-01-01

    The key regulatory step in the biosynthesis of abscisic acid (ABA), a hormone central to the regulation of several important processes in plants, is the oxidative cleavage of the 11,12 double bond of a 9-cis-epoxycarotenoid. The enzyme viviparous14 (VP14) performs this cleavage in maize (Zea mays), making it a target for the rational design of novel chemical agents and genetic modifications that improve plant behavior through the modulation of ABA levels. The structure of VP14, determined to 3.2-{angstrom} resolution, provides both insight into the determinants of regio- and stereospecificity of this enzyme and suggests a possible mechanism for oxidative cleavage. Furthermore, mutagenesis of the distantly related CCD1 of maize shows how the VP14 structure represents a template for all plant carotenoid cleavage dioxygenases (CCDs). In addition, the structure suggests how VP14 associates with the membrane as a way of gaining access to its membrane soluble substrate.

  1. Structural Insights into Maize Viviparous14, a Key Enzyme in the Biosynthesis of the Phytohormone Abscisic Acid

    SciTech Connect

    Messing, Simon A.J.; Gabelli, Sandra B.; Echeverria, Ignacia; Vogel, Jonathan T.; Guan, Jiahn Chou; Tan, Bao Cai; Klee, Harry J.; McCarty, Donald R.; Amzel, L. Mario

    2011-09-06

    The key regulatory step in the biosynthesis of abscisic acid (ABA), a hormone central to the regulation of several important processes in plants, is the oxidative cleavage of the 11,12 double bond of a 9-cis-epoxycarotenoid. The enzyme viviparous14 (VP14) performs this cleavage in maize (Zea mays), making it a target for the rational design of novel chemical agents and genetic modifications that improve plant behavior through the modulation of ABA levels. The structure of VP14, determined to 3.2-{angstrom} resolution, provides both insight into the determinants of regio- and stereospecificity of this enzyme and suggests a possible mechanism for oxidative cleavage. Furthermore, mutagenesis of the distantly related CCD1 of maize shows how the VP14 structure represents a template for all plant carotenoid cleavage dioxygenases (CCDs). In addition, the structure suggests how VP14 associates with the membrane as a way of gaining access to its membrane soluble substrate.

  2. Structural effects of nucleobase variations at key active site residue Ade38 in the hairpin ribozyme.

    PubMed

    MacElrevey, Celeste; Salter, Jason D; Krucinska, Jolanta; Wedekind, Joseph E

    2008-08-01

    The hairpin ribozyme requires functional groups from Ade38 to achieve efficient bond cleavage or ligation. To identify molecular features that contribute to catalysis, structures of position 38 base variants 2,6-diaminopurine (DAP), 2-aminopurine (AP), cytosine (Cyt), and guanine (Gua) were determined between 2.2 and 2.8 A resolution. For each variant, two substrate modifications were compared: (1) a 2'-O-methyl-substituent at Ade-1 was used in lieu of the nucleophile to mimic the precatalytic state, and (2) a 3'-deoxy-2',5'-phosphodiester linkage between Ade-1 and Gua+1 was used to mimic a reaction-intermediate conformation. While the global fold of each variant remained intact, the results revealed the importance of Ade38 N1 and N6 groups. Absence of N6 resulting from AP38 coincided with failure to localize the precatalytic scissile phosphate. Cyt38 severely impaired catalysis in a prior study, and its structures here indicated an anti base conformation that sequesters the imino moiety from the scissile bond. Gua38 was shown to be even more deleterious to activity. Although the precatalytic structure was nominally affected, the reaction-intermediate conformation indicated a severe electrostatic clash between the Gua38 keto oxygen and the pro-Rp oxygen of the scissile bond. Overall, position 38 modifications solved in the presence of 2'-OMe Ade-1 deviated from in-line geometry, whereas variants with a 2',5' linkage exhibited S-turn destabilization, as well as base conformational changes from syn to anti. These findings demonstrate the importance of the Ade38 Watson-Crick face in attaining a reaction-intermediate state and the sensitivity of the RNA fold to restructuring when electrostatic and shape features fail to complement. PMID:18596253

  3. Peroxynitrous acid induces structural and functional modifications to basement membranes and its key component, laminin.

    PubMed

    Degendorfer, Georg; Chuang, Christine Y; Hammer, Astrid; Malle, Ernst; Davies, Michael J

    2015-12-01

    Basement membranes (BM) are specialized extracellular matrices underlying endothelial cells in the artery wall. Laminin, the most abundant BM glycoprotein, is a structural and biologically active component. Peroxynitrous acid (ONOOH), a potent oxidizing and nitrating agent, is formed in vivo at sites of inflammation from superoxide and nitric oxide radicals. Considerable data supports ONOOH formation in human atherosclerotic lesions, and an involvement of this oxidant in atherosclerosis development and lesion rupture. These effects may be mediated, at least in part, via extracellular matrix damage. In this study we demonstrate co-localization of 3-nitrotyrosine (a product of tyrosine damage by ONOOH) and laminin in human atherosclerotic lesions. ONOOH-induced damage to BM was characterized for isolated murine BM, and purified murine laminin-111. Exposure of laminin-111 to ONOOH resulted in dose-dependent loss of protein tyrosine and tryptophan residues, and formation of 3-nitrotyrosine, 6-nitrotryptophan and the cross-linked material di-tyrosine, as detected by amino acid analysis and Western blotting. These changes were accompanied by protein aggregation and fragmentation as detected by SDS-PAGE. Endothelial cell adhesion to isolated laminin-111 exposed to 10?M or higher levels of ONOOH was significantly decreased (~25%) compared to untreated controls. These data indicate that laminin is oxidized by equimolar or greater concentrations of ONOOH, with this resulting in structural and functional changes. These modifications, and resulting compromised cell-matrix interactions, may contribute to endothelial cell dysfunction, a weakening of the structure of atherosclerotic lesions, and an increased propensity to rupture. PMID:26453917

  4. Key Role of the Cation Interstitial Structure in the Radiation Resistance of Pyrochlores

    NASA Astrophysics Data System (ADS)

    Chartier, Alain; Catillon, Gilles; Crocombette, Jean-Paul

    2009-04-01

    The annealing of the B cation interstitial is shown to drive the thermokinetic of the response to irradiations of A2B2O7 pyrochlores. Molecular dynamics simulations evidenced that the annealing of interstitials created by irradiations depends upon the nature of B. As the coordination number of B decreases, the dumbbell interstitial is stabilized at the expense of the isolated interstitial. Unlike the isolated interstitials, the recombination of the dumbbells is thermally activated and hindered at low temperatures. The occurrence of dumbbells drives the structure towards the amorphous state.

  5. Surface topography as key constraint on thermo-rheological structure of cratons

    NASA Astrophysics Data System (ADS)

    Francois, T.; Burov, E.; Meyer, B.; Agard, P.

    2012-04-01

    The question why Archean cratons (i.e., the oldest continental plates such as Canada and Australia) survived for billions of years while the rest of the lithosphere has been reworked for several times is both enigmatic and fundamental for plate tectonics. Craton longetivity has been so far explained by their buoyancy and analysed by testing gravitational stability of hardly detectable cratonic mantle "keels" as a function of a hypothesized plate thickness and thermo-rheological structure. Catastrophic destruction of some cratons suggests that buoyancy is not the only factor of their stability, and previous studies show that their mechanical strength is as important as buoyancy. The upper bounds on their strength are provided by flexural studies demonstrating that Te values (equivalent elastic thickness) in cratons are highest in the world and limited to ~ 150 km. Yet, the lower bounds are still matter of debate, as well as the question how the mechanical strength is partitioned between crust and mantle, and which set of rheological parameters represents this behaviour. We show that primary observed cratonic features - flat topography and "frozen" heterogeneous crustal structure - represent the missing constraints for understanding of craton longevity. The cratonic crust is characterized by huge isostatically misbalanced density heterogeneities, suggesting that the lithosphere has to be strong enough to keep them frozen through the time without producing major gravitational instabilities and topographic undulations. Hence, to constrain thermo-rheological properties of cratons one should first investigate the stability of their topography and internal structure. Our thermo-mechanical numerical experiments accounting for free surface boundary condition notably demonstrate that craton stability cannot be warranted by crustal strength, and that strong dry olivine mantle rheology and cold thick lithosphere (1330°C at ~300 km depth) are needed for craton survival, allowing for discarding weaker, "wetter" or hotter alternatives. Hence, without pretending to explain the whole enigma of cratonic survival, nor to reproduce the evolution of any particular craton, we find fairly robust lower-bound limits on their thermo-rheological structure.

  6. Utilizing a Key Aptamer Structure-Switching Mechanism for the Ultrahigh Frequency Detection of Cocaine.

    PubMed

    Neves, Miguel A D; Blaszykowski, Christophe; Thompson, Michael

    2016-03-15

    Aptasensing of small molecules remains a challenge as detection often requires the use of labels or signal amplification methodologies, resulting in both difficult-to-prepare sensor platforms and multistep, complex assays. Furthermore, many aptasensors rely on the binding mechanism or structural changes associated with target capture by the aptameric probe, resulting in a detection scheme customized to each aptamer. It is in this context that we report herein a sensitive cocaine aptasensor that offers both real-time and label-free measurement capabilities. Detection relies on the electromagnetic piezoelectric acoustic sensor (EMPAS) platform. The sensing interface consists of a S-(11-trichlorosilyl-undecanyl)benzenethiosulfonate (BTS) adlayer-coated quartz disc onto which a structure-switching cocaine aptamer (MN6) is immobilized, completing the preparation of the MN6 cocaine aptasensor (M6CA). The EMPAS system has recently been employed as the foundation of a cocaine aptasensor based on a structurally rigid cocaine aptamer variant (MN4), an aptasensor referred to by analogy as M4CA. M6CA represents a significant increase in terms of analytical performance, compared to not only M4CA but also other cocaine aptamer-based sensors that do not rely on signal amplification, producing an apparent Kd of 27 ± 6 μM and a 0.3 μM detection limit. Remarkably, the latter is in the range of that achieved by cocaine aptasensors relying on signal amplification. Furthermore, M6CA proved to be capable not only of regaining its cocaine-binding ability via simple buffer flow over the sensing interface (i.e., without the necessity to implement an additional regeneration step, such as in the case of M4CA), but also of detecting cocaine in a multicomponent matrix possessing potentially assay-interfering species. Finally, through observation of the distinct shape of its response profiles to cocaine injection, demonstration was made that the EMPAS system in practice offers the possibility to distinguish between the binding mechanisms of structure-switching (MN6) vs rigid (MN4) aptameric probes, an ability that could allow the EMPAS to provide a more universal aptasensing platform than what is ordinarily observed in the literature. PMID:26871312

  7. Structural insights into key sites of vulnerability on HIV-1 Env and influenza HA.

    PubMed

    Julien, Jean-Philippe; Lee, Peter S; Wilson, Ian A

    2012-11-01

    Human immunodeficiency virus-1 (HIV-1) envelope protein (Env) and influenza hemagglutinin (HA) are the surface glycoproteins responsible for viral entry into host cells, the first step in the virus life cycle necessary to initiate infection. These glycoproteins exhibit a high degree of sequence variability and glycosylation, which are used as strategies to escape host immune responses. Nonetheless, antibodies with broadly neutralizing activity against these viruses have been isolated that have managed to overcome these barriers. Here, we review recent advances in the structural characterization of these antibodies with their viral antigens that defines a few sites of vulnerability on these viral spikes. These broadly neutralizing antibodies tend to focus their recognition on the sites of similar function between the two viruses: the receptor-binding site and membrane fusion machinery. However, some sites of recognition are unique to the virus neutralized, such as the dense shield of oligomannose carbohydrates on HIV-1 Env. These observations are discussed in the context of structure-based design strategies to aid in vaccine design or development of antivirals. PMID:23046130

  8. Synthesis of chacotriose analogues.

    PubMed

    Lequart, Vincent; Goethals, Gérard; Usubillaga, Alfredo; Villa, Pierre; Cecchelli, Roméo; Martin, Patrick

    2004-06-01

    We report here the synthesis of three chacotriose analogues, namely beta-L-fucopyranosyl-(1-->2)-[beta-L-fucopyranosyl-(1-->4)]-D-glucopyranose, beta-L-fucopyranosyl-(1-->2)-[beta-L-fucopyranosyl-(1-->4)]-d-galactopyranose, and alpha-L-rhamnopyranosyl-(1-->2)-[alpha-L-rhamnopyranosyl-(1-->4)]-alpha-D-galactopyranose. PMID:15178395

  9. Quantum analogue computing.

    PubMed

    Kendon, Vivien M; Nemoto, Kae; Munro, William J

    2010-08-13

    We briefly review what a quantum computer is, what it promises to do for us and why it is so hard to build one. Among the first applications anticipated to bear fruit is the quantum simulation of quantum systems. While most quantum computation is an extension of classical digital computation, quantum simulation differs fundamentally in how the data are encoded in the quantum computer. To perform a quantum simulation, the Hilbert space of the system to be simulated is mapped directly onto the Hilbert space of the (logical) qubits in the quantum computer. This type of direct correspondence is how data are encoded in a classical analogue computer. There is no binary encoding, and increasing precision becomes exponentially costly: an extra bit of precision doubles the size of the computer. This has important consequences for both the precision and error-correction requirements of quantum simulation, and significant open questions remain about its practicality. It also means that the quantum version of analogue computers, continuous-variable quantum computers, becomes an equally efficient architecture for quantum simulation. Lessons from past use of classical analogue computers can help us to build better quantum simulators in future. PMID:20603371

  10. Study of Kaempferol Glycoside as an Insulin Mimic Reveals Glycon To Be the Key Active Structure

    PubMed Central

    2010-01-01

    Diabetes mellitus is increasing in prevalence with patient numbers rising throughout the world. Current treatments for diabetes mellitus focus on control of blood glucose levels. Certain kinds of flavonoids or their glycosides stimulate cells to improve glucose uptake and lower blood glucose levels. We synthesized kaempferol 3-O-neohesperidoside (1), a naturally occurring substance present in Cyathea phalerata Mart., reported to mimic the action of insulin. Synthetic 1 promoted glucose uptake in the cultured cell line, L6. Further studies to determine the core structure responsible for this activity using synthetic compounds revealed neohesperidose to be the primary pharmacophore. These findings support the use of certain saccharides as a potential novel treatment for diabetes mellitus by replacing or supporting insulin. PMID:24900249

  11. Tertiary Lymphoid Structure-Associated B Cells are Key Players in Anti-Tumor Immunity

    PubMed Central

    Germain, Claire; Gnjatic, Sacha; Dieu-Nosjean, Marie-Caroline

    2015-01-01

    It is now admitted that the immune system plays a major role in tumor control. Besides the existence of tumor-specific T cells and B cells, many studies have demonstrated that high numbers of tumor-infiltrating lymphocytes are associated with good clinical outcome. In addition, not only the density but also the organization of tumor-infiltrating immune cells has been shown to determine patient survival. Indeed, more and more studies describe the development within the tumor microenvironment of tertiary lymphoid structures (TLS), whose presence has a positive impact on tumor prognosis. TLS are transient ectopic lymphoid aggregates displaying the same organization and functionality as canonical secondary lymphoid organs, with T-cell-rich and B-cell-rich areas that are sites for the differentiation of effector and memory T cells and B cells. However, factors favoring the emergence of such structures within tumors still need to be fully characterized. In this review, we survey the state of the art of what is known about the general organization, induction, and functionality of TLS during chronic inflammation, and more especially in cancer, with a particular focus on the B-cell compartment. We detail the role played by TLS B cells in anti-tumor immunity, both as antigen-presenting cells and tumor antigen-specific antibody-secreting cells, and raise the question of the capacity of chemotherapeutic and immunotherapeutic agents to induce the development of TLS within tumors. Finally, we explore how to take advantage of our knowledge on TLS B cells to develop new therapeutic tools. PMID:25755654

  12. Crystal structure and site-directed mutational analysis reveals key residues involved in Escherichia coli ZapA function.

    PubMed

    Roach, Elyse J; Kimber, Matthew S; Khursigara, Cezar M

    2014-08-22

    FtsZ is an essential cell division protein in Escherichia coli, and its localization, filamentation, and bundling at the mid-cell are required for Z-ring stability. Once assembled, the Z-ring recruits a series of proteins that comprise the bacterial divisome. Zaps (FtsZ-associated proteins) stabilize the Z-ring by increasing lateral interactions between individual filaments, bundling FtsZ to provide a scaffold for divisome assembly. The x-ray crystallographic structure of E. coli ZapA was determined, identifying key structural differences from the existing ZapA structure from Pseudomonas aeruginosa, including a charged ?-helix on the globular domains of the ZapA tetramer. Key helix residues in E. coli ZapA were modified using site-directed mutagenesis. These ZapA variants significantly decreased FtsZ bundling in protein sedimentation assays when compared with WT ZapA proteins. Electron micrographs of ZapA-bundled FtsZ filaments showed the modified ZapA variants altered the number of FtsZ filaments per bundle. These in vitro results were corroborated in vivo by expressing the ZapA variants in an E. coli ?zapA strain. In vivo, ZapA variants that altered FtsZ bundling showed an elongated phenotype, indicating improper cell division. Our findings highlight the importance of key ZapA residues that influence the extent of FtsZ bundling and that ultimately affect Z-ring formation in dividing cells. PMID:25002581

  13. Crystal Structure and Site-directed Mutational Analysis Reveals Key Residues Involved in Escherichia coli ZapA Function*

    PubMed Central

    Roach, Elyse J.; Kimber, Matthew S.; Khursigara, Cezar M.

    2014-01-01

    FtsZ is an essential cell division protein in Escherichia coli, and its localization, filamentation, and bundling at the mid-cell are required for Z-ring stability. Once assembled, the Z-ring recruits a series of proteins that comprise the bacterial divisome. Zaps (FtsZ-associated proteins) stabilize the Z-ring by increasing lateral interactions between individual filaments, bundling FtsZ to provide a scaffold for divisome assembly. The x-ray crystallographic structure of E. coli ZapA was determined, identifying key structural differences from the existing ZapA structure from Pseudomonas aeruginosa, including a charged ?-helix on the globular domains of the ZapA tetramer. Key helix residues in E. coli ZapA were modified using site-directed mutagenesis. These ZapA variants significantly decreased FtsZ bundling in protein sedimentation assays when compared with WT ZapA proteins. Electron micrographs of ZapA-bundled FtsZ filaments showed the modified ZapA variants altered the number of FtsZ filaments per bundle. These in vitro results were corroborated in vivo by expressing the ZapA variants in an E. coli ?zapA strain. In vivo, ZapA variants that altered FtsZ bundling showed an elongated phenotype, indicating improper cell division. Our findings highlight the importance of key ZapA residues that influence the extent of FtsZ bundling and that ultimately affect Z-ring formation in dividing cells. PMID:25002581

  14. Key Sites for P2X Receptor Function and Multimerization: Overview of Mutagenesis Studies on a Structural Basis

    PubMed Central

    Hausmann, Ralf; Kless, Achim; Schmalzing, Günther

    2015-01-01

    P2X receptors constitute a seven-member family (P2X1-7) of extracellular ATP-gated cation channels of widespread expression. Because P2X receptors have been implicated in neurological, inflammatory and cardiovascular diseases, they constitute promising drug targets. Since the first P2X cDNA sequences became available in 1994, numerous site-directed mutagenesis studies have been conducted to disclose key sites of P2X receptor function and oligomerization. The publication of the 3-Å crystal structures of the zebrafish P2X4 (zfP2X4) receptor in the homotrimeric apo-closed and ATP-bound open states in 2009 and 2012, respectively, has ushered a new era by allowing for the interpretation of the wealth of molecular data in terms of specific three-dimensional models and by paving the way for designing more-decisive experiments. Thanks to these structures, the last five years have provided invaluable insight into our understanding of the structure and function of the P2X receptor class of ligandgated ion channels. In this review, we provide an overview of mutagenesis studies of the pre- and post-crystal structure eras that identified amino acid residues of key importance for ligand binding, channel gating, ion flow, formation of the pore and the channel gate, and desensitization. In addition, the sites that are involved in the trimerization of P2X receptors are reviewed based on mutagenesis studies and interface contacts that were predicted by the zfP2X4 crystal structures. PMID:25439586

  15. Structural and functional conservation of key domains in InsP[subscript 3] and ryanodine receptors

    SciTech Connect

    Seo, Min-Duk; Velamakanni, Saroj; Ishiyama, Noboru; Stathopulos, Peter B.; Rossi, Ana M.; Khan, Samir A.; Dale, Philippa; Li, Congmin; Ames, James B.; Ikura, Mitsuhiko; Taylor, Colin W.

    2012-07-11

    Inositol-1,4,5-trisphosphate receptors (InsP{sub 3}Rs) and ryanodine receptors (RyRs) are tetrameric intracellular Ca{sup 2+} channels. In each of these receptor families, the pore, which is formed by carboxy-terminal transmembrane domains, is regulated by signals that are detected by large cytosolic structures. InsP{sub 3}R gating is initiated by InsP{sub 3} binding to the InsP{sub 3}-binding core (IBC, residues 224-604 of InsP{sub 3}R1) and it requires the suppressor domain (SD, residues 1-223 of InsP{sub 3}R1). Here we present structures of the amino-terminal region (NT, residues 1-604) of rat InsP{sub 3}R1 with (3.6 {angstrom}) and without (3.0 {angstrom}) InsP{sub 3} bound. The arrangement of the three NT domains, SD, IBC-{beta} and IBC-{alpha}, identifies two discrete interfaces ({alpha} and {beta}) between the IBC and SD. Similar interfaces occur between equivalent domains (A, B and C) in RyR1 (ref. 9). The orientations of the three domains when docked into a tetrameric structure of InsP{sub 3}R and of the ABC domains docked into RyR are remarkably similar. The importance of the {alpha}-interface for activation of InsP{sub 3}R and RyR is confirmed by mutagenesis and, for RyR, by disease-causing mutations. Binding of InsP{sub 3} causes partial closure of the clam-like IBC, disrupting the {beta}-interface and pulling the SD towards the IBC. This reorients an exposed SD loop ('hotspot' (HS) loop) that is essential for InsP{sub 3}R activation. The loop is conserved in RyR and includes mutations that are associated with malignant hyperthermia and central core disease. The HS loop interacts with an adjacent NT, suggesting that activation re-arranges inter-subunit interactions. The A domain of RyR functionally replaced the SD in full-length InsP{sub 3}R, and an InsP{sub 3}R in which its C-terminal transmembrane region was replaced by that from RyR1 was gated by InsP{sub 3} and blocked by ryanodine. Activation mechanisms are conserved between InsP{sub 3}R and RyR. Allosteric modulation of two similar domain interfaces within an N-terminal subunit reorients the first domain (SD or A domain), allowing it, through interactions of the second domain of an adjacent subunit (IBC-{beta} or B domain), to gate the pore.

  16. Structural heritage as a key factor controlling the South China Sea opening

    NASA Astrophysics Data System (ADS)

    Meresse, F.; Savva, D.; Wong, P.; Pubellier, M.; Chamot-Rooke, N.; Steuer, S.; Franke, D.; Sapin, F.; Auxietre, J.

    2012-12-01

    Since the Palaeozoic times, the South China Sea area has recorded multiple tectono-thermal events (Indosinian and Yenshanian orogeny) whose influence regarding the formation of the basin remains to be clarified. The aim of this work is to document the vertical movements associated with the extensional tectonic, and to address the issue of the role of the structural inheritance in the context of the opening of an oceanic basin. The work is based on a thermochronological multi-method approach, i.e., U/Pb on zircon and fission tracks on zircon (ZFT) and apatite (AFT). These thermochronological data were then combined with field observations, seismic lines and drill-holes data to perform a reconstruction of the pre-rifting stage of the South China Sea. Dating gives a Triassic to lower Cretaceous age for the emplacement of the Yenshanian granitic arc, which was quickly exhumed during the middle of the Cretaceous. Sample analyses from onland northern margin sediments indicate a range of burial temperatures from 120C to 250C. The cretaceous basins, filled with the erosional products of the Yanshanian granites, have been partly recycled within the tertiary basins. Thermochronometers from northern margin samples also attest for a middle-late Eocene cooling event below the 120C isotherm. Thermochronological results from the Palawan Island, which consists of an inverted cretaceous basin, the Proto South China Sea (PSCS) whose crust has nowadays totally been subducted, show that the source of the sediments is the erosion of the Yanshanian magmatic arc. Finally, a middle-late Miocene cooling event recorded both by Apatite and Zircon attests of a major uplift stage that affected the whole Palawan and Borneo accretionary wedges. The interpretation of seismic and drill-hole data supports a new reconstruction of the SCS pre-rift setting that shows crustal necking zones filled with deep marine deposits, fault-bounded troughs showing thick pre-Tertiary syn-tectonic series and zones of thick crust covered by shallow marine sediments. We propose a step-by-step cartographic reconstruction of the SCS opening that emphasizes a partitioning process along major N-S strike-slip faults, probably corresponding to the on-land continuation of PSCS transform faults. The pre-rift architecture of the crust is characterised by fault-bounded depressions that had trapped Tertiary syn-rift sediments. These depressions delimit areas of thick crust often constituted by intruded Mesozoic granitic plutons on which SCS rifting faults tend to root. This work combining a thermochronological and a structural approach brings fundamental information regarding both the sources of the SCS syn-rift sediments and the pre-rift structures that control both the localisation of the deformation and the distribution of the syn-rift sediments.

  17. Thermophysical Fluid Dynamics: the Key to the Structures of Fluid Objects

    NASA Astrophysics Data System (ADS)

    Houben, H.

    2013-12-01

    It has become customary to model the hydrodynamics of fluid planets like Jupiter and Saturn by spinning up general circulation models until they reach a statistical steady state. This approach is physically sound, based on the thermodynamic expectation that the system will eventually achieve a state of maximum entropy, but the models have not been specifically designed for this purpose. Over the course of long integrations, numerical artifacts can drive the system to a state that does not correspond to the physically realistic end state. A different formulation of the governing equations promises better results. The equations of motion are recast as scalar conservation laws in which the diabatic and irreversible terms (both entropy-changing) are clearly identified. The balance between these terms defines the steady state of the system analytically, without the need for any temporal integrations. The conservation of mass in this system is trivial. Conservation of angular momentum replaces the zonal momentum equation and determines the zonal wind from a balance between the tidal torque and frictional dissipation. The principle of wave-mean flow non-interaction is preserved. Bernoulli's Theorem replaces the energy equation. The potential temperature structure is determined by the balance between work done against friction and heat transfer by convection and radiation. An equation of state and the traditional momentum equations in the meridional plane are sufficient to complete the model. Based on the assumption that the final state vertical and meridional winds are small compared to the zonal wind (in any case they are impossible to predict ab initio as they are driven by wave flux convergences), these last equations determine the pressure and density (and hence gravity) fields of the basic state. The thermal wind relation (in its most general form with the axial derivative of the zonal wind balancing the baroclinicity) is preserved. The model is not hydrostatic (in the sense used in planetary modeling) and the zonal wind is not constant on cylinders. Rather, the zonal wind falls off more rapidly with depth --- at least as fast as r3. A similar reformulation of the equations of magnetohydrodynamics is possible. It is found that wave-mean flow non-interaction extends to Alfven waves. Bernoulli's Theorem is augmented by the Poynting Theorem. The components of the traditional dynamo equation can be written as conservation laws. Only a single element of the alpha tensor contributes to the generation of axisymmetric magnetic fields and the mean meridional circulation provides a significant feedback, quenching the omega effect and limiting the amplitudes of non-axisymmetric fields. Thus analytic models are available for all the state variables of Jupiter and Saturn. The unknown independent variables are terms in the equation of state, the eddy viscosity and heat transport coefficients, the magnetic resistivity, and the strength of the tidal torques (which are dependent on the vertical structure of the planet's troposphere). By making new measurements of the atmospheric structure and higher order gravitational moments of Jupiter, JUNO has the potential to constrain these unknowns and contribute greatly to our understanding of the interior of that planet.

  18. ?-Synuclein interactions with phospholipid model membranes: Key roles for electrostatic interactions and lipid-bilayer structure.

    PubMed

    Pirc, Katja; Ulrih, Nataa Poklar

    2015-10-01

    ?-Synuclein is a small presynaptic protein that is critically implicated in the onset of Parkinson's disease and other neurodegenerative disorders. It has been assumed that the pathogenesis of ?-synuclein is associated with its aggregation, while for its physiological function, binding of ?-synuclein to the synaptic vesicle membrane appears to be most important. The present study investigated the mechanism of ?-synuclein binding to the lipid membrane. Upon binding to negatively charged small unilamellar vesicles consisting of 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol or 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol in the liquid-crystalline state, ?-synuclein undergoes conformational transition from its native unfolded form to an ?-helical structure. The positively charged N-terminal part of ?-synuclein is likely to be involved in interactions with the negatively charged lipid surface. ?-Synuclein did not associate with vesicles consisting of the zwitterionic (neutral) lipids 1,2-dipalmitoyl-sn-glycero-3-phosphocholine or 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine. The data obtained by circular dichroism spectroscopy, fluorescence anisotropy measurements, differential scanning calorimetry, and calcein efflux assays indicate that in addition to electrostatic interactions, hydrophobic interactions are important in the association of ?-synuclein with membranes. The mechanism of ?-synuclein binding to lipid membranes is primarily dependent on the surface charge density of the lipid bilayer and the phase state of the lipids. We propose that ?-synuclein has a lipid ordering effect and thermally stabilises vesicles. PMID:26119565

  19. Limitations and Extensions of the Lock-and-Key Principle: Differences between Gas State, Solution and Solid State Structures

    PubMed Central

    Schneider, Hans-Jörg

    2015-01-01

    The lock-and-key concept is discussed with respect to necessary extensions. Formation of supramolecular complexes depends not only, and often not even primarily on an optimal geometric fit between host and guest. Induced fit and allosteric interactions have long been known as important modifications. Different binding mechanisms, the medium used and pH effects can exert a major influence on the affinity. Stereoelectronic effects due to lone pair orientation can lead to variation of binding constants by orders of magnitude. Hydrophobic interactions due to high-energy water inside cavities modify the mechanical lock-and-key picture. That optimal affinities are observed if the cavity is only partially filled by the ligand can be in conflict with the lock-and-key principle. In crystals other forces than those between host and guest often dominate, leading to differences between solid state and solution structures. This is exemplified in particular with calixarene complexes, which by X-ray analysis more often than other hosts show guest molecules outside their cavity. In view of this the particular problems with the identification of weak interactions in crystals is discussed. PMID:25815592

  20. On the mechanics of mother-of-pearl: A key feature in the material hierarchical structure

    NASA Astrophysics Data System (ADS)

    Barthelat, F.; Tang, H.; Zavattieri, P. D.; Li, C.-M.; Espinosa, H. D.

    2007-02-01

    Mother-of-pearl, also known as nacre, is the iridescent material which forms the inner layer of seashells from gastropods and bivalves. It is mostly made of microscopic ceramic tablets densely packed and bonded together by a thin layer of biopolymer. The hierarchical microstructure of this biological material is the result of millions of years of evolution, and it is so well organized that its strength and toughness are far superior to the ceramic it is made of. In this work the structure of nacre is described over several length scales. The tablets were found to have wavy surfaces, which were observed and quantified using various experimental techniques. Tensile and shear tests performed on small samples revealed that nacre can withstand relatively large inelastic strains and exhibits strain hardening. In this article we argue that the inelastic mechanism responsible for this behavior is sliding of the tablets on one another accompanied by transverse expansion in the direction perpendicular to the tablet planes. Three dimensional representative volume elements, based on the identified nacre microstructure and incorporating cohesive elements with a constitutive response consistent with the interface material and nanoscale features were numerically analyzed. The simulations revealed that even in the absence of nanoscale hardening mechanism at the interfaces, the microscale waviness of the tablets could generate strain hardening, thereby spreading the inelastic deformation and suppressing damage localization leading to material instability. The formation of large regions of inelastic deformations around cracks and defects in nacre are believed to be an important contribution to its toughness. In addition, it was shown that the tablet junctions (vertical junctions between tablets) strengthen the microstructure but do not contribute to the overall material hardening. Statistical variations within the microstructure were found to be beneficial to hardening and to the overall mechanical stability of nacre. These results provide new insights into the microstructural features that make nacre tough and damage tolerant. Based on these findings, some design guidelines for composites mimicking nacre are proposed.

  1. MOBILIZING COMMUNITIES AROUND HIV PREVENTION FOR YOUTH: HOW THREE COALITIONS APPLIED KEY STRATEGIES TO BRING ABOUT STRUCTURAL CHANGES

    PubMed Central

    Chutuape, Kate S.; Willard, Nancy; Sanchez, Kenia; Straub, Diane M.; Ochoa, Tara N.; Howell, Kourtney; Rivera, Carmen; Ramos, Ibrahim; Ellen, Jonathan M.

    2010-01-01

    Increasingly, HIV prevention efforts must focus on altering features of the social and physical environment to reduce risks associated with HIV acquisition and transmission. Community coalitions provide a vehicle for bringing about sustainable structural changes. This article shares lessons and key strategies regarding how three community coalitions located in Miami and Tampa, Florida, and San Juan, Puerto Rico engaged their respective communities in bringing about structural changes affecting policies, practices and programs related to HIV prevention for 12–24-year-olds. Outcomes of this work include increased access to HIV testing and counseling in the juvenile correctional system (Miami), increased monitoring of sexual abuse between young women and older men within public housing, and support services to deter age discordant relationships (Tampa) and increased access to community-based HIV testing (San Juan). PMID:20166784

  2. Mobilizing communities around HIV prevention for youth: how three coalitions applied key strategies to bring about structural changes.

    PubMed

    Chutuape, Kate S; Willard, Nancy; Sanchez, Kenia; Straub, Diane M; Ochoa, Tara N; Howell, Kourtney; Rivera, Carmen; Ramos, Ibrahim; Ellen, Jonathan M

    2010-02-01

    Increasingly, HIV prevention efforts must focus on altering features of the social and physical environment to reduce risks associated with HIV acquisition and transmission. Community coalitions provide a vehicle for bringing about sustainable structural changes. This article shares lessons and key strategies regarding how three community coalitions located in Miami and Tampa, Florida, and San Juan, Puerto Rico engaged their respective communities in bringing about structural changes affecting policies, practices and programs related to HIV prevention for 12-24-year-olds. Outcomes of this work include increased access to HIV testing and counseling in the juvenile correctional system (Miami), increased monitoring of sexual abuse between young women and older men within public housing, and support services to deter age discordant relationships (Tampa) and increased access to community-based HIV testing (San Juan). PMID:20166784

  3. A Gallium-Substituted Distibene and an Antimony-Analogue Bicyclo[1.1.0]butane: Synthesis and Solid-State Structures.

    PubMed

    Tuscher, Lars; Ganesamoorthy, Chelladurai; Blser, Dieter; Wlper, Christoph; Schulz, Stephan

    2015-09-01

    RGa {R=HC[C(Me)N(2,6-iPr2C6H3)]2} reacts with Sb(NMe2)3 with insertion into the Sb-N bond and elimination of RGa(NMe2)2 (2), yielding the Ga-substituted distibene R(Me2N)GaSb=SbGa(NMe2 )R (1). Thermolysis of 1 proceeded with elimination of RGa and 2 and subsequent formation of the bicyclo[1.1.0]butane analogue [R(Me2N)Ga]2Sb4 (3). PMID:26248643

  4. Synthesis and Biological Evaluation of Manassantin Analogues for Hypoxia-Inducible Factor 1α Inhibition

    PubMed Central

    2015-01-01

    To cope with hypoxia, tumor cells have developed a number of adaptive mechanisms mediated by hypoxia-inducible factor 1 (HIF-1) to promote angiogenesis and cell survival. Due to significant roles of HIF-1 in the initiation, progression, metastasis, and resistance to treatment of most solid tumors, a considerable amount of effort has been made to identify HIF-1 inhibitors for treatment of cancer. Isolated from Saururus cernuus, manassantins A (1) and B (2) are potent inhibitors of HIF-1 activity. To define the structural requirements of manassantins for HIF-1 inhibition, we prepared and evaluated a series of manassantin analogues. Our SAR studies examined key regions of manassantin’s structure in order to understand the impact of these regions on biological activity and to define modifications that can lead to improved performance and drug-like properties. Our efforts identified several manassantin analogues with reduced structural complexity as potential lead compounds for further development. Analogues MA04, MA07, and MA11 down-regulated hypoxia-induced expression of the HIF-1α protein and reduced the levels of HIF-1 target genes, including cyclin-dependent kinase 6 (Cdk6) and vascular endothelial growth factor (VEGF). These findings provide an important framework to design potent and selective HIF-1α inhibitors, which is necessary to aid translation of manassantin-derived natural products to the clinic as novel therapeutics for cancers. PMID:26394152

  5. Continuous analogues of matrix factorizations

    PubMed Central

    Townsend, Alex; Trefethen, Lloyd N.

    2015-01-01

    Analogues of singular value decomposition (SVD), QR, LU and Cholesky factorizations are presented for problems in which the usual discrete matrix is replaced by a ‘quasimatrix’, continuous in one dimension, or a ‘cmatrix’, continuous in both dimensions. Two challenges arise: the generalization of the notions of triangular structure and row and column pivoting to continuous variables (required in all cases except the SVD, and far from obvious), and the convergence of the infinite series that define the cmatrix factorizations. Our generalizations of triangularity and pivoting are based on a new notion of a ‘triangular quasimatrix’. Concerning convergence of the series, we prove theorems asserting convergence provided the functions involved are sufficiently smooth. PMID:25568618

  6. Identification of a novel vardenafil analogue in herbal product.

    PubMed

    Lam, Ying-Hoo; Poon, Wing-Tat; Lai, Chi-Kong; Chan, Albert Yan-Wo; Mak, Tony Wing-Lai

    2008-03-13

    A new herbal health product marketed for enhancing erectile function, namely Power58 Platinum, was purchased over-the-counter in Hong Kong. The product was tested for adulteration with sildenafil, tadalafil, and vardenafil as well as their structurally modified analogues. A new analogue of vardenafil, in which the N-ethylpiperazine ring and the sulphonyl group were removed from the vardenafil structure, was identified in the product. PMID:18248930

  7. Laboratory study of cometary analogues

    NASA Astrophysics Data System (ADS)

    Colangeli, L.; Brucato, J.; Mennella, V.; Palumbo, P.

    In situ exploration (e.g., GIOTTO mission) and astronomical observations (e.g., ISO) of comets have provided fundamental information about the structure, chemistry and physical properties of materials present in such primordial bodies of the Solar System. Moreover, it is known that cosmic materials evolve, depending on the efficiency of active processes (e.g., thermal annealing, UV irradiation, ion bombardment, gassolid interactions) in different space environments. Thus, the properties of cometary constituents must be considered in a wider perspective, including cosmic dust formation around cold stars and evolution in the interstellar medium until the formation of proto-planetary nebulae. In this scenario, laboratory experiments provide important hints to clarify the status of cometary compounds. The laboratory work is aimed at both reproducing material properties and at simulating their evolution based on the most effective mechanisms active in space. Several techniques are used to synthesise "analogues" of cometary compounds with controlled chemical and physical characteristics. The study of optical properties, complemented by other analytical techniques, is applied to investigate the products of synthesis in the experiments. The monitoring of the effects produced by processing methods, similar to those active in space, provides information both on the reactivity of materials and on the efficiency of treatments. Such an approach is able to provide quantitative information on chemical and structural modifications produced on organic and refractory materials. The comparison of laboratory results with data coming from space observations and in situ measurements provides a powerful tool to understand the real nature of comets and to place constraints on formation and evolution pathways. The laboratory experiments on analogues gain even more relevance as a sort of training in the future perspective of analysing cometary samples returned to Earth by space missions (e.g., Stardust).

  8. Structures of Rhodopsin Kinase in Different Ligand States Reveal Key Elements Involved in G Protein-coupled Receptor Kinase Activation

    SciTech Connect

    Singh, Puja; Wang, Benlian; Maeda, Tadao; Palczewski, Krzysztof; Tesmer, John J.G.

    2008-10-08

    G protein-coupled receptor (GPCR) kinases (GRKs) phosphorylate activated heptahelical receptors, leading to their uncoupling from G proteins. Here we report six crystal structures of rhodopsin kinase (GRK1), revealing not only three distinct nucleotide-binding states of a GRK but also two key structural elements believed to be involved in the recognition of activated GPCRs. The first is the C-terminal extension of the kinase domain, which was observed in all nucleotide-bound GRK1 structures. The second is residues 5-30 of the N terminus, observed in one of the GRK1{center_dot}(Mg{sup 2+}){sub 2} {center_dot}ATP structures. The N terminus was also clearly phosphorylated, leading to the identification of two novel phosphorylation sites by mass spectral analysis. Co-localization of the N terminus and the C-terminal extension near the hinge of the kinase domain suggests that activated GPCRs stimulate kinase activity by binding to this region to facilitate full closure of the kinase domain.

  9. Protective activity of (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol analogues against diisopropylfluorophosphate neurotoxicity: preliminary structure-activity relationship and pharmacophore modeling.

    PubMed

    Eterović, Vesna A; Del Valle-Rodriguez, Angelie; Pérez, Dinely; Carrasco, Marimée; Khanfar, Mohammad A; El Sayed, Khalid A; Ferchmin, Pedro A

    2013-08-01

    Diisopropylfluorophosphate (DFP) is an organophosphorous insecticide used as a surrogate for the more toxic chemical warfare nerve agent sarin. DFP produces neurotoxicity in vivo and irreversibly decreases the area of population spikes recorded from the CA1 region of acute hippocampal slices. (1S,2E,4R,6R,7E,11E)-2,7,11-Cembratriene-4,6-diol (1) is a neuroprotective natural cembranoid that reverses DFP-induced damage both in vivo and in the hippocampal slice. Cembranoid 1 acts by noncompetitive inhibition of the α7 nicotinic acetylcholine receptor. This study aims at establishing a preliminary structure-activity relationship to define the neuroprotective cembranoid pharmacophores using the hippocampal slice assay and pharmacophore modeling. Fourteen natural, semisynthetic, or biocatalytic cembranoid analogues 2-15 related to 1 were tested for their capacity to protect the population spikes from DFP-induced damage and intrinsic toxicity. Twelve cembranoids caused significant reversal of DFP toxicity; only 3 active analogues displayed minor intrinsic toxicity at 10 μM. The C-4 epimer of 1 (2) and the 4-O-methyl ether analogue of 1 (3), were totally devoid of neuroprotective activity. The results suggested a model for cembranoid binding where the hydrophobic ring surface binds to a hydrophobic (Hbic) patch on the receptor molecule and an electronegative atom (oxygen or sulfur) in proper spatial relationship to the ring surface interacts with an electropositive group in the receptor binding site. A pharmacophore model consisting of 1 hydrogen bond acceptor (HBA), 2 Hbic, and 10 exclusion spheres was established using HipHop-REFINE and supported the above mentioned pharmacophoric hypothesis. PMID:23769165

  10. Protective activity of (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol analogues against diisopropylfluorophosphate neurotoxicity: Preliminary structure-activity relationship and pharmacophore modeling

    PubMed Central

    Eterović, Vesna A.; Valle-Rodriguez, Angelie Del; Pérez, Dinely; Carrasco, Marimée; Khanfar, Mohammad A.; El Sayed, Khalid A.; Ferchmin, Pedro A.

    2013-01-01

    Diisopropylfluorophosphate (DFP) is an organophosphorous insecticide used as a surrogate for the more toxic chemical warfare nerve agent sarin. DFP produces neurotoxicity in vivo and irreversibly decreases the area of population spikes recorded from the CA1 region of acute hippocampal slices. (1S,2E,4R,6R,7E,11E)-2,7,11-Cembratriene-4,6-diol (1) is a neuroprotective natural cembranoid that reverses DFP-induced damage both in vivo and in the hippocampal slice. Cembranoid 1 acts by noncompetitive inhibition of the α7 nicotinic acetylcholine receptor. This study aims at establishing a preliminary structure-activity relationship to define the neuroprotective cembranoid pharmacophores using the hippocampal slice assay and pharmacophore modeling. Fourteen natural, semisyntheti or biocatalytic cembranoid analogues 2-15 related to 1 were tested for their capacity to protect the population spikes from DFP-induced damage and intrinsic toxicity. Twelve cembranoids caused significant reversal of DFP toxicity; only 3 active analogues displayed minor intrinsic toxicity at 10 μM. The C-4 epimer of 1 (2) and the 4-O-methyl ether analogue of 1 (3), were totally devoid of neuroprotective activity. The results suggested a model for cembranoid binding where the hydrophobic ring surface binds to a hydrophobic (Hbic) patch on the receptor molecule and an electronegative atom (oxygen or sulfur) in proper spatial relationship to the ring surface interacts with an electropositive group in the receptor binding site. A pharmacophore model consisting of 1 hydrogen bond acceptor (HBA), 2 Hbic, and 10 exclusion spheres was established using HipHop-REFINE and supported the above mentioned pharmacophoric hypothesis. PMID:23769165

  11. Hydrogen bonding between aromatic H and F groups leading to a stripe structure with R- and S-columns: the crystal structure of (2,7-dimethoxynaphthalen-1-yl)(3-fluorophenyl)methanone and comparison with its 1-aroylnaphthalene analogues.

    PubMed

    Mohri, Saki; Ohisa, Shinji; Isozaki, Katsuhiro; Yonezawa, Noriyuki; Okamoto, Akiko

    2015-05-01

    In the molecule of (2,7-dimethoxynaphthalen-1-yl)(3-fluorophenyl)methanone, C19H15FO3, (I), the dihedral angle between the plane of the naphthalene ring system and that of the benzene ring is 85.90?(5). The molecules exhibit axial chirality, with either an R- or an S-stereogenic axis. In the crystal structure, each enantiomer is stacked into a columnar structure and the columns are arranged alternately to form a stripe structure. A pair of (methoxy)C-H...F hydrogen bonds and ?-? interactions between the benzene rings of the aroyl groups link an R- and an S-isomer to form a dimeric pair. These dimeric pairs are piled up in a columnar fashion through (benzene)C-H...O=C and (benzene)C-H...OCH3 hydrogen bonds. The analogous 1-benzoylated compound, namely (2,7-dimethoxynaphthalen-1-yl)(phenyl)methanone [Kato et al. (2010). Acta Cryst. E66, o2659], (II), affords three independent molecules having slightly different dihedral angles between the benzene and naphthalene rings. The three independent molecules form separate columns and the three types of column are connected to each other via two C-H...OCH3 hydrogen bonds and one C-H...O=C hydrogen bond. Two of the three columns are formed by the same enantiomeric isomer, whereas the remaining column consists of the counterpart isomer. In the case of the fluorinated 1-benzoylated naphthalene analogue, namely (2,7-dimethoxynaphthalen-1-yl)(4-fluorophenyl)methanone [Watanabe et al. (2011). Acta Cryst. E67, o1466], (III), the molecular packing is similar to that of (I), i.e. it consists of stripes of R- and S-enantiomeric columns. A pair of C-H...F hydrogen bonds between R- and S-isomers, and C-H...O=C hydrogen bonds between R(or S)-isomers, are also observed. Consequently, the stripe structure is apparently induced by the formation of R...S dimeric pairs stacked in a columnar fashion. The pair of C-H...F hydrogen bonds effectively stabilizes the dimeric pair of R- and S-enantiomers. In addition, the co-existence of C-H...F and C-H...O=C hydrogen bonds makes possible the formation of a structure with just one independent molecule. PMID:25940888

  12. Immunogold Localization of Key Metabolic Enzymes in the Anammoxosome and on the Tubule-Like Structures of Kuenenia stuttgartiensis

    PubMed Central

    de Almeida, Naomi M.; Neumann, Sarah; Mesman, Rob J.; Ferousi, Christina; Keltjens, Jan T.; Jetten, Mike S. M.; van Niftrik, Laura

    2015-01-01

    ABSTRACT Anaerobic ammonium-oxidizing (anammox) bacteria oxidize ammonium with nitrite as the terminal electron acceptor to form dinitrogen gas in the absence of oxygen. Anammox bacteria have a compartmentalized cell plan with a central membrane-bound prokaryotic organelle called the anammoxosome. The anammoxosome occupies most of the cell volume, has a curved membrane, and contains conspicuous tubule-like structures of unknown identity and function. It was suggested previously that the catalytic reactions of the anammox pathway occur in the anammoxosome, and that proton motive force was established across its membrane. Here, we used antibodies raised against five key enzymes of the anammox catabolism to determine their cellular location. The antibodies were raised against purified native hydroxylamine oxidoreductase-like protein kustc0458 with its redox partner kustc0457, hydrazine dehydrogenase (HDH; kustc0694), hydroxylamine oxidase (HOX; kustc1061), nitrite oxidoreductase (NXR; kustd1700/03/04), and hydrazine synthase (HZS; kuste2859-61) of the anammox bacterium Kuenenia stuttgartiensis. We determined that all five protein complexes were exclusively located inside the anammoxosome matrix. Four of the protein complexes did not appear to form higher-order protein organizations. However, the present data indicated for the first time that NXR is part of the tubule-like structures, which may stretch the whole length of the anammoxosome. These findings support the anammoxosome as the locus of catabolic reactions of the anammox pathway. IMPORTANCE Anammox bacteria are environmentally relevant microorganisms that contribute significantly to the release of fixed nitrogen in nature. Furthermore, the anammox process is applied for nitrogen removal from wastewater as an environment-friendly and cost-effective technology. These microorganisms feature a unique cellular organelle, the anammoxosome, which was proposed to contain the energy metabolism of the cell and tubule-like structures with hitherto unknown function. Here, we purified five native enzymes catalyzing key reactions in the anammox metabolism and raised antibodies against these in order to localize them within the cell. We showed that all enzymes were located within the anammoxosome, and nitrite oxidoreductase was located exclusively at the tubule-like structures, providing the first insights into the function of these subcellular structures. PMID:25962914

  13. Key stabilizing elements of protein structure identified through pressure and temperature perturbation of its hydrogen bond network

    NASA Astrophysics Data System (ADS)

    Nisius, Lydia; Grzesiek, Stephan

    2012-09-01

    Hydrogen bonds are key constituents of biomolecular structures, and their response to external perturbations may reveal important insights about the most stable components of a structure. NMR spectroscopy can probe hydrogen bond deformations at very high resolution through hydrogen bond scalar couplings (HBCs). However, the small size of HBCs has so far prevented a comprehensive quantitative characterization of protein hydrogen bonds as a function of the basic thermodynamic parameters of pressure and temperature. Using a newly developed pressure cell, we have now mapped pressure- and temperature-dependent changes of 31 hydrogen bonds in ubiquitin by measuring HBCs with very high precision. Short-range hydrogen bonds are only moderately perturbed, but many hydrogen bonds with large sequence separations (high contact order) show greater changes. In contrast, other high-contact-order hydrogen bonds remain virtually unaffected. The specific stabilization of such topologically important connections may present a general principle with which to achieve protein stability and to preserve structural integrity during protein function.

  14. Structural studies of cinnamoyl-CoA reductase and cinnamyl-alcohol dehydrogenase, key enzymes of monolignol biosynthesis.

    PubMed

    Pan, Haiyun; Zhou, Rui; Louie, Gordon V; Mühlemann, Joëlle K; Bomati, Erin K; Bowman, Marianne E; Dudareva, Natalia; Dixon, Richard A; Noel, Joseph P; Wang, Xiaoqiang

    2014-09-01

    The enzymes cinnamoyl-CoA reductase (CCR) and cinnamyl alcohol dehydrogenase (CAD) catalyze the two key reduction reactions in the conversion of cinnamic acid derivatives into monolignol building blocks for lignin polymers in plant cell walls. Here, we describe detailed functional and structural analyses of CCRs from Medicago truncatula and Petunia hybrida and of an atypical CAD (CAD2) from M. truncatula. These enzymes are closely related members of the short-chain dehydrogenase/reductase (SDR) superfamily. Our structural studies support a reaction mechanism involving a canonical SDR catalytic triad in both CCR and CAD2 and an important role for an auxiliary cysteine unique to CCR. Site-directed mutants of CAD2 (Phe226Ala and Tyr136Phe) that enlarge the phenolic binding site result in a 4- to 10-fold increase in activity with sinapaldehyde, which in comparison to the smaller coumaraldehyde and coniferaldehyde substrates is disfavored by wild-type CAD2. This finding demonstrates the potential exploitation of rationally engineered forms of CCR and CAD2 for the targeted modification of monolignol composition in transgenic plants. Thermal denaturation measurements and structural comparisons of various liganded and unliganded forms of CCR and CAD2 highlight substantial conformational flexibility of these SDR enzymes, which plays an important role in the establishment of catalytically productive complexes of the enzymes with their NADPH and phenolic substrates. PMID:25217505

  15. Preliminary structural design and key technology demonstration of cryogenic assembly in the next-generation infrared space telescope SPICA

    NASA Astrophysics Data System (ADS)

    Mizutani, Tadahito; Yamawaki, Toshihiko; Komatsu, Keiji; Goto, Ken; Takeuchi, Shinsuke; Shinozaki, Keisuke; Matsuhara, Hideo; Nakagawa, Takao

    2015-04-01

    The infrared space telescope SPICA (Space Infrared Telescope for Cosmology and Astrophysics) is a next-generation astronomical project of the Japan Aerospace Exploration Agency, which features a 3 m class and 6 K cryogenically cooled space telescope. This paper outlines the current status for the preliminary structural design of the SPICA payload module. Dedicated studies were conducted for key technologies to enhance the design accuracy of the SPICA cryogenic assembly and mitigate the development risk. One of the results is described for the concept of the on-orbit truss separation mechanisms, which aim to both reduce the heat load from the main truss assembly and isolate the microvibration by changing the natural frequency of the spacecraft.

  16. Polyamine Analogues Bind Human Serum Albumin

    PubMed Central

    Beauchemin, R.; Nsoukpo-Kossi, C. N.; Thomas, T. J.; Thomas, T.; Carpentier, R.; Tajmir-Riahi, H. A.

    2008-01-01

    Polyamine analogues show antitumor activity in experimental models and their ability to alter activity of cytotoxic chemotherapeutic agents in breast cancer is well documented. Association of polyamines with nucleic acids and protein is included in their mechanism of action. The aim of this study was to examine the interaction of human serum albumin (HSA) with several polyamine analogues such as 1,11-diamino-4,8-diazaundecane (333), 3,7,11,15-tetrazaheptadecane.4HCl (BE-333) and 3,7,11,15,19-pentazahenicosane.5HCl (BE-3333) in aqueous solution at physiological conditions, using a constant protein concentration and various polyamine contents (?M to mM). FTIR, UV-visible and CD spectroscopic methods were used to determine the polyamine binding mode and the effects of polyamine complexation on protein stability and secondary structure. Structural analysis showed that polyamines bind non-specifically (H-bonding) via polypeptide polar groups with binding constants of K333 = 9.30 103 M?1, KBE-333 = 5.63 102 M?1 and KBE-3333 = 3.66 102 M?1. The protein secondary structure showed major alterations with reduction of ?-helix from 55% (free protein) to 4350% and increase of ?-sheet from 17% (free protein) to 2936% in the 333-, BE-333- and BE-3333 complexes, indicating a partial protein unfolding upon polyamine interaction. HSA structure was less perturbed by polyamine analogues than those of the biogenic polyamines. PMID:17887793

  17. Detection of Transient Intermediates Generated from Subsite Analogues of [FeFe] Hydrogenases.

    PubMed

    Hunt, Neil T; Wright, Joseph A; Pickett, Christopher

    2016-01-19

    This article reviews the application of transient techniques in the elucidation of electron, proton, and photon chemistry related to the catalytic subsite of [FeFe] hydrogenase from the perspective of research in this area carried out at the UEA and Strathclyde laboratories. The detection of mixed-valence states, bridging CO intermediates, paramagnetic hydrides, and coordinatively unsaturated species has both informed understanding of biological catalysis and stimulated the search for stable analogues of key structural motifs likely involved in turnover states. PMID:26689103

  18. Network structure and the role of key players in a translational cancer research network: a study protocol

    PubMed Central

    Cunningham, Frances C; Braithwaite, Jeffrey

    2012-01-01

    Introduction Translational research networks are a deliberate strategy to bridge the gulf between biomedical research and clinical practice through interdisciplinary collaboration, supportive funding and infrastructure. The social network approach examines how the structure of the network and players who hold important positions within it constrain or enable function. This information can be used to guide network management and optimise its operations. The aim of this study was to describe the structure of a translational cancer research network (TCRN) in Australia over its first year, identify the key players within the network and explore these players' opportunities and constraints in maximising important network collaborations. Methods and analysis This study deploys a mixed-method longitudinal design using social network analysis augmented by interviews and review of TCRN documents. The study will use network documents and interviews with governing body members to explore the broader context into which the network is embedded as well as the perceptions and expectations of members. Of particular interest are the attitudes and perceptions of clinicians compared with those of researchers. A co-authorship network will be constructed of TCRN members using journal and citation databases to assess the success of past pre-network collaborations. Two whole network social network surveys will be administered 12?months apart and parameters such as density, clustering, centrality and betweenness centrality computed and compared using UCINET and Netdraw. Key players will be identified and interviewed to understand the specific activities, barriers and enablers they face in that role. Ethics and dissemination Ethics approvals were obtained from the University of New South Wales, South Eastern Sydney Northern Sector Local Health Network and Calvary Health Care Sydney. Results will be discussed with members of the TCRN, submitted to relevant journals and presented as oral presentations to clinicians, researchers and policymakers. PMID:22734122

  19. Structural Re-arrangement and Peroxidase Activation of Cytochrome c by Anionic Analogues of Vitamin E, Tocopherol Succinate and Tocopherol Phosphate*

    PubMed Central

    Yanamala, Naveena; Kapralov, Alexander A.; Djukic, Mirjana; Peterson, Jim; Mao, Gaowei; Klein-Seetharaman, Judith; Stoyanovsky, Detcho A.; Stursa, Jan; Neuzil, Jiri; Kagan, Valerian E.

    2014-01-01

    Cytochrome c is a multifunctional hemoprotein in the mitochondrial intermembrane space whereby its participation in electron shuttling between respiratory complexes III and IV is alternative to its role in apoptosis as a peroxidase activated by interaction with cardiolipin (CL), and resulting in selective CL peroxidation. The switch from electron transfer to peroxidase function requires partial unfolding of the protein upon binding of CL, whose specific features combine negative charges of the two phosphate groups with four hydrophobic fatty acid residues. Assuming that other endogenous small molecule ligands with a hydrophobic chain and a negatively charged functionality may activate cytochrome c into a peroxidase, we investigated two hydrophobic anionic analogues of vitamin E, ?-tocopherol succinate (?-TOS) and ?-tocopherol phosphate (?-TOP), as potential inducers of peroxidase activity of cytochrome c. NMR studies and computational modeling indicate that they interact with cytochrome c at similar sites previously proposed for CL. Absorption spectroscopy showed that both analogues effectively disrupt the Fe-S(Met80) bond associated with unfolding of cytochrome c. We found that ?-TOS and ?-TOP stimulate peroxidase activity of cytochrome c. Enhanced peroxidase activity was also observed in isolated rat liver mitochondria incubated with ?-TOS and tBOOH. A mitochondria-targeted derivative of TOS, triphenylphosphonium-TOS (mito-VES), was more efficient in inducing H2O2-dependent apoptosis in mouse embryonic cytochrome c+/+ cells than in cytochrome c?/? cells. Essential for execution of the apoptotic program peroxidase activation of cytochrome c by ?-TOS may contribute to its known anti-cancer pharmacological activity. PMID:25278024

  20. Effect of beta-casomorphin and its analogue on serum prolactin in the rat.

    PubMed

    Nedvdkov, J; Kasafrek, E; Dlabac, A; Felt, V

    1985-04-01

    The effects of exogenous opioid peptides beta-casomorphin Tyr-Pro-Phe-Pro-Gly-Pro-Ile and its analogue Tyr-Pro-Gly-Pro-Phe-Pro-Ile (analogue I) were found to increase prolactin level in plasma after intraperitoneal injection. Analogue I was more potent. This effect of beta-casomorphin and analogue I were blocked by an opioid antagonist, naloxone. These results indicate that the exogenous opioid peptides (exorphins) may participate in the regulation of prolactin secretion. The similarity of analogue I with enkephalin structure was discussed. PMID:4018163

  1. Structure of the Trehalose-6-phosphate Phosphatase from Brugia malayi Reveals Key Design Principles for Anthelmintic Drugs

    PubMed Central

    Farelli, Jeremiah D.; Galvin, Brendan D.; Li, Zhiru; Liu, Chunliang; Aono, Miyuki; Garland, Megan; Hallett, Olivia E.; Causey, Thomas B.; Ali-Reynolds, Alana; Saltzberg, Daniel J.; Carlow, Clotilde K. S.; Dunaway-Mariano, Debra; Allen, Karen N.

    2014-01-01

    Parasitic nematodes are responsible for devastating illnesses that plague many of the world's poorest populations indigenous to the tropical areas of developing nations. Among these diseases is lymphatic filariasis, a major cause of permanent and long-term disability. Proteins essential to nematodes that do not have mammalian counterparts represent targets for therapeutic inhibitor discovery. One promising target is trehalose-6-phosphate phosphatase (T6PP) from Brugia malayi. In the model nematode Caenorhabditis elegans, T6PP is essential for survival due to the toxic effect(s) of the accumulation of trehalose 6-phosphate. T6PP has also been shown to be essential in Mycobacterium tuberculosis. We determined the X-ray crystal structure of T6PP from B. malayi. The protein structure revealed a stabilizing N-terminal MIT-like domain and a catalytic C-terminal C2B-type HAD phosphatase fold. Structure-guided mutagenesis, combined with kinetic analyses using a designed competitive inhibitor, trehalose 6-sulfate, identified five residues important for binding and catalysis. This structure-function analysis along with computational mapping provided the basis for the proposed model of the T6PP-trehalose 6-phosphate complex. The model indicates a substrate-binding mode wherein shape complementarity and van der Waals interactions drive recognition. The mode of binding is in sharp contrast to the homolog sucrose-6-phosphate phosphatase where extensive hydrogen-bond interactions are made to the substrate. Together these results suggest that high-affinity inhibitors will be bi-dentate, taking advantage of substrate-like binding to the phosphoryl-binding pocket while simultaneously utilizing non-native binding to the trehalose pocket. The conservation of the key residues that enforce the shape of the substrate pocket in T6PP enzymes suggest that development of broad-range anthelmintic and antibacterial therapeutics employing this platform may be possible. PMID:24992307

  2. Structure of the trehalose-6-phosphate phosphatase from Brugia malayi reveals key design principles for anthelmintic drugs.

    PubMed

    Farelli, Jeremiah D; Galvin, Brendan D; Li, Zhiru; Liu, Chunliang; Aono, Miyuki; Garland, Megan; Hallett, Olivia E; Causey, Thomas B; Ali-Reynolds, Alana; Saltzberg, Daniel J; Carlow, Clotilde K S; Dunaway-Mariano, Debra; Allen, Karen N

    2014-07-01

    Parasitic nematodes are responsible for devastating illnesses that plague many of the world's poorest populations indigenous to the tropical areas of developing nations. Among these diseases is lymphatic filariasis, a major cause of permanent and long-term disability. Proteins essential to nematodes that do not have mammalian counterparts represent targets for therapeutic inhibitor discovery. One promising target is trehalose-6-phosphate phosphatase (T6PP) from Brugia malayi. In the model nematode Caenorhabditis elegans, T6PP is essential for survival due to the toxic effect(s) of the accumulation of trehalose 6-phosphate. T6PP has also been shown to be essential in Mycobacterium tuberculosis. We determined the X-ray crystal structure of T6PP from B. malayi. The protein structure revealed a stabilizing N-terminal MIT-like domain and a catalytic C-terminal C2B-type HAD phosphatase fold. Structure-guided mutagenesis, combined with kinetic analyses using a designed competitive inhibitor, trehalose 6-sulfate, identified five residues important for binding and catalysis. This structure-function analysis along with computational mapping provided the basis for the proposed model of the T6PP-trehalose 6-phosphate complex. The model indicates a substrate-binding mode wherein shape complementarity and van der Waals interactions drive recognition. The mode of binding is in sharp contrast to the homolog sucrose-6-phosphate phosphatase where extensive hydrogen-bond interactions are made to the substrate. Together these results suggest that high-affinity inhibitors will be bi-dentate, taking advantage of substrate-like binding to the phosphoryl-binding pocket while simultaneously utilizing non-native binding to the trehalose pocket. The conservation of the key residues that enforce the shape of the substrate pocket in T6PP enzymes suggest that development of broad-range anthelmintic and antibacterial therapeutics employing this platform may be possible. PMID:24992307

  3. The investigation of blind continental earthquake sources through analogue and numerical models

    NASA Astrophysics Data System (ADS)

    Bonini, L.; Toscani, G.; Seno, S.

    2012-04-01

    One of the most challenging topic in earthquake geology is to characterize the seismogenic sources, i.e. the potential causative faults of earthquakes. The main seismogenic layer is located in the upper brittle crust. Nevertheless it does not mean that a fault take up the whole schizosphere: i.e. from the brittle-plastic transition to the surface. Indeed, latest damaging earthquakes were generated by blind or "hidden" faults: 23 Oct. 2011, Van earthquake (Mw 7.1, Turkey); 3 Sep 2010, Darfield earthquake (Mw 7.1, New Zealand); 12 January 2010 Haiti earthquake (Mw 7.0); 6 April 2009 L'Aquila earthquake (Mw 6.3, Italy). Therefore understand how a fault grows and develops is a key question to evaluate the seismogenic potential of an area. Analogue model was used to understand kinematics and geometry of the geological structures since the beginning of the modern geology. On the other hand, numerical model develops much more during the last thirty years. Nowadays we can use these two methods working together providing mutual interactions. In the two-three most recent years we tried to use both numerical and analogue models to investigate the long-term and short-term evolution of a blind normal fault. To do this we improved the Analogue Model Laboratory of the University of Pavia with a laser scanner, a stepper motor and other high resolution tools in order to detect the distribution of the deformation mainly induced by blind faults. The goal of this kind of approach is to mimic the effects of the faults movements in a scaled model. We selected two seismogenic source cases: the causative fault of the 1908 Messina earthquake (Mw 7.1) and that of the 2009 L'Aquila earthquake (Mw 6.3). In the first case we investigate the long term evolution of this structure using a set of analogue models and afterwards a numerical model of our sandbox allow us to investigate stress and strain partitioning. In the second case we performed only an analogue model of short-term evolution of the L'Aquila seismogenic source comparing our result with pre-existing numerical models. In both cases we obtain mutual advantages using together experimental results. We believe that the analogue modelling approach coupled with numerical modelling applied to the study of active faults can provide useful insights to investigate the seismic potential of a structure with important appliances also for the seismic risk assessment.

  4. Synthesis and acetylcholinesterase inhibitory activity of several pyrimidone analogues of huperzine A

    SciTech Connect

    Kozlkowski, A.P.; Campiani, G.; Saxena, A.; Doctor, S.P.

    1995-12-31

    Synthesis of four new pyrimidone analogues of the acetyicholinesterase (AChE) inhibitor huperzine A are reported together with the inhibitory potendes of these compounds for foetal bovine calf serum AChE; t3-lactone formation followed by a thermal cycloreversion reaction serves as the key step for introduction of the ethylidene appendage of analogue 12 in the stereochemically correct form.

  5. Syntheses of Cyclotriveratrylene Analogues and Their Long Elusive Triketone Congeners

    PubMed Central

    2015-01-01

    Although interest in cyclotriveratrylene and its analogues has been significant, limitations in the ability to adjust its structure fully have hampered studies into their complete range of properties. A unique strategy to synthesize a previously unobtainable cyclotriveratrylene analogue and a procedure which adjusts the inner methylene bridges of that material to a triketone is reported. A second triketone synthesis and computational studies indicate the parameters needed for success. PMID:24987807

  6. NASA/ESMD Analogue Mission Plans

    NASA Technical Reports Server (NTRS)

    Hoffman, Stephen J.

    2007-01-01

    A viewgraph presentation exploring Earth and its analogues is shown. The topics include: 1) ESMD Goals for the Use of Earth Analogues; 2) Stakeholders Summary; 3) Issues with Current Analogue Situation; 4) Current state of Analogues; 5) External Implementation Plan (Second Step); 6) Recent Progress in Utilizing Analogues; 7) Website Layout Example-Home Page; 8) Website Layout Example-Analogue Site; 9) Website Layout Example-Analogue Mission; 10) Objectives of ARDIG Analog Initiatives; 11) Future Plans; 12) Example: Cold-Trap Sample Return; 13) Example: Site Characterization Matrix; 14) Integrated Analogue Studies-Prerequisites for Human Exploration; and 15) Rating Scale Definitions.

  7. Analogue models of pull-apart basins

    NASA Astrophysics Data System (ADS)

    McClay, Ken; Dooley, Tim

    1995-08-01

    Sandbox analogue models of pull-apart basins that developed in sedimentary strata above releasing steps in underlying basement faults are characterized by rhombic basins that are flat-bottomed box grabens with a subhorizontal synkinematic basin infill. Steep to nearly vertical, sigmoidal oblique-slip and segmented oblique-extensional faults are the dominant bounding structures of the pull-apart basins. Cross-basin, short-cut faults link the offset principal displacement zones that are characterized by flower structure development. The structural architectures of the physical models compare directly in form and dimensions to natural examples of strike-slip pull-apart basins.

  8. Complexes of an anionic gallium(I) N-heterocyclic carbene analogue with group 14 element(II) fragments: synthetic, structural and theoretical studies.

    PubMed

    Green, Shaun P; Jones, Cameron; Lippert, Kai-Alexander; Mills, David P; Stasch, Andreas

    2006-09-01

    The reactions of the anionic gallium(I) N-heterocyclic carbene (NHC) analogue, [K(tmeda)][:Ga{[N(Ar)C(H)]2}], Ar = C6H3Pri2-2,6, with the heavier group 14 alkene analogues, R2E=ER2, E = Ge or Sn, R = -CH(SiMe3)2, have been carried out. In 2:1 stoichiometries, these lead to the ionic [K(tmeda)][R2EGa{[N(Ar)C(H)]2}] complexes which exhibit long E-Ga bonds. The nature of these bonds has been probed by DFT calculations, and the complexes have been compared to neutral NHC adducts of group 14 dialkyls. The 4:1 reaction of [K(tmeda)][:Ga{[N(Ar)C(H)]2}] with R2Sn=SnR2 leads to the digallyl stannate complex, [K(tmeda)][RSn[Ga{[N(Ar)C(H)]2}]2], presumably via elimination of KR. In contrast, the reaction of the gallium heterocycle with PbR2 affords the digallane4, [Ga{[N(Ar)C(H)]2}]2, via an oxidative coupling reaction. For sake of comparison, the reactions of [K(tmeda)][:Ga{[N(Ar)C(H)]2}] with Ar'2E=EAr'2, E = Ge, Sn or Pb, Ar' = C6H2Pri3-2,4,6, were carried out and led to either no reaction (E = Ge), the formation of [K(tmeda)][Ar'2SnGa{[N(Ar)C(H)]2}] (E = Sn), or the gallium(III) heterocycle, [Ar'Ga{[N(Ar)C(H)]2}] (E = Pb). Salt elimination reactions between [K(tmeda)][:Ga{[N(Ar)C(H)]2}] and the guanidinato group 14 complexes [(Giso)ECl], E = Ge or Sn, Giso = [Pri2NC{N(Ar)}2]-, gave the neutral [(Giso)EGa{[N(Ar)C(H)]2}] complexes. All complexes have been characterized by NMR spectroscopy and X-ray crystallographic studies. PMID:16933925

  9. Bithiopheneimide-dithienosilole/dithienogermole copolymers for efficient solar cells: information from structure-property-device performance correlations and comparison to thieno[3,4-c]pyrrole-4,6-dione analogues.

    PubMed

    Guo, Xugang; Zhou, Nanjia; Lou, Sylvia J; Hennek, Jonathan W; Ponce Ortiz, Rocío; Butler, Melanie R; Boudreault, Pierre-Luc T; Strzalka, Joseph; Morin, Pierre-Olivier; Leclerc, Mario; López Navarrete, Juan T; Ratner, Mark A; Chen, Lin X; Chang, Robert P H; Facchetti, Antonio; Marks, Tobin J

    2012-11-01

    Rational creation of polymeric semiconductors from novel building blocks is critical to polymer solar cell (PSC) development. We report a new series of bithiopheneimide-based donor-acceptor copolymers for bulk-heterojunction (BHJ) PSCs. The bithiopheneimide electron-deficiency compresses polymer bandgaps and lowers the HOMOs--essential to maximize power conversion efficiency (PCE). While the dithiophene bridge progression R(2)Si→R(2)Ge minimally impacts bandgaps, it substantially alters the HOMO energies. Furthermore, imide N-substituent variation has negligible impact on polymer opto-electrical properties, but greatly affects solubility and microstructure. Grazing incidence wide-angle X-ray scattering (GIWAXS) indicates that branched N-alkyl substituents increased polymer π-π spacings vs linear N-alkyl substituents, and the dithienosilole-based PBTISi series exhibits more ordered packing than the dithienogermole-based PBTIGe analogues. Further insights into structure-property-device performance correlations are provided by a thieno[3,4-c]pyrrole-4,6-dione (TPD)-dithienosilole copolymer PTPDSi. DFT computation and optical spectroscopy show that the TPD-based polymers achieve greater subunit-subunit coplanarity via intramolecular (thienyl)S···O(carbonyl) interactions, and GIWAXS indicates that PBTISi-C8 has lower lamellar ordering, but closer π-π spacing than does the TPD-based analogue. Inverted BHJ solar cells using bithiopheneimide-based polymer as donor and PC(71)BM as acceptor exhibit promising device performance with PCEs up to 6.41% and V(oc) > 0.80 V. In analogous cells, the TPD analogue exhibits 0.08 V higher V(oc) with an enhanced PCE of 6.83%, mainly attributable to the lower-lying HOMO induced by the higher imide group density. These results demonstrate the potential of BTI-based polymers for high-performance solar cells, and provide generalizable insights into structure-property relationships in TPD, BTI, and related polymer semiconductors. PMID:23030837

  10. Synthesis of (+)-crocacin D and simplified bioactive analogues.

    PubMed

    Pasqua, Adele E; Ferrari, Frank D; Crawford, James J; Whittingham, William G; Marquez, Rodolfo

    2015-03-01

    The total synthesis of (+)-crocacin D has been achieved in 15 steps (9 isolated intermediates) and 14% overall yield from commercially available starting materials and using (+)-crocacin C as a key intermediate. A number of simplified analogues and their biological activities are also reported. PMID:25638500

  11. Novel selective PDE4 inhibitors. 1. Synthesis, structure-activity relationships, and molecular modeling of 4-(3,4-dimethoxyphenyl)-2H-phthalazin-1-ones and analogues.

    PubMed

    Van der Mey, M; Hatzelmann, A; Van der Laan, I J; Sterk, G J; Thibaut, U; Timmerman, H

    2001-08-01

    A number of 6-(3,4-dimethoxyphenyl)-4,5-dihydro-2H-pyridazin-3-ones and a novel series of 4-(3,4-dimethoxyphenyl)-2H-phthalazin-1-ones were prepared and tested on the cGMP-inhibited phosphodiesterase (PDE3) and cAMP-specific phosphodiesterase (PDE4) enzymes. All tested compounds were found to specifically inhibit PDE4 except for pyridazinone 3b, which showed moderate PDE4 (pIC(50) = 6.5) as well as PDE3 (pIC(50) = 6.6) inhibitory activity. In both the pyridazinone and phthlazinone series it was found that N-substitution is beneficial for PDE4 inhibition, whereas in the pyridazinone series it also accounts for PDE4 selectivity. In the phthalazinone series, the cis-4a,5,6,7,8,8a-hexahydrophthalazinones and their corresponding 4a,5,8,8a-tetrahydro analogues showed potent PDE4 inhibitory potency (10/11c,d: pIC(50) = 7.6-8.4). A molecular modeling study revealed that the cis-fused cyclohexa(e)ne rings occupy a region in space different from that occupied by the other fused (un)saturated hydrocarbon rings applied; we therefore assume that the steric interactions of these rings with the binding site play an important role in enzyme inhibition. PMID:11472205

  12. Novel analogues of the therapeutic complement inhibitor compstatin with significantly improved affinity and potency.

    PubMed

    Qu, Hongchang; Magotti, Paola; Ricklin, Daniel; Wu, Emilia L; Kourtzelis, Ioannis; Wu, You-Qiang; Kaznessis, Yiannis N; Lambris, John D

    2011-01-01

    Compstatin is a 13-residue disulfide-bridged peptide that inhibits a key step in the activation of the human complement system. Compstatin and its derivatives have shown great promise for the treatment of many clinical disorders associated with unbalanced complement activity. To obtain more potent compstatin analogues, we have now performed an N-methylation scan of the peptide backbone and amino acid substitutions at position 13. One analogue (Ac-I[CVW(Me)QDW-Sar-AHRC](NMe)I-NH(2)) displayed a 1000-fold increase in both potency (IC(50) = 62 nM) and binding affinity for C3b (K(D) = 2.3 nM) over that of the original compstatin. Biophysical analysis using surface plasmon resonance and isothermal titration calorimetry suggests that the improved binding originates from more favorable free conformation and stronger hydrophobic interactions. This study provides a series of significantly improved drug leads for therapeutic applications in complement-related diseases, and offers new insights into the structure-activity relationships of compstatin analogues. PMID:21067811

  13. Structure and function analysis of Escherichia coli inorganic pyrophosphatase: is a hydroxide ion the key to catalysis?

    PubMed

    Salminen, T; Kpyl, J; Heikinheimo, P; Kankare, J; Goldman, A; Heinonen, J; Baykov, A A; Cooperman, B S; Lahti, R

    1995-01-24

    Using site-directed mutagenesis, we have completed replacing all 17 putative active site residues of Escherichia coli inorganic pyrophosphatase (PPase). We report here the production of 11 new variant proteins and their initial characterization, including thermostability, hydrophobicity, oligomeric structure, and specific activity at pH 8. Studies of the pH-rate profiles of 12 variants containing substitutions for potentially essential residues showed that the effect of the mutation was always to increase the pKa of a basic group essential for both substrate binding and catalysis by 1-3 pH units. The D70E variant had the lowest activity at all pHs; the K29R, R43K, and K142R variants also had low kcat/Km values. The principal effect seen in the other variant proteins was higher and sharper pH optima; their pH-independent kcat and kcat/Km values changed at most by a factor of 8. Our results suggest that the most likely candidate for the essential basic group affected by all mutations in the active site is a hydroxide ion stabilized by coordination to the essential Mg2+ ions. Analyzing our results using the structure recently obtained for E. coli PPase [Kankare et al. (1994) Protein Eng. 7, 823-830] led us to identify a group of residues, centered around Asp70 and including Tyr55, Asp65, Asp67, Asp102, and Lys104, that we believe binds the magnesium ions that are critical for the activity, possibly by stabilizing the essential hydroxide. Others, including Lys29, Arg43, and Lys142, are more spread out and more positively charged. They appear to be involved in binding substrate and product. Tyr55 is also a key part of the hydrophobic core of E. coli PPase; when it or residues that interact with it are conservatively mutated, there are changes in the overall structure of the enzyme as assayed by thermostability, hydrophobicity, or oligomeric structure. PMID:7827037

  14. Transfer RNA structural change is a key element in the reassignment of the CUG codon in Candida albicans.

    PubMed Central

    Santos, M A; Perreau, V M; Tuite, M F

    1996-01-01

    The human pathogenic yeast Candida albicans and a number of other Candida species translate the standard leucine CUG codon as serine. This is the latest addition to an increasing number of alterations to the standard genetic code which invalidate the theory that the code is frozen and universal. The unexpected finding that some organisms evolved alternative genetic codes raises two important questions: how have these alternative codes evolved and what evolutionary advantages could they create to allow for their selection? To address these questions in the context of serine CUG translation in C.albicans, we have searched for unique structural features in seryl-tRNA(CAG), which translates the leucine CUG codon as serine, and attempted to reconstruct the early stages of this genetic code switch in the closely related yeast species Saccharomyces cerevisiae. We show that a purine at position 33 (G33) in the C.albicans Ser-tRNA(CAG) anticodon loop, which replaces a conserved pyrimidine found in all other tRNAs, is a key structural element in the reassignment of the CUG codon from leucine to serine in that it decreases the decoding efficiency of the tRNA, thereby allowing cells to survive low level serine CUG translation. Expression of this tRNA in S.cerevisiae induces the stress response which allows cells to acquire thermotolerance. We argue that acquisition of thermotolerance may represent a positive selection for this genetic code change by allowing yeasts to adapt to sudden changes in environmental conditions and therefore colonize new ecological niches. Images PMID:8890179

  15. Effect of chirality and lipophilicity in the functional activity of evodiamine and its analogues at TRPV1 channels

    PubMed Central

    De Petrocellis, Luciano; Schiano Moriello, Aniello; Fontana, Gabriele; Sacchetti, Alessandro; Passarella, Daniele; Appendino, Giovanni; Di Marzo, Vincenzo

    2014-01-01

    Background and Purpose Evodiamine, a racemic quinazolinocarboline alkaloid isolated from the traditional Chinese medicine Evodiae fructus, has been reported to act as an agonist of the transient receptor potential vanilloid type-1 (TRPV1) cation channel both in vitro and in vivo. Evodiamine is structurally different from all known TRPV1 activators, and has significant clinical potential as a thermogenic agent. Nevertheless, the molecular bases for its actions are still poorly understood. Experimental Approach To investigate the structure-activity relationships of evodiamine, the natural racemate was resolved, and a series of 23 synthetic analogues was prepared, using as the end point the intracellular Ca2+ elevation in HEK-293 cells stably overexpressing either the human or the rat recombinant TRPV1. Key Results S-(+) evodiamine was more efficacious and potent than R-(?) evodiamine, and a new potent lead (Evo30) was identified, more potent than the reference TRPV1 agonist, capsaicin. In general, potency and efficacy correlated with the lipophilicity of the analogues. Like other TRPV1 agonists, several synthetic analogues could efficiently desensitize TRPV1 to activation by capsaicin. Conclusions and Implications Evodiamine qualifies as structurally unique lead structure to develop new potent TRPV1 agonists/desensitizers. Linked Articles This article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-10 PMID:23902373

  16. Analogue to digital transformation

    NASA Astrophysics Data System (ADS)

    1992-12-01

    ESDU 92044 examines the replacement of an analog controller element by an equivalent digital controller element while retaining for the new hybrid system performance characteristics that are acceptably similar to those of the original continuous system. The main features are described of a system containing both analog and digital elements within the same loop, and the analog-to-digital and digital-to-analog components that are then necessarily a part of the system. The frequency response characteristics of transformation are discussed, introducing the problem of aliasing whereby a digital output can be matched by continuous sine waves of different frequencies that are then indistinguishable to the digital sampler. The need to avoid aliasing is considered and the concept of a folding frequency introduced below which aliasing is impossible. Two transformation methods for designing digital filters equivalent to analog filters are discussed: the impulse invariance and bilinear transformations. They are compared by examining digital equivalents of such analogue filters as simple and compound first-order lag and lead filters, second-order lag filters and first-order notch filters. The methods are compared for two sampling rates using Bode plots illustrating the gain and phase variation with frequency. An example based on an electromechanical instrument servo illustrates the transformation of an analog lag-lead controller using the bilinear transformation.

  17. Analogue Missions on Earth, a New Approach to Prepare Future Missions on the Moon

    NASA Astrophysics Data System (ADS)

    Lebeuf, Martin

    Human exploration of the Moon is a target by 2020 with an initial lunar outpost planned in polar regions. Current architectures maintain a capability for sorties to other latitudes for science activities. In the early stages of design of lunar outpost infrastructure and science activity planning, it has been recognized that analogue missions could play a major role in Moon mission design. Analogue missions, as high fidelity simulations of human and robotic surface operations, can help field scientists and engineers develop and test strategies as well as user requirements, as they provide opportunities to groundtruth measurements, and for the team to share understanding of key science needs and key engineering trades. These types of missions also provide direct training in planning science operations, and in team building and communication. The Canadian Space Agency's Exploration Core Program targets the development of technology infrastructure elements in key areas of science, technology and robotics in preparation for its role in the future exploration of the Moon and Mars. Within this Program, Analogue Missions specifically target the operations requirements and lessons learned that will reduce costs and lower the risk of planetary surface missions. Analogue missions are simulations of planetary surface operations that take place at analogue sites on Earth. A terrestrial analogue site resembles in some key way: eg. geomorphologically or geochemically, a surface environment of another planet. An analogue mission can, therefore, be defined as an integrated set of activities that represent (or simulate) entire mission designs or narrowly focus on specific aspects of planned or potential future planetary exploration missions. Within the CSA's Exploration Core Program, Analogue Missions facilitate the maturation of science instruments and mission concepts by integrating ongoing space instrument and technology development programs with science and analogue elements. As well as using analogue missions to meet agency programmatic needs, the Canadian Space Agency encourages scientists and engineers to make use of opportunities presented by analogue missions to further their own research objectives. Specific objectives of Analogue Missions are to (1) foster a multidisciplinary approach to planning, data acquisition, processing and interpretation, calibration of instruments, and telemetry during mission operations; (2) integrate new science with emerging technologies; and (3) develop an expertise on exploration architecture design from projects carried out at terrestrial analogue sites. Within Analogue Missions, teams develop planning tools, use mission-specific software and technology, and communicate results as well as lessons learned during tactical operations. The expertise gained through Analogue Missions will contribute to inform on all aspects of exploration architectures, including planetary mobility requirements and astronaut training.

  18. Influence of the Charge State on the Structures and Interactions of Vancomycin Antibiotics with Cell-Wall Analogue Peptides: Experimental and Theoretical Studies

    SciTech Connect

    Yang, Zhibo; Vorpagel, Erich R.; Laskin, Julia

    2009-02-16

    In this study we examined the effect of the charge state on the energetics and dynamics of dissociation of the non-covalent complex between the vancomycin and the cell wall peptide analogue Nα,Nε-diacetyl-L-Lys-D-Ala-D-Ala (V-Ac2KDADA). The binding energies between the vancomycin and the peptide were obtained from the RRKM modeling of the time- and energy resolved surface-induced dissociation (SID) experiments. Our results demonstrate that the stability of the complex toward fragmentation increases in the order: [V+Ac2KDADA+H]+2 < [V+Ac2KDADA+H]+ < [V+Ac2KDADA-H]-. Dissociation of the singly protonated and singly deprotonated complex is characterized by very large entropy effects indicating substantial increase in the conformational flexibility of the resulting products. The experimental threshold energies of 1.75 eV and 1.34 eV obtained for the [V+Ac2KDADA-H]- and [V+Ac2KDADA+H]+ , respectively, are in excellent agreement with the results of density functional theory (DFT) calculations. The increased stability of the deprotonated complex observed experimentally is attributed to the presence of three charged sites in the deprotonated complex as compared to only one charged site in the singly protonated complex. The low binding energy of 0.93 eV obtained for the doubly protonated complex suggests that this ion is destabilized by Coulomb repulsion between the singly protonated vancomycin and the singly protonated peptide comprising the complex.

  19. Antimicrobial activity of resveratrol analogues.

    PubMed

    Chalal, Malik; Klinguer, Agns; Echairi, Abdelwahad; Meunier, Philippe; Vervandier-Fasseur, Dominique; Adrian, Marielle

    2014-01-01

    Stilbenes, especially resveratrol and its derivatives, have become famous for their positive effects on a wide range of medical disorders, as indicated by a huge number of published studies. A less investigated area of research is their antimicrobial properties. A series of 13 trans-resveratrol analogues was synthesized via Wittig or Heck reactions, and their antimicrobial activity assessed on two different grapevine pathogens responsible for severe diseases in the vineyard. The entire series, together with resveratrol, was first evaluated on the zoospore mobility and sporulation level of Plasmopara viticola (the oomycete responsible for downy mildew). Stilbenes displayed a spectrum of activity ranging from low to high. Six of them, including the most active ones, were subsequently tested on the development of Botrytis cinerea (fungus responsible for grey mold). The results obtained allowed us to identify the most active stilbenes against both grapevine pathogens, to compare the antimicrobial activity of the evaluated series of stilbenes, and to discuss the relationship between their chemical structure (number and position of methoxy and hydroxy groups) and antimicrobial activity. PMID:24918540

  20. The 'Vertical Structure and Diabatic Processes of the Madden-Julian Oscillation' model evaluation project: Overview and key results (Invited)

    NASA Astrophysics Data System (ADS)

    Klingaman, N. P.; Jiang, X.; Xavier, P.; Petch, J.; Waliser, D. E.; Woolnough, S.

    2013-12-01

    The Madden-Julian oscillation (MJO) is the dominant mode of tropical sub-seasonal (30-60 day) variability. By modulating regional monsoon circulation and precipitation, interacting with ENSO and influences modes of extra-tropical variability (e.g., the NAO), the MJO provides a key source of weekly and monthly predictability globally. Despite this, most weather and climate models exhibit large biases in their simulations of the MJO. We will introduce a model evaluation project, endorsed by YoTC and GASS, designed to identify and reduce sources of error in the models' MJO representations. A key advantage of this project over previous intercomparisons is that temperature, moisture and momentum tendencies have been requested from all sub-grid parameterization schemes. This allows detailed analysis of the links between biases in MJO activity and biases in the vertical profiles of diabatic heating, moistening and momentum. The project comprises three components: 20-year simulations, from which the overall level of MJO activity can be assessed; serial 2-day hindcasts of two strong events in winter 2009-2010, in which the behavior of model parameterizations can be evaluated close to the initial, observed state; and serial 20-day hindcasts of the same two MJO events, which bridge the gap between the other two components by permitting analysis of the degradation of the simulated MJO from the initial state towards the model's climatology. Analysis of the 20-year simulations suggests that many proposed process-oriented MJO metrics, such as the relationship between precipitation and the vertical structure of relative humidity, do not sufficiently distinguish between those models that simulate the MJO well and those that simulate it poorly. It is assumed that the processes described by these metrics are necessary, but not sufficient, for an adequate simulation of the MJO in GCMs. Analysis of the 2-day hindcasts demonstrates that models develop substantial biases in upper-level temperature and humidity, evaluated against YoTC analyses, within 48 hours. These biases stem from large differences in cloud cover above the freezing level in models, which lead to discrepancies in the magnitude and even sign of the radiative temperature increments; this points to errors in cloud-radiative interactions in these models. In the 20-day hindcasts, there is no relationship between a model's ability to predict the MJO and its vertical profile of diabatic heating; models with similar diabatic-heating profiles have very different levels of skill in these hindcasts. A more consistent association is found between MJO skill and diabatic-moistening profiles, with high-skill models showing a clear transition from shallow moistening in suppressed conditions to deep moistening during the active phase. We will present an overview of the evaluation project, its goals and objectives; highlight key results from each components of the project; and discuss the next steps for further analysis, including the dissemination of data to the wider community.

  1. Condensed matter analogues of cosmology

    NASA Astrophysics Data System (ADS)

    Kibble, Tom; Srivastava, Ajit

    2013-10-01

    It is always exciting when developments in one branch of physics turn out to have relevance in a quite different branch. It would be hard to find two branches farther apart in terms of energy scales than early-universe cosmology and low-temperature condensed matter physics. Nevertheless ideas about the formation of topological defects during rapid phase transitions that originated in the context of the very early universe have proved remarkably fruitful when applied to a variety of condensed matter systems. The mathematical frameworks for describing these systems can be very similar. This interconnection has led to a deeper understanding of the phenomena in condensed matter systems utilizing ideas from cosmology. At the same time, one can view these condensed matter analogues as providing, at least in a limited sense, experimental access to the phenomena of the early universe for which no direct probe is possible. As this special issue well illustrates, this remains a dynamic and exciting field. The basic idea is that when a system goes through a rapid symmetry-breaking phase transition from a symmetric phase into one with spontaneously broken symmetry, the order parameter may make different choices in different regions, creating domains that when they meet can trap defects. The scale of those domains, and hence the density of defects, is constrained by the rate at which the system goes through the transition and the speed with which order parameter information propagates. This is what has come to be known as the Kibble-Zurek mechanism. The resultant scaling laws have now been tested in a considerable variety of different systems. The earliest experiments illustrating the analogy between cosmology and condensed matter were in liquid crystals, in particular on the isotropic-to-nematic transition, primarily because it is very easy to induce the phase transition (typically at room temperature) and to image precisely what is going on. This field remains one of the liveliest. A number of new experiments are reported here studying the dynamical evolution of domains and defects. Another phenomenon that played a key early role was the formation of vortices in the normal-to-superfluid transition in liquid helium-3. The complicated nature of the order parameter energy surface gives rise to a variety of intriguing effects. This too is still a vigorous field. Superconductivity is a special case because the symmetry that is broken is a gauge symmetry. This is also true in fundamental particle physics theories of relevance to cosmology, and for that reason experiments on superconductors are of particular interest to cosmologists. The situation in this case is more complicated because there are competing mechanisms of defect formation. Experiments in the field have not proved easy, either to perform or to interpret, but the papers in this collection show that good progress has been made of late. In recent years a new type of system has proved immensely fruitful, namely atomic Bose-Einstein or Fermi-gas condensates. Experiments on condensates with tunable parameters have in general provided broad support for the theory, and have also revealed a wide range of interesting and novel features, with intriguing possible analogues in cosmology (e.g. causal horizons and particle creation). The basic idea of the Kibble-Zurek mechanism has been shown to be relevant in this whole range of systems. But numerous complexities have also emerged, concerned for example with the role of inhomogeneity or the existence of composite defects. The field is still developing rapidly. Acknowledgments Finally, we would like to thank all the authors who have contributed to this issue, and the staff of Journal of Physics: Condensed Matter who have made it possible. Condensed matter analogues of cosmology contents Condensed matter analogues of cosmologyTom Kibble and Ajit Srivastava Symmetry breaking in nematic liquid crystals: analogy with cosmology and magnetismR Repnik, A Ranjkesh, V Simonka, M Ambrozic, Z Bradac and S Kralj Morphogenesis of defects and tactoids during isotropic-nematic phase transition in self-assembled lyotropic chromonic liquid crystalsYoung-Ki Kim, Sergij V Shiyanovskii and Oleg D Lavrentovich Annihilation dynamics of stringlike topological defects in a nematic lyotropic liquid crystalR R Guimares, R S Mendes, P R G Fernandes and H Mukai Duality between the dynamics of line-like brushes of point defects in 2D and strings in 3D in liquid crystalsSanatan Digal, Rajarshi Ray, P S Saumia and Ajit M Srivastava The multiuniverse transition in superfluid 3HeYury Bunkov Coherent topological defect dynamics and collective modes in superconductors and electronic crystalsD Mihailovic, T Mertelj, V V Kabanov and S Brazovskii Gaussianity revisited: exploring the Kibble-Zurek mechanism with superconducting ringsD J Weir, R Monaco, V P Koshelets, J Mygind and R J Rivers The Kibble-Zurek mechanism in a subcritical bifurcationM A Miranda, D Laroze and W Gonzlez-Vias Topological relics of symmetry breaking: winding numbers and scaling tilts from random vortex-antivortex pairsW H Zurek Causality and non-equilibrium second-order phase transitions in inhomogeneous systemsA del Campo, T W B Kibble and W H Zurek The role of causality in tunable Fermi gas condensatesJen-Tsung Hsiang, Chi-Yong Lin, Da-Shin Lee and Ray J Rivers Kibble-Zurek mechanism in a trapped ferromagnetic Bose-Einstein condensateHiroki Saito, Yuki Kawaguchi and Masahito Ueda D-brane solitons and boojums in field theory and Bose-Einstein condensatesKenichi Kasamatsu, Hiromitsu Takeuchi and Muneto Nitta Kibble-Zurek scaling and string-net coarsening in topologically ordered systemsAnushya Chandran, F J Burnell, Vedika Khemani and S L Sondhi Universal frozen spectra after time-dependent symmetry restoring phase transitionsFriedemann Queisser, Patrick Navez and Ralf Schtzhold Microscopic theory of non-adiabatic response in real and imaginary timeC De Grandi, A Polkovnikov and A W Sandvik

  2. Potent cytotoxic C-11 modified geldanamycin analogues.

    PubMed

    Tian, Zong-Qiang; Wang, Zhan; MacMillan, Karen S; Zhou, Yiqing; Carreras, Christopher W; Mueller, Thomas; Myles, David C; Liu, Yaoquan

    2009-05-28

    17-Allylamino-17-demethoxygeldanamycin (17-AAG) inhibits the activity of Hsp90, an important target for treatment of cancers. In an effort to identify analogues of geldanamycin (GDM) with properties superior to those of 17-AAG, we synthesized C-11 modified derivatives of GDM including ethers, esters, carbazates, ketones, and oximes and measured their affinity for Hsp90 and their ability to inhibit growth of human cancer cells. In accordance with crystal structures reported for complexes of GDMs with Hsp90, bulky groups attached to C-11 interfered with Hsp90 binding while smaller groups such as 11-O-methyl allowed Hsp90 binding. In addition, these analogues also showed in vitro cytotoxicity against human cancer cell lines. Esterification of the 11-OH of 17-AAG eliminated Hsp90 binding in vitro. The readily hydrolyzed esters acted as prodrugs during the measurement of cytotoxicity. Thus, during these experiments, the esters were hydrolyzed, releasing 17-AAG. Several 11-O-methyl-17-alkylaminogeldanamycin analogues were identified with improved potency relative to 17-AAG. PMID:19405528

  3. Thymidine analogues for tracking DNA synthesis.

    PubMed

    Cavanagh, Brenton L; Walker, Tom; Norazit, Anwar; Meedeniya, Adrian C B

    2011-01-01

    Replicating cells undergo DNA synthesis in the highly regulated, S-phase of the cell cycle. Analogues of the pyrimidine deoxynucleoside thymidine may be inserted into replicating DNA, effectively tagging dividing cells allowing their characterisation. Tritiated thymidine, targeted using autoradiography was technically demanding and superseded by 5-bromo-2-deoxyuridine (BrdU) and related halogenated analogues, detected using antibodies. Their detection required the denaturation of DNA, often constraining the outcome of investigations. Despite these limitations BrdU alone has been used to target newly synthesised DNA in over 20,000 reviewed biomedical studies. A recent breakthrough in "tagging DNA synthesis" is the thymidine analogue 5-ethynyl-2'-deoxyuridine (EdU). The alkyne group in EdU is readily detected using a fluorescent azide probe and copper catalysis using 'Huisgen's reaction' (1,3-dipolar cycloaddition or 'click chemistry'). This rapid, two-step biolabelling approach allows the tagging and imaging of DNA within cells whilst preserving the structural and molecular integrity of the cells. The bio-orthogonal detection of EdU allows its application in more experimental assays than previously possible with other "unnatural bases". These include physiological, anatomical and molecular biological experimentation in multiple fields including, stem cell research, cancer biology, and parasitology. The full potential of EdU and related molecules in biomedical research remains to be explored. PMID:21921870

  4. Vertical structure and physical processes of the Madden-Julian oscillation: Exploring key model physics in climate simulations

    NASA Astrophysics Data System (ADS)

    Jiang, Xianan; Waliser, Duane E.; Xavier, Prince K.; Petch, Jon; Klingaman, Nicholas P.; Woolnough, Steven J.; Guan, Bin; Bellon, Gilles; Crueger, Traute; DeMott, Charlotte; Hannay, Cecile; Lin, Hai; Hu, Wenting; Kim, Daehyun; Lappen, Cara-Lyn; Lu, Mong-Ming; Ma, Hsi-Yen; Miyakawa, Tomoki; Ridout, James A.; Schubert, Siegfried D.; Scinocca, John; Seo, Kyong-Hwan; Shindo, Eiki; Song, Xiaoliang; Stan, Cristiana; Tseng, Wan-Ling; Wang, Wanqiu; Wu, Tongwen; Wu, Xiaoqing; Wyser, Klaus; Zhang, Guang J.; Zhu, Hongyan

    2015-05-01

    Aimed at reducing deficiencies in representing the Madden-Julian oscillation (MJO) in general circulation models (GCMs), a global model evaluation project on vertical structure and physical processes of the MJO was coordinated. In this paper, results from the climate simulation component of this project are reported. It is shown that the MJO remains a great challenge in these latest generation GCMs. The systematic eastward propagation of the MJO is only well simulated in about one fourth of the total participating models. The observed vertical westward tilt with altitude of the MJO is well simulated in good MJO models but not in the poor ones. Damped Kelvin wave responses to the east of convection in the lower troposphere could be responsible for the missing MJO preconditioning process in these poor MJO models. Several process-oriented diagnostics were conducted to discriminate key processes for realistic MJO simulations. While large-scale rainfall partition and low-level mean zonal winds over the Indo-Pacific in a model are not found to be closely associated with its MJO skill, two metrics, including the low-level relative humidity difference between high- and low-rain events and seasonal mean gross moist stability, exhibit statistically significant correlations with the MJO performance. It is further indicated that increased cloud-radiative feedback tends to be associated with reduced amplitude of intraseasonal variability, which is incompatible with the radiative instability theory previously proposed for the MJO. Results in this study confirm that inclusion of air-sea interaction can lead to significant improvement in simulating the MJO.

  5. Synthesis and Biological Evaluation of Carbocyclic Analogues of Pachastrissamine

    PubMed Central

    Kwon, Yongseok; Song, Jayoung; Bae, Hoon; Kim, Woo-Jung; Lee, Joo-Youn; Han, Geun-Hee; Lee, Sang Kook; Kim, Sanghee

    2015-01-01

    A series of carbocyclic analogues of naturally-occurring marine sphingolipid pachastrissamine were prepared and biologically evaluated. The analogues were efficiently synthesized via a tandem enyne/diene-ene metathesis reaction as a key step. We found that the analogue 4b exhibited comparable cytotoxicity and more potent inhibitory activity against sphingosine kinases, compared to pachastrissamine. Molecular modeling studies were conducted to provide more detailed insight into the binding mode of 4b in sphingosine kinase. In our docking model, pachastrissamine and 4b were able to effectively bind to the binding pocket of sphingosine kinase 1 as co-crystalized sphingosine. However, 4b showed a hydrophobic interaction with Phe192, which suggests that it contributes to its increased inhibitory activity against sphingosine kinase 1. PMID:25654428

  6. Chloramphenicol Binding Site with Analogues of Chloramphenicol and Puromycin

    PubMed Central

    Vince, Robert; Almquist, Ronald G.; Ritter, Clare L.; Daluge, Susan

    1975-01-01

    The effect of a series of puromycin analogues and aminoacyl chloramphenicol derivatives on poly(U,C)-directed polyphenylalanine synthesis in an Escherichia coli cell-free system was examined. A comparison between the structures and activities of the puromycin and chloramphenicol analogues was made to examine the proposal that ribosomal binding sites for both antibiotics overlap. Our results suggest that the dichloroacetamido group in the chloramphenicol molecule does not correspond to the role of the aminoacyl moieties of either puromycin or aminoacyl transfer ribonucleic acid. These results comparing the structures and activities of puromycin and chloramphenicol analogues also seem inconsistent with a common binding site for the p-substituted phenyl moieties of the two antibiotics. Previous data have indicated that both sites are mutually affected by the prior binding of either antibiotic. Although it is possible that chloramphenicol and puromycin may have overlapping bindings sites, no common structural features between the two antibiotics are supported by our data. PMID:1103725

  7. The 2.5 Å crystal structure of the SIRT1 catalytic domain bound to nicotinamide adenine dinucleotide (NAD+) and an indole (EX527 analogue) reveals a novel mechanism of histone deacetylase inhibition.

    PubMed

    Zhao, Xun; Allison, Dagart; Condon, Bradley; Zhang, Feiyu; Gheyi, Tarun; Zhang, Aiping; Ashok, Sheela; Russell, Marijane; MacEwan, Iain; Qian, Yuewei; Jamison, James A; Luz, John Gately

    2013-02-14

    The sirtuin SIRT1 is a NAD(+)-dependent histone deacetylase, a Sir2 family member, and one of seven human sirtuins. Sirtuins are conserved from archaea to mammals and regulate transcription, genome stability, longevity, and metabolism. SIRT1 regulates transcription via deacetylation of transcription factors such as PPARγ, NFκB, and the tumor suppressor protein p53. EX527 (27) is a nanomolar SIRT1 inhibitor and a micromolar SIRT2 inhibitor. To elucidate the mechanism of SIRT inhibition by 27, we determined the 2.5 Å crystal structure of the SIRT1 catalytic domain (residues 241-516) bound to NAD(+) and the 27 analogue compound 35. 35 binds deep in the catalytic cleft, displacing the NAD(+) nicotinamide and forcing the cofactor into an extended conformation. The extended NAD(+) conformation sterically prevents substrate binding. The SIRT1/NAD(+)/35 crystal structure defines a novel mechanism of histone deacetylase inhibition and provides a basis for understanding, and rationally improving, inhibition of this therapeutically important target by drug-like molecules. PMID:23311358

  8. Phonon analogue of topological nodal semimetals

    NASA Astrophysics Data System (ADS)

    Po, Hoi Chun; Bahri, Yasaman; Vishwanath, Ashvin

    2015-03-01

    Recently, Kane and Lubensky proposed a mapping between bosonic phonon problems on isostatic lattices to chiral fermion systems based on factorization of the dynamical matrix [Nat. Phys. 10, 39 (2014)]. The existence of topologically protected zero modes in such mechanical problems is related to their presence in the fermionic system and is dictated by a local index theorem. Here we adopt the proposed mapping to construct a two-dimensional mechanical analogue of a fermionic topological nodal semimetal that hosts a robust bulk node in its linearized phonon spectrum. Such topologically protected soft modes with tunable wavevector may be useful in designing mechanical structures with fault-tolerant properties.

  9. High-definition NMR structure of PED/PEA-15 death effector domain reveals details of key polar side chain interactions.

    PubMed

    Twomey, Edward C; Wei, Yufeng

    2012-07-20

    Death effector domain (DED) proteins constitute a subfamily of the large death domain superfamily that is primarily involved in apoptosis pathways. DED structures have characteristic side chain-side chain interactions among polar residues on the protein surface, forming a network of hydrogen bonds and salt bridges. The polar interaction network is functionally important in promoting protein-protein interactions by maintaining optimal side chain orientations. We have refined the solution DED structure of the PED/PEA-15 protein, a representative member of DED subfamily, using traditional NMR restraints with the addition of residual dipolar coupling (RDC) restraints from two independent alignment media, and employed the explicit solvent refinement protocol. The newly refined DED structure of PED/PEA-15 possesses higher structural quality as indicated by WHAT IF Z-scores, with most significant improvement in the backbone conformation normality quality factor. This higher quality DED structure of PED/PEA-15 leads to the identification of a number of key polar side chain interactions, which are not typically observed in NMR protein structures. The elucidation of polar side chain interactions is a key step towards the understanding of protein-protein interactions involving the death domain superfamily. The NMR structures with extensive details of protein structural features are thereby termed high-definition (HD) NMR structures. PMID:22732408

  10. Dimetallaborane analogues of pentaborane.

    PubMed

    Brânzanic, Adrian M V; Lupan, Alexandru; King, R Bruce

    2015-04-28

    The structures of five-vertex dimetallaboranes Cp2M2B3H7 (Cp = η(5)-C5H5) of the second and third row transition metals, including the experimentally known Cp*2Rh2B3H7 (Cp* = η(5)-Me5C5), have been investigated by density functional theory. The predicted low-energy structures for Cp2M2B3H7 (M = Rh, Ir) are tetragonal pyramids similar to Cp*2Rh2B3H7 and pentaborane-9 B5H9 and consistent with their 14 Wadean skeletal electrons. Two Cp*2Rh2B3H7 structures with the same central Rh2B3 tetragonal prism are found with energies within ∼1 kcal mol(-1) of each other, consistent with the experimental observation of two isomers in solution. The electron-richer Cp2M2B3H7 (M = Pd, Pt) systems having 16 Wadean skeletal electrons are predicted to exhibit more open structures analogous to the known structure for the valence isoelectronic pentaborane-11 B5H11. Trigonal bipyramids with the metal atoms at equatorial vertices are typically found to be low-energy structures for the hypoelectronic Cp2M2B3H7 systems (M = Ru, Os, Re, Mo, W, Ta). In addition, the low-energy Cp2Re2B3H7 structures of the rhenium derivatives Cp2Re2B3H7 provide examples of structures based on a central Re2B2 tetrahedron with the Re-Re edge bridged by the third boron atom. Such structures can be derived from a trigonal bipyramid by the rupture of one of the axial-equatorial edges. PMID:25797320

  11. FK228 Analogues Induce Fetal Hemoglobin in Human Erythroid Progenitors

    PubMed Central

    Makala, Levi; Di Maro, Salvatore; Lou, Tzu-Fang; Sivanand, Sharanya; Ahn, Jung-Mo; Pace, Betty S.

    2012-01-01

    Fetal hemoglobin (HbF) improves the clinical severity of sickle cell disease (SCD), therefore, research to identify HbF-inducing agents for treatment purposes is desirable. The focus of our study is to investigate the ability of FK228 analogues to induce HbF using a novel KU812 dual-luciferase reporter system. Molecular modeling studies showed that the structure of twenty FK228 analogues with isosteric substitutions did not disturb the global structure of the molecule. Using the dual-luciferase system, a subgroup of FK228 analogues was shown to be inducers of HbF at nanomolar concentrations. To determine the physiological relevance of these compounds, studies in primary erythroid progenitors confirmed that JMA26 and JMA33 activated HbF synthesis at levels comparable to FK228 with low cellular toxicity. These data support our lead compounds as potential therapeutic agents for further development in the treatment of SCD. PMID:22655179

  12. Structure of a fusion peptide analogue at the air-water interface, determined from surface activity, infrared spectroscopy and scanning force microscopy.

    PubMed

    Taylor, S E; Desbat, B; Blaudez, D; Jacobi, S; Chi, L F; Fuchs, H; Schwarz, G

    2000-09-15

    We have investigated a point mutant of the HIV-1 fusion peptide in a compressed monolayer at the air-water interface. A variety of surface sensitive techniques were applied to study structural features under conditions mimicking the hydrophobic/hydrophilic environment of a biomembrane. Possible partitioning into the aqueous bulk phase and molecular areas were examined by surface activity based mass conservation plots. This shows that the peptide is practically fully accumulated in the interface. Secondary structure and orientation was analyzed by means of polarized infrared reflectivity. Brewster angle microscopy and scanning force microscopy contributed nanostructural images. At low surface pressures the molecules form anti-parallel beta-sheets lying flat on the interface. Upon a moderate increase of the lateral pressure a flat beta-turn structure appears with inter- and intramolecular H-bonds. We also observed aggregates forming fingerprint-like structures with a diameter of approximately double the hydrophobic length of a beta-turn conformation. Beyond approximately 18 mN m(-1) the beta-turns straighten up. The lowest measured tilt angle was 45 degrees at 36 mN m(-1). PMID:11036970

  13. Cyclic heterotetrameric and low-dimensional hydrogen-bonded polymeric structures in the morpholinium salts of ring-substituted benzoic acid analogues.

    PubMed

    Smith, Graham; Lynch, Daniel E

    2016-02-01

    The morpholinium (tetrahydro-2H-1,4-oxazin-4-ium) cation has been used as a counter-ion in both inorganic and organic salt formation and particularly in metal complex stabilization. To examine the influence of interactive substituent groups in the aromatic rings of benzoic acids upon secondary structure generation, the anhydrous salts of morpholine with salicylic acid, C4H10NO(+)·C7H5O3(-), (I), 3,5-dinitrosalicylic acid, C4H10NO(+)·C7H3N2O7(-), (II), 3,5-dinitrobenzoic acid, C4H10NO(+)·C7H3N2O6(-), (III), and 4-nitroanthranilic acid, C4H10NO(+)·C7H5N2O4(-), (IV), have been prepared and their hydrogen-bonded crystal structures are described. In the crystal structures of (I), (III) and (IV), the cations and anions are linked by moderately strong N-H...Ocarboxyl hydrogen bonds, but the secondary structure propagation differs among the three, viz. one-dimensional chains extending along [010] in (I), a discrete cyclic heterotetramer in (III), and in (IV), a heterotetramer with amine N-H...O hydrogen-bond extensions along b, giving a two-layered ribbon structure. With the heterotetramers in both (III) and (IV), the ion pairs are linked though inversion-related N-H...Ocarboxylate hydrogen bonds, giving cyclic R4(4)(12) motifs. With (II), in which the anion is a phenolate rather than a carboxylate, the stronger assocation is through a symmetric lateral three-centre cyclic R1(2)(6) N-H...(O,O') hydrogen-bonding linkage involving the phenolate and nitro O-atom acceptors of the anion, with extension through a weaker O-H...Ocarboxyl hydrogen bond. This results in a one-dimensional chain structure extending along [100]. In the structures of two of the salts [i.e. (II) and (IV)], there are also π-π ring interactions, with ring-centroid separations of 3.5516 (9) and 3.7700 (9) Å in (II), and 3.7340 (9) Å in (IV). PMID:26846493

  14. U-Pb Composition and Shock Microstructures of In-Situ Accessory Phases Across the Vredefort Impact Structure, South Africa: A Terrestrial Analogue for Dating the Lunar Surface and Other Planetary Bodies

    NASA Astrophysics Data System (ADS)

    Davis, C. L.; Moser, D. E.

    2015-02-01

    Accessory phases (i.e. zircon, monazite) co-exist within individual samples of the Vredefort dome, with a dichotomy of U-Pb ages and microstructural evolution. Vredefort is a terrestrial analogue for complex craters on other planetary bodies.

  15. Crystal structures and magnetic properties of new europium melilites Eu(2)MSi(2)O(7) (M = Mg, Mn) and their strontium analogues.

    PubMed

    Endo, Takashi; Doi, Yoshihiro; Wakeshima, Makoto; Hinatsu, Yukio

    2010-12-01

    Synthesis, crystal structures, and magnetic properties of melilite-type oxides A(2)MSi(2)O(7) (A = Sr, Eu; M = Mg, Mn) were investigated. These compounds crystallize in the melilite structure with space group P4?2(1)m. The (151)Eu Mo?ssbauer measurements show that the Eu ions are in the divalent state. The Eu(2)MgSi(2)O(7) is paramagnetic down to 1.8 K. Long-range antiferromagnetic ordering is observed at 3.4 K for Sr(2)MnSi(2)O(7). On the other hand, the Eu(2)MnSi(2)O(7) shows a ferrimagnetic transition at 10.7 K. From the magnetization and specific heat measurements, it is found that the Eu(2+) (14 ?(B)) and Mn(2+) (5 ?(B)) sublattices order antiferromagnetically. This result indicates that an interaction between f-d electrons (Eu-Mn) predominantly operate in this compound. PMID:21033688

  16. Florida Keys

    NASA Technical Reports Server (NTRS)

    2002-01-01

    The Florida Keys are a chain of islands, islets and reefs extending from Virginia Key to the Dry Tortugas for about 309 kilometers (192 miles). The keys are chiefly limestone and coral formations. The larger islands of the group are Key West (with its airport), Key Largo, Sugarloaf Key, and Boca Chica Key. A causeway extends from the mainland to Key West.

    This image was acquired on October 28, 2001, by the Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) on NASA's Terra satellite. With its 14 spectral bands from the visible to the thermal infrared wavelength region, and its high spatial resolution of 15 to 90 meters (about 50 to 300 feet), ASTER images Earth to map and monitor the changing surface of our planet.

    ASTER is one of five Earth-observing instruments launched December 18, 1999, on NASA's Terra satellite. The instrument was built by Japan's Ministry of Economy, Trade and Industry. A joint U.S./Japan science team is responsible for validation and calibration of the instrument and the data products.

    The broad spectral coverage and high spectral resolution of ASTER will provide scientists in numerous disciplines with critical information for surface mapping, and monitoring of dynamic conditions and temporal change. Example applications are: monitoring glacial advances and retreats; monitoring potentially active volcanoes; identifying crop stress; determining cloud morphology and physical properties; wetlands evaluation; thermal pollution monitoring; coral reef degradation; surface temperature mapping of soils and geology; and measuring surface heat balance.

    Dr. Anne Kahle at NASA's Jet Propulsion Laboratory, Pasadena, Calif., is the U.S. Science team leader; Bjorn Eng of JPL is the project manager. The Terra mission is part of NASA's Earth Science Enterprise, a long- term research effort to understand and protect our home planet. Through the study of Earth, NASA will help to provide sound science to policy and economic decision-makers so as to better life here, while developing the technologies needed to explore the universe and search for life beyond our home planet.

    Size: 51.6 by 29.7 kilometers ( 32.0 by 18.4 miles) Location: 24.7 degrees North latitude, 81.5 degrees West longitude Orientation: North at top Image Data: ASTER bands 1, 2, and 3 Original Data Resolution: 15 meters (49.2 feet) Date Acquired: October 28, 2001

  17. Ultradeep pyrosequencing and molecular modeling identify key structural features of hepatitis B virus RNase H, a putative target for antiviral intervention.

    PubMed

    Hayer, Juliette; Rodriguez, Christophe; Germanidis, Georgios; Delage, Gilbert; Zoulim, Fabien; Pawlotsky, Jean-Michel; Combet, Christophe

    2014-01-01

    Last-generation nucleoside/nucleotide analogues are potent against hepatitis B virus (HBV) and have a high barrier to resistance. However, delayed responses have been observed in patients previously exposed to other drugs of the same class, long-term resistance is possible, and cure of infection cannot be achieved with these therapies, emphasizing the need for alternative therapeutic approaches. The HBV RNase H represents an interesting target because its enzyme activity is essential to the HBV life cycle. The goal of our study was to characterize the structure of the HBV RNase H by computing a 3-dimensional molecular model derived from E. coli RNase H and analyzing 2,326 sequences of all HBV genotypes available in public databases and 958,000 sequences generated by means of ultradeep pyrosequencing of sequences from a homogenous population of 73 treatment-naive patients infected with HBV genotype D. Our data revealed that (i) the putative 4th catalytic residue displays unexpected variability that could be explained by the overlap of the HBx gene and has no apparent impact on HBV replicative capacity and that (ii) the C-helix-containing basic protrusion, which is required to guide the RNA/DNA heteroduplex into the catalytic site, is highly conserved and bears unique structural properties that can be used to target HBV-specific RNase H inhibitors without cross-species activity. The model shows substantial differences from other known RNases H and paves the way for functional and structural studies as a prerequisite to the development of new inhibitors of the HBV cell cycle specifically targeting RNase H activity. PMID:24173223

  18. Models and Analogues

    ERIC Educational Resources Information Center

    Maloney, Jane; Curtis, Sheila

    2012-01-01

    How do teachers help children understand the difference between the structure of a flower and that of a root? Depending on the time of year this activity is quite easy. Get a bunch of flowers, germinate some chickpeas and raid the kitchen for carrots and beetroots--the children can experience the "real thing". But what if teachers want the

  19. Models and Analogues

    ERIC Educational Resources Information Center

    Maloney, Jane; Curtis, Sheila

    2012-01-01

    How do teachers help children understand the difference between the structure of a flower and that of a root? Depending on the time of year this activity is quite easy. Get a bunch of flowers, germinate some chickpeas and raid the kitchen for carrots and beetroots--the children can experience the "real thing". But what if teachers want the…

  20. Key Nutrients.

    ERIC Educational Resources Information Center

    Federal Extension Service (USDA), Washington, DC.

    Lessons written to help trainer agents prepare aides for work with families in the Food and Nutrition Program are presented in this booklet. The key nutrients discussed in the 10 lessons are protein, carbohydrates, fat, calcium, iron, iodine, and Vitamins A, B, C, and D. the format of each lesson is as follows: Purpose, Presentation, Application…

  1. Key Literature.

    ERIC Educational Resources Information Center

    New Directions for Community Colleges, 2002

    2002-01-01

    Provides an annotated bibliography of the literature considered by the contributing authors to this journal issue to be of key importance to the subjects covered in their articles. These subjects include: transfer, vocational education, remedial education, English as a second language (ESL), assessment, student services, faculty and professional

  2. Conformationally constrained analogues of diacylglycerol (DAG). 16. How much structural complexity is necessary for recognition and high binding affinity to protein kinase C?

    PubMed

    Nacro, K; Bienfait, B; Lee, J; Han, K C; Kang, J H; Benzaria, S; Lewin, N E; Bhattacharyya, D K; Blumberg, P M; Marquez, V E

    2000-03-01

    The design of potent protein kinase C (PK-C) ligands with low nanomolar binding affinities was accomplished by the combined use of pharmacophore- and receptor-guided approaches based on the structure of the physiological enzyme activator, diacylglycerol (DAG). Earlier use of the former approach, which was based on the structural equivalence of DAG and phorbol ester pharmacophores, identified a fixed template for the construction of a semirigid "recognition domain" that contained the three principal pharmacophores of DAG constrained into a lactone ring (DAG-lactones). In the present work, the pharmacophore-guided approach was refined to a higher level based on the X-ray structure of the C1b domain of PK-Cdelta complexed with phorbol-13-O-acetate. A systematic search that involved modifying the DAG-lactone template with a combination of linear or branched acyl and alpha-alkylidene chains, which functioned as variable hydrophobic "affinity domains", helped identify compounds that optimized hydrophobic contacts with a group of conserved hydrophobic amino acids located on the top half of the C1 domain where the phorbol binds. The hydrophilic/hydrophobic balance of the molecules was estimated by the octanol/water partition coefficients (log P) calculated according to a fragment-based approach. The presence of branched alpha-alkylidene or acyl chains was of critical importance to reach low nanomolar binding affinities for PK-C. These branched chains appear to facilitate important van der Waals contacts with hydrophobic segments of the protein and help promote the activation of PK-C through critical membrane interactions. Molecular modeling of these DAG-lactones into an empty C1b domain using the program AutoDock 2.4 suggests the existence of competing binding modes (sn-1 and sn-2) depending on which carbonyl is directly involved in binding to the protein. Inhibition of epidermal growth factor (EGF) binding, an indirect PK-C mediated response, was realized with some DAG-lactones at a dose 10-fold higher than with the standard phorbol-12, 13-dibutyrate (PDBU). Through the National Cancer Institute (NCI) 60-cell line in vitro screen, DAG-lactone 31 was identified as a very selective and potent antitumor agent. The NCI's computerized, pattern-recognition program COMPARE, which analyzes the degree of similarity of mean-graph profiles produced by the screen, corroborated our principles of drug design by matching the profile of compound 31 with that of the non-tumor-promoting antitumor phorbol ester, prostratin. The structural simplicity and the degree of potency achieved with some of the DAG-lactones described here should dispel the myth that chemical complexity and pharmacological activity go hand in hand. Even as a racemate, DAG-lactone 31 showed low namomolar binding affinity for PK-C and displayed selective antitumor activity at equivalent nanomolar levels. Our present approach should facilitate the generation of multiple libraries of structurally similar DAG-lactones to help exploit molecular diversity for PK-C and other high-affinity receptors for DAG and the phorbol esters. The success of this work suggests that substantially simpler, high-affinity structures could be identified to function as surrogates of other complex natural products. PMID:10715158

  3. Structure of Bacillus subtilis ?-glutamyltranspeptidase in complex with acivicin: diversity of the binding mode of a classical and electrophilic active-site-directed glutamate analogue.

    PubMed

    Ida, Tomoyo; Suzuki, Hideyuki; Fukuyama, Keiichi; Hiratake, Jun; Wada, Kei

    2014-02-01

    ?-Glutamyltranspeptidase (GGT) is an enzyme that plays a central role in glutathione metabolism, and acivicin is a classical inhibitor of GGT. Here, the structure of acivicin bound to Bacillus subtilis GGT determined by X-ray crystallography to 1.8? resolution is presented, in which it binds to the active site in a similar manner to that in Helicobacter pylori GGT, but in a different binding mode to that in Escherichia coli GGT. In B. subtilis GGT, acivicin is bound covalently through its C3 atom with sp2 hybridization to Thr403?O?, the catalytic nucleophile of the enzyme. The results show that acivicin-binding sites are common, but the binding manners and orientations of its five-membered dihydroisoxazole ring are diverse in the binding pockets of GGTs. PMID:24531494

  4. Naturally occurring crystalline phases: analogues for radioactive waste forms

    SciTech Connect

    Haaker, R.F.; Ewing, R.C.

    1981-01-01

    Naturally occurring mineral analogues to crystalline phases that are constituents of crystalline radioactive waste forms provide a basis for comparison by which the long-term stability of these phases may be estimated. The crystal structures and the crystal chemistry of the following natural analogues are presented: baddeleyite, hematite, nepheline; pollucite, scheelite;sodalite, spinel, apatite, monazite, uraninite, hollandite-priderite, perovskite, and zirconolite. For each phase in geochemistry, occurrence, alteration and radiation effects are described. A selected bibliography for each phase is included.

  5. Crystal Structures of Human MdmX (HdmX) in Complex with p53 Peptide Analogues Reveal Surprising Conformational Changes*

    PubMed Central

    Kallen, Joerg; Goepfert, Arnaud; Blechschmidt, Anke; Izaac, Aude; Geiser, Martin; Tavares, Gisele; Ramage, Paul; Furet, Pascal; Masuya, Keiichi; Lisztwan, Joanna

    2009-01-01

    p53 tumor suppressor activity is negatively regulated through binding to the oncogenic proteins Hdm2 and HdmX. The p53 residues Leu26, Trp23, and Phe19 are crucial to mediate these interactions. Inhibiting p53 binding to both Hdm2 and HdmX should be a promising clinical approach to reactivate p53 in the cancer setting, but previous studies have suggested that the discovery of dual Hdm2/HdmX inhibitors will be difficult. We have determined the crystal structures at 1.3 of the N-terminal domain of HdmX bound to two p53 peptidomimetics without and with a 6-chlorine substituent on the indole (which binds in the same subpocket as Trp23 of p53). The latter compound is the most potent peptide-based antagonist of the p53-Hdm2 interaction yet to be described. The x-ray structures revealed surprising conformational changes of the binding cleft of HdmX, including an open conformation of Tyr99 and unexpected cross-talk between the Trp and Leu pockets. Notably, the 6-chloro p53 peptidomimetic bound with high affinity to both HdmX and Hdm2 (Kd values of 36 and 7 nm, respectively). Our results suggest that the development of potent dual inhibitors for HdmX and Hdm2 should be feasible. They also reveal possible conformational states of HdmX, which should lead to a better prediction of its interactions with potential biological partners. PMID:19153082

  6. Synthesis and Temperature-Induced Structural Phase and Spin Transitions in Hexadecylboron-Capped Cobalt(II) Hexachloroclathrochelate and Its Diamagnetic Iron(II)-Encapsulating Analogue.

    PubMed

    Vologzhanina, Anna V; Belov, Alexander S; Novikov, Valentin V; Dolganov, Alexander V; Romanenko, Galina V; Ovcharenko, Victor I; Korlyukov, Alexander A; Buzin, Mikhail I; Voloshin, Yan Z

    2015-06-15

    Template condensation of dichloroglyoxime with n-hexadecylboronic acid on the corresponding metal ion as a matrix under vigorous reaction conditions afforded n-hexadecylboron-capped iron and cobalt(II) hexachloroclathrochelates. The complexes obtained were characterized using elemental analysis, MALDI-TOF mass spectrometry, IR, UV-vis, (1)H and (13)C{(1)H} NMR, (57)Fe Mssbauer spectroscopies, SQUID magnetometry, electron paramagnetic resonance, and cyclic voltammetry (CV) and by X-ray crystallography. The multitemperature single-crystal X-ray diffraction, SQUID magnetometry, and differential scanning calorimetry experiments were performed to study the temperature-induced spin-crossover [for the paramagnetic cobalt(II) complex] and the crystal-to-crystal phase transitions (for both of these clathrochelates) in the solid state. Analysis of their crystal packing using the molecular Voronoi polyhedra and the Hirshfeld surfaces reveals the structural rearrangements of the apical long-chain alkyl substituents resulting from such phase transitions being more pronounced for a macrobicyclic cobalt(II) complex. Its fine-crystalline sample undergoes the gradual and fully reversible spin transition centered at approximately 225 K. The density functional theory calculated parameters for an isolated molecule of this cobalt(II) hexachloroclathrochelate in its low- and high-spin states were found to be in excellent agreement with the experimental data and allowed to localize the spin density within a macrobicyclic framework. CV of the cobalt(II) complex in the cathodic range contains one reversible wave assigned to the Co(2+/+) redox couple with the reduced anionic cobalt(I)-containing species stabilized by the electronic effect of six strong electron-withdrawing chlorine substituents. The quasireversible character of the Fe(2+/+) wave suggests that the anionic iron(I)-containing macrobicyclic species undergo substantial structural changes and side chemical reactions after such metal-centered reduction. PMID:26017024

  7. Structures of yeast peroxisomal ?(3),?(2)-enoyl-CoA isomerase complexed with acyl-CoA substrate analogues: the importance of hydrogen-bond networks for the reactivity of the catalytic base and the oxyanion hole.

    PubMed

    Onwukwe, Goodluck U; Koski, M Kristian; Pihko, Petri; Schmitz, Werner; Wierenga, Rik K

    2015-11-01

    ?(3),?(2)-Enoyl-CoA isomerases (ECIs) catalyze the shift of a double bond from 3Z- or 3E-enoyl-CoA to 2E-enoyl-CoA. ECIs are members of the crotonase superfamily. The crotonase framework is used by many enzymes to catalyze a wide range of reactions on acyl-CoA thioesters. The thioester O atom is bound in a conserved oxyanion hole. Here, the mode of binding of acyl-CoA substrate analogues to peroxisomal Saccharomyces cerevisiae ECI (ScECI2) is described. The best defined part of the bound acyl-CoA molecules is the 3',5'-diphosphate-adenosine moiety, which interacts with residues of loop 1 and loop 2, whereas the pantetheine part is the least well defined. The catalytic base, Glu158, is hydrogen-bonded to the Asn101 side chain and is further hydrogen-bonded to the side chain of Arg100 in the apo structure. Arg100 is completely buried in the apo structure and a conformational change of the Arg100 side chain appears to be important for substrate binding and catalysis. The oxyanion hole is formed by the NH groups of Ala70 (loop 2) and Leu126 (helix 3). The O atoms of the corresponding peptide units, Gly69?O and Gly125?O, are both part of extensive hydrogen-bond networks. These hydrogen-bond networks are a conserved feature of the crotonase oxyanion hole and their importance for catalysis is discussed. PMID:26527136

  8. The inflamed axis: the interaction between stress, hormones, and the expression of inflammatory-related genes within key structures comprising the hypothalamic-pituitary-adrenal axis.

    PubMed

    Hueston, Cara M; Deak, Terrence

    2014-01-30

    Acute stress increases the expression of cytokines and other inflammatory-related factors in the CNS, plasma, and endocrine glands, and activation of inflammatory signaling pathways within the hypothalamic-pituitary-adrenal (HPA) axis may play a key role in later stress sensitization. In addition to providing a summary of stress effects on neuroimmune changes within the CNS, we present a series of experiments that characterize stress effects on members of the interleukin-1β (IL-1) super-family and other inflammatory-related genes in key structures comprising the HPA axis (PVN, pituitary and adrenal glands), followed by a series of experiments examining the impact of exogenous hormone administration (CRH and ACTH) and dexamethasone on the expression of inflammatory-related genes in adult male Sprague-Dawley rats. The results demonstrated robust, time-dependent, and asynchronous expression patterns for IL-1 and IL-1R2 in the PVN, with substantial increases in IL-6 and COX-2 in the adrenal glands emerging as key findings. The effects of exogenous CRH and ACTH were predominantly isolated within the adrenals. Finally, pretreatment with dexamethasone severely blunted neuroimmune changes in the adrenal glands, but not in the PVN. These findings provide novel insight into the relationship between stress, the expression of inflammatory signaling factors within key structures comprising the HPA axis, and their interaction with HPA hormones, and provide a foundation for better understanding the role of cytokines as modulators of hypothalamic, pituitary and adrenal sensitivity. PMID:24184413

  9. Design of novel CSA analogues as potential safeners and fungicides.

    PubMed

    Zheng, Yang; Liu, Bin; Gou, Zhaopin; Li, Yao; Zhang, Xiao; Wang, Yanqing; Yu, Shujing; Li, Yonghong; Sun, Dequn

    2015-02-15

    Study of safeners has been seldom reported in literature. In this work, a series of novel acylsulfamoylbenzamide analogues was designed and synthesized with newly developed safener cyprosulfamide (CSA) as the leading compound. The activity assay against the herbicide thiencarbazone-methyl (TCM) on maize revealed that fifteen compounds showed better protective effect than CSA on the fresh weight of aerial parts, twelve compounds exhibited better activity on the dry weight of aerial parts. Remarkably, two compounds (6Ih, 7II) had protective effect on the four aspects of TCM treated maize. Further antifungal assay showed their excellent activity against Physollospora piricola. The structure-activity relationships of CSA analogues as safeners and fungicides were discussed and it might be valuable for further molecular modification of new CSA analogues. PMID:25582601

  10. Migrastatin analogues target fascin to block tumour metastasis

    SciTech Connect

    Chen, L.; Jakoncic, J.; Yang, S.; Zhang, J.; Huang, X.Y.

    2010-04-15

    Tumour metastasis is the primary cause of death of cancer patients. Development of new therapeutics preventing tumour metastasis is urgently needed. Migrastatin is a natural product secreted by Streptomyces, and synthesized migrastatin analogues such as macroketone are potent inhibitors of metastatic tumour cell migration, invasion and metastasis. Here we show that these migrastatin analogues target the actin-bundling protein fascin to inhibit its activity. X-ray crystal structural studies reveal that migrastatin analogues bind to one of the actin-binding sites on fascin. Our data demonstrate that actin cytoskeletal proteins such as fascin can be explored as new molecular targets for cancer treatment, in a similar manner to the microtubule protein tubulin.

  11. Migrastatin Analogues Target Fascin to Block Tumor Metastasis

    PubMed Central

    Chen, Lin; Yang, Shengyu; Jakoncic, Jean; Zhang, J. Jillian; Huang, Xin-Yun

    2010-01-01

    Tumor metastasis is the primary cause of death of cancer patients. Development of new therapeutics preventing tumor metastasis is urgently needed. Migrastatin is a natural product secreted by Streptomyces 1,2, and synthesized migrastatin analogues are potent inhibitors of metastatic tumor cell migration, invasion and tumor metastasis 3–6. Here we show that these migrastatin analogues target the actin-bundling protein fascin to inhibit its activity. X-ray crystal structural studies reveal that migrastatin analogues bind to one of the actin-binding sites on fascin. Our data demonstrate that actin cytoskeletal proteins, such as fascin, can be explored as new molecular targets for cancer treatment, similar to the microtubule protein tubulin. PMID:20393565

  12. Synthesis and characterization of sulfur-voided cubanes. Structural analogues for the MoFe(3)S(3) subunit in the nitrogenase cofactor.

    PubMed

    Coucouvanis, Dimitri; Han, Jaehong; Moon, Namdoo

    2002-01-16

    A new class of Mo/Fe/S clusters with the MoFe(3)S(3) core has been synthesized in attempts to model the FeMo-cofactor in nitrogenase. These clusters are obtained in reactions of the (Cl(4)-cat)(2)Mo(2)Fe(6)S(8)(PR(3))(6) [R = Et (I), (n)Pr (II)] clusters with CO. The new clusters include those preliminarily reported: (Cl(4)-cat)MoFe(3)S(3)(PEt(3))(2)(CO)(6) (III), (Cl(4)-cat)(O)MoFe(3)S(3)(PEt(3))(3)(CO)(5) (IV), (Cl(4)-cat)(Pyr)MoFe(3)S(3)(PEt(3))(2)(CO)(6) (VI), and (Cl(4)-cat)(Pyr)MoFe(3)S(3)(P(n)Pr(3))(3)(CO)(4) (VIII). In addition the new (Cl(4)-cat)(O)MoFe(3)S(3)(P(n)Pr(3))(3)(CO)(5) cluster (IVa), the (Cl(4)-cat)(O)MoFe(3)S(3)(PEt(3))(2)(CO)(6)cluster (V), the (Cl(4)-cat)(O)MoFe(3)S(3)(P(n)Pr(3))(2)(CO)(6) cluster (Va), the (Cl(4)-cat)(Pyr)MoFe(3)S(3)(P(n)Pr(3))(2)(CO)(6) cluster (VIa), and the (Cl(4)-cat)(P(n)Pr(3))MoFe(3)S(3)(P(n)Pr(3))(2)(CO)(6) cluster (VII) also are reported. Clusters III-VIII have been structurally and spectroscopically characterized. EPR, zero-field (57)Fe-Mssbauer spectroscopic characterizations, and magnetic susceptibility measurements have been used for a tentative assignment of the electronic and oxidation states of the MoFe(3)S(3) sulfur-voided cuboidal clusters. A structural comparison of the clusters with the MoFe(3)S(3) subunit of the FeMo-cofactor has led to the suggestion that the storage of reducing equivalents into M-M bonds, and their use in the reduction of substrates, may occur with the FeMo-cofactor, which also appears to have M-M bonding. On the basis of this argument, a possible N(2)-binding and reduction mechanism on the FeMoco-cofactor is proposed. PMID:11782173

  13. Synthesis and bioactivity of analogues of the marine antibiotic tropodithietic acid

    PubMed Central

    Rabe, Patrick; Klapschinski, Tim A; Brock, Nelson L; Citron, Christian A; DAlvise, Paul; Gram, Lone

    2014-01-01

    Summary Tropodithietic acid (TDA) is a structurally unique sulfur-containing antibiotic from the Roseobacter clade bacterium Phaeobacter inhibens DSM 17395 and a few other related species. We have synthesised several structural analogues of TDA and used them in bioactivity tests against Staphylococcus aureus and Vibrio anguillarum for a structureactivity relationship (SAR) study, revealing that the sulfur-free analogue of TDA, tropone-2-carboxylic acid, has an antibiotic activity that is even stronger than the bioactivity of the natural product. The synthesis of this compound and of several analogues is presented and the bioactivity of the synthetic compounds is discussed. PMID:25161739

  14. Synthesis, in vitro antitumor activity, dihydrofolate reductase inhibition, DNA intercalation and structure-activity relationship studies of 1,3,5-triazine analogues.

    PubMed

    Singla, Prinka; Luxami, Vijay; Paul, Kamaldeep

    2016-01-15

    A series of triazine-benzimidazoles with 4-fluoroaniline substitution has been designed and synthesized. These compounds were further substituted with different primary and secondary amines. The structures of newly synthesized compounds were confirmed by (1)H, (13)C NMR, mass spectrometry and, in case of compound 18, by single crystal X-ray diffraction analysis. The newly synthesized compounds were evaluated against 60 human tumor cell lines at one dose and five dose concentration levels. Compounds 7, 8 and 22 have been found to be the most active antitumor agents with GI50 values of 1.77, 1.94 and 2.87?M, respectively. The synthesized compounds were then evaluated for their inhibitory activity to mammalian dihydrofolate reductase. Compound 22 was depicted as the most active compound for the inhibition of dihydrofolate reductase with IC50 value of 2.0nM. DNA binding studies were also revealed strong interacting properties of triazine derivatives towards calf thymus-DNA. PMID:26670841

  15. Direct Observation of Short-Range Structural Coherence During a Charge Transfer Induced Spin Transition in a CoFe Prussian Blue Analogue by Transmission Electron Microscopy.

    PubMed

    Itoi, Miho; Jike, Toyoharu; Nishio-Hamane, Daisuke; Udagawa, Seiichi; Tsuda, Tetsuya; Kuwabata, Susumu; Boukheddaden, Kamel; Andrus, Matthew J; Talham, Daniel R

    2015-11-25

    The local structure within the Co-Fe atomic array of the photoswitchable coordination polymer magnet, K0.3Co[Fe(CN)6]0.77nH2O, is directly observed during charge transfer induced spin transition (CTIST), a solid-solid phase change, using high-resolution transmission electron microscopy (HRTEM). Along with the low-spin (LS) or thermally quenched high-spin (HS) states normally observed in CTIST solids at low temperature, slow cooling of K0.3Co[Fe(CN)6]0.77nH2O results in an intermediate phase containing both HS and LS domains with short coherence length. By mapping individual metal-metal distances, the nanometer-scale HS domains are directly visualized within the LS array. Temperature-dependent analyses allow monitoring of HS domain coarsening along the warming branch of the CTIST, providing direct visualization of the elastic process and insight into the mechanism of phase propagation. Normally sensitive to electron beam damage, the low-temperature TEM measurements of the porous coordination polymer are enabled by using appropriate ionic liquids instead of usual conductive thin-film coatings, an approach that should find general utility in related classes of materials. PMID:26510096

  16. Biointeractions of C.I. Acid Red 2 and its structural analogues with transporter albumin: Fluorescence, circular dichroism, and ligand docking approaches.

    PubMed

    Peng, Wei; Ding, Fei; Xie, Yong

    2016-01-01

    In this contribution, the toxicological effects of C.I. Acid Red 2 and 1-(2-pyridylazo)-2-naphthol (PAN) have been elucidated by utilizing plasma albumin as a biological model. Fluorescence data indicated that the Trp-214 residue was quenched by both azo compounds, but the quenching degree of C.I. Acid Red 2 is less than PAN. According to the results of time-resolved fluorescence decay, it may be observed that the quenching of Trp-214 residue is controlled by static type; this corroborates the Stern-Volmer analyses and the conformational transition of protein was concurred. The experiments also found that azo colorants are situated within subdomain IIA, several amino acid residues, such as Ser-202, Ala-210, and Trp-214 were believed to be yielded direct interaction with the two chemicals, yet the operating distances between C.I. Acid Red 2 and relevant residues are greater than PAN. Interestingly, we may ascertain that the azo colorants with naphthalene ring possess stronger affinity with protein than those just having benzene ring in their molecular structure. This suggested that the existence of naphthalene ring substituent could hold relatively great risk for the human body due to large hydrophobicity (cLogP); therefore, the hydrophobicity of azo colorants can probably be a major element of its toxicological activities. PMID:26682933

  17. Comparative analysis of the electrostatic potentials of some structural analogues of 2,3,7,8-tetrachlorodibenzo-p-dioxin and of related aromatic systems

    SciTech Connect

    Murray, J.S.; Evans, P.; Politzer, P.

    1990-01-01

    An ab initio STO-5G computational analysis of the electrostatic potentials of four structural analogs of the highly toxic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and four related aromatic systems (benzo(a)pyrene, benz(a)anthracene and two isomeric benzoflavones) was carried out. The systems, to varying degrees, induce aryl hydrocarbon hydroxylase activity and are believed to interact with the same cytosolic receptor in initiating their biochemical responses. It was found that a high degree of activity appears to require negative potentials that are non-overlapping above all or most of the lateral regions, with an observed optimum range of magnitudes. In systems with central oxygens, it is required that the negative oxygen potentials be small and weak; however, oxygen negative regions in the molecule are not necessary for high activity. The observed differences between the potential patterns of the four aromatic systems and those of TCDD and its active analogs may reflect an inherent dissimilarity in the nature of their interactions with the cytosolic receptor.

  18. Hexanuclear, heterometallic, Ni?Ln? complexes possessing O-capped homo- and heterometallic structural subunits: SMM behavior of the dysprosium analogue.

    PubMed

    Goura, Joydeb; Guillaume, Rogez; Rivire, Eric; Chandrasekhar, Vadapalli

    2014-08-01

    The reaction of hetero donor chelating mannich base ligand 6,6'-{(2-(dimethylamino)ethylazanediyl)bis(methylene)}bis(2-methoxy-4-methylphenol) with Ni(ClO4)26H2O and lanthanide(III) salts [Dy(III) (1); Tb(III) (2); Gd (III) (3); Ho(III) (4); and Er(III) (5)] in the presence of triethylamine and pivalic acid afforded a series of heterometallic hexanuclear Ni(II)-Ln(III) coordination compounds, [Ni3Ln3(?3-O)(?3-OH)3(L)3(?-OOCCMe3)3](ClO4)wCH3CNxCH2Cl2yCH3OHzH2O [for 1, w = 8, x = 3, y = 0, z = 5.5; for 2, w = 0, x = 5, y = 0, z = 6.5; for 3, w = 15, x = 18, y = 3, z = 7.5; for 4, w = 15, x = 20, y = 6, z = 9.5; and for 5, w = 0, x = 3, y = 2, z = 3]. The molecular structure of these complexes reveals the presence of a monocationic hexanuclear derivative containing one perchlorate counteranion. The asymmetric unit of each of the hexanuclear derivatives comprises the dinuclear motif [NiLn(L)(?3-O)(?3-OH)(?-Piv)]. The cation contains three interlinked O-capped clusters: one Ln(III)3O and three Ni(II)Ln(III)2O. Each of the lanthanide centers is eight- coordinated (distorted trigonal-dodecahedron), while the nickel centers are hexacoordinate (distorted octahedral). The study of the magnetic properties of all compounds are reported and suggests single molecule magnet behavior for the Dy(III) derivative (1). PMID:25050753

  19. Methane storage capabilities of diamond analogues

    SciTech Connect

    Haranczyk, M; Lin, LC; Lee, K; Martin, RL; Neaton, JB; Smit, B

    2013-01-01

    Methane can be an alternative fuel for vehicular usage provided that new porous materials are developed for its efficient adsorption-based storage. Herein, we search for materials for this application within the family of diamond analogues. We used density functional theory to investigate structures in which tetrahedral C atoms of diamond are separated by-CC-or-BN-groups, as well as ones involving substitution of tetrahedral C atoms with Si and Ge atoms. The adsorptive and diffusive properties of methane are studied using classical molecular simulations. Our results suggest that the all-carbon structure has the highest volumetric methane uptake of 280 VSTP/V at p = 35 bar and T = 298 K. However, it suffers from limited methane diffusion. Alternatively, the considered Si and Ge-containing analogies have fast diffusive properties but their adsorption is lower, ca. 172-179 VSTP/V, at the same conditions.

  20. Engineering of Insulin Receptor Isoform-Selective Insulin Analogues

    PubMed Central

    Glendorf, Tine; Stidsen, Carsten E.; Norrman, Mathias; Nishimura, Erica; Srensen, Anders R.; Kjeldsen, Thomas

    2011-01-01

    Background The insulin receptor (IR) exists in two isoforms, A and B, and the isoform expression pattern is tissue-specific. The C-terminus of the insulin B chain is important for receptor binding and has been shown to contact the IR just adjacent to the region where the A and B isoforms differ. The aim of this study was to investigate the importance of the C-terminus of the B chain in IR isoform binding in order to explore the possibility of engineering tissue-specific/liver-specific insulin analogues. Methodology/Principal Findings Insulin analogue libraries were constructed by total amino acid scanning mutagenesis. The relative binding affinities for the A and B isoform of the IR were determined by competition assays using scintillation proximity assay technology. Structural information was obtained by X-ray crystallography. Introduction of B25A or B25N mutations resulted in analogues with a 2-fold preference for the B compared to the A isoform, whereas the opposite was observed with a B25Y substitution. An acidic amino acid residue at position B27 caused an additional 2-fold selective increase in affinity for the receptor B isoform for analogues bearing a B25N mutation. Furthermore, the combination of B25H with either B27D or B27E also resulted in B isoform-preferential analogues (2-fold preference) even though the corresponding single mutation analogues displayed no differences in relative isoform binding affinity. Conclusions/Significance We have discovered a new class of IR isoform-selective insulin analogues with 24-fold differences in relative binding affinities for either the A or the B isoform of the IR compared to human insulin. Our results demonstrate that a mutation at position B25 alone or in combination with a mutation at position B27 in the insulin molecule confers IR isoform selectivity. Isoform-preferential analogues may provide new opportunities for developing insulin analogues with improved clinical benefits. PMID:21625452

  1. Structure of Rhodococcus equi virulence-associated protein B (VapB) reveals an eight-stranded antiparallel β-barrel consisting of two Greek-key motifs

    SciTech Connect

    Geerds, Christina; Wohlmann, Jens; Haas, Albert; Niemann, Hartmut H.

    2014-06-18

    The structure of VapB, a member of the Vap protein family that is involved in virulence of the bacterial pathogen R. equi, was determined by SAD phasing and reveals an eight-stranded antiparallel β-barrel similar to avidin, suggestive of a binding function. Made up of two Greek-key motifs, the topology of VapB is unusual or even unique. Members of the virulence-associated protein (Vap) family from the pathogen Rhodococcus equi regulate virulence in an unknown manner. They do not share recognizable sequence homology with any protein of known structure. VapB and VapA are normally associated with isolates from pigs and horses, respectively. To contribute to a molecular understanding of Vap function, the crystal structure of a protease-resistant VapB fragment was determined at 1.4 Å resolution. The structure was solved by SAD phasing employing the anomalous signal of one endogenous S atom and two bound Co ions with low occupancy. VapB is an eight-stranded antiparallel β-barrel with a single helix. Structural similarity to avidins suggests a potential binding function. Unlike other eight- or ten-stranded β-barrels found in avidins, bacterial outer membrane proteins, fatty-acid-binding proteins and lysozyme inhibitors, Vaps do not have a next-neighbour arrangement but consist of two Greek-key motifs with strand order 41238567, suggesting an unusual or even unique topology.

  2. Structural and Functional Insights into (S)-Ureidoglycine Aminohydrolase, Key Enzyme of Purine Catabolism in Arabidopsis thaliana*

    PubMed Central

    Shin, Inchul; Percudani, Riccardo; Rhee, Sangkee

    2012-01-01

    The ureide pathway has recently been identified as the metabolic route of purine catabolism in plants and some bacteria. In this pathway, uric acid, which is a major product of the early stage of purine catabolism, is degraded into glyoxylate and ammonia via stepwise reactions of seven different enzymes. Therefore, the pathway has a possible physiological role in mobilization of purine ring nitrogen for further assimilation. (S)-Ureidoglycine aminohydrolase enzyme converts (S)-ureidoglycine into (S)-ureidoglycolate and ammonia, providing the final substrate to the pathway. Here, we report a structural and functional analysis of this enzyme from Arabidopsis thaliana (AtUGlyAH). The crystal structure of AtUGlyAH in the ligand-free form shows a monomer structure in the bicupin fold of the ?-barrel and an octameric functional unit as well as a Mn2+ ion binding site. The structure of AtUGlyAH in complex with (S)-ureidoglycine revealed that the Mn2+ ion acts as a molecular anchor to bind (S)-ureidoglycine, and its binding mode dictates the enantioselectivity of the reaction. Further kinetic analysis characterized the functional roles of the active site residues, including the Mn2+ ion binding site and residues in the vicinity of (S)-ureidoglycine. These analyses provide molecular insights into the structure of the enzyme and its possible catalytic mechanism. PMID:22493446

  3. Structural insights into a key carotenogenesis related enzyme phytoene synthase of P. falciparum: a novel drug target for malaria.

    PubMed

    Agarwal, Shalini; Sharma, Vijeta; Phulera, Swastik; Abdin, M Z; Ayana, R; Singh, Shailja

    2015-12-01

    Carotenoids represent a diverse group of pigments derived from the common isoprenoid precursors and fulfill a variety of critical functions in plants and animals. Phytoene synthase (PSY), a transferase enzyme that catalyzes the first specific step in carotenoid biosynthesis plays a central role in the regulation of a number of essential functions mediated via carotenoids. PSYs have been deeply investigated in plants, bacteria and algae however in apicomplexans it is poorly studied. In an effort to characterize PSY in apicomplexans especially the malaria parasite Plasmodium falciparum (P. falciparum), a detailed bioinformatics analysis is undertaken. We have analysed the Phylogenetic relationship of PSY also referred to as octaprenyl pyrophosphate synthase (OPPS) in P. falciparum with other taxonomic groups. Further, we in silico characterized the secondary and tertiary structures of P. falciparum PSY/OPPS and compared the tertiary structures with crystal structure of Thermotoga maritima (T. maritima) OPPS. Our results evidenced the resemblance of P. falciparum PSY with the active site of T. maritima OPPS. Interestingly, the comparative structural analysis revealed an unconserved unique loop in P. falciparum OPPS/PSY. Such structural insights might contribute novel accessory functions to the protein thus, offering potential drug targets. PMID:26702306

  4. Tris(2,2'-azobispyridine) complexes of copper(II): X-ray structures, reactivities, and the radical nonradical bis(ligand) analogues.

    PubMed

    Maity, Suvendu; Kundu, Suman; Weyhermüller, Thomas; Ghosh, Prasanta

    2015-02-16

    Tris(abpy) complexes of types mer-[Cu(II)(abpy)3][PF6]2 (mer-1(2+)[PF6(–)]2) and ctc-[Cu(II)(abpy)2(bpy)][PF6]2 (ctc-2(2+)[PF6(–)]2) were successfully isolated and characterized by spectra and single-crystal X-ray structure determinations (abpy = 2,2′-azobispyridine; bpy = 2,2′-bipyridine). Reactions of mer-1(2+) and ctc-2(2+) ions with catechol, o-aminophenol, p-phenylenediamine, and diphenylamine (Ph–NH–Ph) in 2:1 molar ratio afford [CuI(abpy)2](+) (3(+)) and corresponding quinone derivatives. The similar reactions of [Cu(II)(bpy)3](2+) and [Cu(II)(phen)3](2+) with these substrates yielding [Cu(I)(bpy)2](+) and [Cu(I)(phen)2](+) imply that these complexes undergo reduction-induced ligand dissociation reactions (phen = 1,10-phenanthroline). The average −N═N– lengths in mer-1(2+)[PF6(–)]2 and ctc-2(2+)[PF6(–)]2 are 1.248(4), while that in 3(+)[PF6(–)]·2CH2Cl2 is relatively longer, 1.275(2) Å, due to dCu → πazo* back bonding. In cyclic voltammetry, mer-1(2+) exhibits one quasi-reversible wave at −0.42 V due to Cu(II)/Cu(I) and abpy/abpy(•–) couples and two reversible waves at −0.90 and −1.28 V due to abpy/abpy(•–) couple, while those of ctc-2(2+) ion appear at −0.44, −0.86, and −1.10 V versus Fc(+)/Fc couple. The anodic 3(2+)/3(+) and the cathodic 3(+)/3 redox waves at +0.33 and −0.40 V are reversible. The electron paramagnetic resonance spectra and density functional theory (DFT) calculations authenticated the existence of abpy anion radical (abpy(•–)) in 3, which is defined as a hybrid state of [Cu(I)(abpy(0.5•–))(abpy(0.5•–))] and [Cu(II)(abpy(•–))(abpy(•–))] states. 3(2+) ion is a neutral abpy complex of copper(II) of type [Cu(II)(abpy)2](2+). 3 exhibits a near-IR absorption band at 2400–3000 nm because of the intervalence ligand-to-ligand charge transfer, elucidated by time-dependent DFT calculations in CH2Cl2. PMID:25650719

  5. An evaluation of indirubin analogues as phosphorylase kinase inhibitors.

    PubMed

    Begum, Jaida; Skamnaki, Vassiliki T; Moffatt, Colin; Bischler, Nicolas; Sarrou, Josephine; Skaltsounis, Alexios-Leandros; Leonidas, Demetres D; Oikonomakos, Nikos G; Hayes, Joseph M

    2015-09-01

    Phosphorylase kinase (PhK) has been linked with a number of conditions such as glycogen storage diseases, psoriasis, type 2 diabetes and more recently, cancer (Camus et al., 2012 [6]). However, with few reported structural studies on PhK inhibitors, this hinders a structure based drug design approach. In this study, the inhibitory potential of 38 indirubin analogues have been investigated. 11 of these ligands had IC50 values in the range 0.170-0.360?M, with indirubin-3'-acetoxime (1c) the most potent. 7-Bromoindirubin-3'-oxime (13b), an antitumor compound which induces caspase-independent cell-death (Ribas et al., 2006 [20]) is revealed as a specific inhibitor of PhK (IC50=1.8?M). Binding assay experiments performed using both PhK-holo and PhK-?trnc confirmed the inhibitory effects to arise from binding at the kinase domain (? subunit). High level computations using QM/MM-PBSA binding free energy calculations were in good agreement with experimental binding data, as determined using statistical analysis, and support binding at the ATP-binding site. The value of a QM description for the binding of halogenated ligands exhibiting ?-hole effects is highlighted. A new statistical metric, the 'sum of the modified logarithm of ranks' (SMLR), has been defined which measures performance of a model for both the "early recognition" (ranking earlier/higher) of active compounds and their relative ordering by potency. Through a detailed structure activity relationship analysis considering other kinases (CDK2, CDK5 and GSK-3?/?), 6'(Z) and 7(L) indirubin substitutions have been identified to achieve selective PhK inhibition. The key PhK binding site residues involved can also be targeted using other ligand scaffolds in future work. PMID:26364215

  6. Phosphoinositide 3-kinase (PI3K(p110alpha)) directly regulates key components of the Z-disc and cardiac structure.

    PubMed

    Waardenberg, Ashley J; Bernardo, Bianca C; Ng, Dominic C H; Shepherd, Peter R; Cemerlang, Nelly; Sbroggiò, Mauro; Wells, Christine A; Dalrymple, Brian P; Brancaccio, Mara; Lin, Ruby C Y; McMullen, Julie R

    2011-09-01

    Maintenance of cardiac structure and Z-disc signaling are key factors responsible for protecting the heart in a setting of stress, but how these processes are regulated is not well defined. We recently demonstrated that PI3K(p110α) protects the heart against myocardial infarction. The aim of this study was to determine whether PI3K(p110α) directly regulates components of the Z-disc and cardiac structure. To address this question, a unique three-dimensional virtual muscle model was applied to gene expression data from transgenic mice with increased or decreased PI3K(p110α) activity under basal conditions (sham) and in a setting of myocardial infarction to display the location of structural proteins. Key findings from this analysis were then validated experimentally. The three-dimensional virtual muscle model visually highlighted reciprocally regulated transcripts associated with PI3K activation that encoded key components of the Z-disc and costamere, including melusin. Studies were performed to assess whether PI3K and melusin interact in the heart. Here, we identify a novel melusin-PI3K interaction that generates lipid kinase activity. The direct impact of PI3K(p110α) on myocyte structure was assessed by treating neonatal rat ventricular myocytes with PI3K(p110α) inhibitors and examining the myofiber morphology of hearts from PI3K transgenic mice. Results demonstrate that PI3K is critical for myofiber maturation and Z-disc alignment. In summary, PI3K regulates the expression of genes essential for cardiac structure and Z-disc signaling, interacts with melusin, and is critical for Z-disc alignment. PMID:21757757

  7. Substrate analogues for isoprenoid enzymes

    SciTech Connect

    Stremler, K.E.

    1987-01-01

    Diphosphonate analogues of geranyl diphosphate, resistant to degradation by phosphatases, were found to be alternate substrates for the reaction with farnesyl diphosphate synthetase isolated from avian liver. The difluoromethane analogue was shown to be the better alternate substrate, in agreement with solvolysis results which indicate that the electronegativity of the difluoromethylene unit more closely approximates that of the normal bridging oxygen. The usefulness of the C/sub 10/ difluoro analogue, for detecting low levels of isoprenoid enzymes in the presence of high levels of phosphatase activity, was demonstrated with a cell-free preparation from lemon peel. A series of C/sub 5/ through C/sub 15/ homoallylic and allylic diphosphonates, as well as two 5'-nucleotide diphosphonates, was prepared in high overall yield using the activation-displacement sequence. Radiolabeled samples of several of the allylic diphosphonates were prepared with tritium located at C1. A series of geraniols, stereospecifically deuterated at C1, was prepared. The enantiomeric purities and absolute configurations were determined by derivatization as the mandelate esters for analysis by /sup 1/H NMR. The stereochemistry of the activation-displacement sequence was examined using C1-deuterated substrates.

  8. Policy issues in space analogues

    NASA Astrophysics Data System (ADS)

    Auger, Robin N.; Facktor, Debra D.

    Space mission planning is increasingly focusing on destinations beyond Earth orbit. Advancements in technology will inevitably be required to enable long-duration human spaceflight missions, and breakthroughs in the policy arena will also be needed to achieve success in such missions. By exploring how policy issues have been addressed in analogous extreme environments, policymakers can develop a framework for addressing these issues as they apply to long-term human spaceflight. Policy issues that need to be addressed include: crew selection, training, organization, and activities, medical testing, illness, injury, and death; communication; legal accountability and liability; mission safety and risk management; and environmental contamination. This paper outlines the approach of a study underway by The George Washington University and ANSER to examine how these policy issues have been addressed in several analogues and how the experiences of these analogues can help formulate policies for long-duration human spaceflight missions. Analogues being studied include Antarctic bases, submarine voyages, undersea stations, Biosphere 2, and the U.S. Skylab and Russian Mir space stations.

  9. Hippocampal Structure and Human Cognition: Key Role of Spatial Processing and Evidence Supporting the Efficiency Hypothesis in Females

    ERIC Educational Resources Information Center

    Colom, Roberto; Stein, Jason L.; Rajagopalan, Priya; Martinez, Kenia; Hermel, David; Wang, Yalin; Alvarez-Linera, Juan; Burgaleta, Miguel; Quiroga, Ma. Angeles; Shih, Pei Chun; Thompson, Paul M.

    2013-01-01

    Here we apply a method for automated segmentation of the hippocampus in 3D high-resolution structural brain MRI scans. One hundred and four healthy young adults completed twenty one tasks measuring abstract, verbal, and spatial intelligence, along with working memory, executive control, attention, and processing speed. After permutation tests…

  10. Hippocampal Structure and Human Cognition: Key Role of Spatial Processing and Evidence Supporting the Efficiency Hypothesis in Females

    ERIC Educational Resources Information Center

    Colom, Roberto; Stein, Jason L.; Rajagopalan, Priya; Martinez, Kenia; Hermel, David; Wang, Yalin; Alvarez-Linera, Juan; Burgaleta, Miguel; Quiroga, Ma. Angeles; Shih, Pei Chun; Thompson, Paul M.

    2013-01-01

    Here we apply a method for automated segmentation of the hippocampus in 3D high-resolution structural brain MRI scans. One hundred and four healthy young adults completed twenty one tasks measuring abstract, verbal, and spatial intelligence, along with working memory, executive control, attention, and processing speed. After permutation tests

  11. Probing High School Students' Cognitive Structures and Key Areas of Learning Difficulties on Ethanoic Acid Using the Flow Map Method

    ERIC Educational Resources Information Center

    Zhou, Qing; Wang, Tingting; Zheng, Qi

    2015-01-01

    The purpose of this study was primarily to explore high school students' cognitive structures and to identify their learning difficulties on ethanoic acid through the flow map method. The subjects of this study were 30 grade 1 students from Dong Yuan Road Senior High School in Xi'an, China. The interviews were conducted a week after the students

  12. Probing High School Students' Cognitive Structures and Key Areas of Learning Difficulties on Ethanoic Acid Using the Flow Map Method

    ERIC Educational Resources Information Center

    Zhou, Qing; Wang, Tingting; Zheng, Qi

    2015-01-01

    The purpose of this study was primarily to explore high school students' cognitive structures and to identify their learning difficulties on ethanoic acid through the flow map method. The subjects of this study were 30 grade 1 students from Dong Yuan Road Senior High School in Xi'an, China. The interviews were conducted a week after the students…

  13. Adenosine monophosphate-activated kinase and its key role in catabolism: structure, regulation, biological activity, and pharmacological activation.

    PubMed

    Krishan, Sukriti; Richardson, Des R; Sahni, Sumit

    2015-01-01

    Adenosine monophosphate-activated protein kinase (AMPK) is a cellular energy sensor, which once activated, plays a role in several processes within the cell to restore energy homeostasis. The protein enhances catabolic pathways, such as ?-oxidation and autophagy, to generate ATP, and inhibits anabolic processes that require energy, including fatty acid, cholesterol, and protein synthesis. Due to its key role in the regulation of critical cellular pathways, deregulation of AMPK is associated with the pathology of many diseases, including cancer, Wolff-Parkinson-White syndrome, neurodegenerative disorders, diabetes, and metabolic syndrome. In fact, AMPK is a target of some pharmacological agents implemented in the treatment of diabetes (metformin and thiazolidinediones) as well as other naturally derived products, such as berberine, which is used in traditional medicine. Due to its critical role in the cell and the pathology of several disorders, research into developing AMPK as a therapeutic target is becoming a burgeoning and exciting field of pharmacological research. A profound understanding of the regulation and activity of AMPK would enhance its development as a promising therapeutic target. PMID:25422142

  14. Structural Characterisation of FabG from Yersinia pestis, a Key Component of Bacterial Fatty Acid Synthesis.

    PubMed

    Nanson, Jeffrey D; Forwood, Jade K

    2015-01-01

    Ketoacyl-acyl carrier protein reductases (FabG) are ubiquitously expressed enzymes that catalyse the reduction of acyl carrier protein (ACP) linked thioesters within the bacterial type II fatty acid synthesis (FASII) pathway. The products of these enzymes, saturated and unsaturated fatty acids, are essential components of the bacterial cell envelope. The FASII reductase enoyl-ACP reductase (FabI) has been the focus of numerous drug discovery efforts, some of which have led to clinical trials, yet few studies have focused on FabG. Like FabI, FabG appears to be essential for survival in many bacteria, similarly indicating the potential of this enzyme as a drug target. FabG enzymes are members of the short-chain alcohol dehydrogenase/reductase (SDR) family, and like other SDRs, exhibit highly conserved secondary and tertiary structures, and contain a number of conserved sequence motifs. Here we describe the crystal structures of FabG from Yersinia pestis (YpFabG), the causative agent of bubonic, pneumonic, and septicaemic plague, and three human pandemics. Y. pestis remains endemic in many parts of North America, South America, Southeast Asia, and Africa, and a threat to human health. YpFabG shares a high degree of structural similarity with bacterial homologues, and the ketoreductase domain of the mammalian fatty acid synthase from both Homo sapiens and Sus scrofa. Structural characterisation of YpFabG, and comparison with other bacterial FabGs and the mammalian fatty acid synthase, provides a strong platform for virtual screening of potential inhibitors, rational drug design, and the development of new antimicrobial agents to combat Y. pestis infections. PMID:26539719

  15. Structural Characterisation of FabG from Yersinia pestis, a Key Component of Bacterial Fatty Acid Synthesis

    PubMed Central

    Nanson, Jeffrey D.; Forwood, Jade K.

    2015-01-01

    Ketoacyl-acyl carrier protein reductases (FabG) are ubiquitously expressed enzymes that catalyse the reduction of acyl carrier protein (ACP) linked thioesters within the bacterial type II fatty acid synthesis (FASII) pathway. The products of these enzymes, saturated and unsaturated fatty acids, are essential components of the bacterial cell envelope. The FASII reductase enoyl-ACP reductase (FabI) has been the focus of numerous drug discovery efforts, some of which have led to clinical trials, yet few studies have focused on FabG. Like FabI, FabG appears to be essential for survival in many bacteria, similarly indicating the potential of this enzyme as a drug target. FabG enzymes are members of the short-chain alcohol dehydrogenase/reductase (SDR) family, and like other SDRs, exhibit highly conserved secondary and tertiary structures, and contain a number of conserved sequence motifs. Here we describe the crystal structures of FabG from Yersinia pestis (YpFabG), the causative agent of bubonic, pneumonic, and septicaemic plague, and three human pandemics. Y. pestis remains endemic in many parts of North America, South America, Southeast Asia, and Africa, and a threat to human health. YpFabG shares a high degree of structural similarity with bacterial homologues, and the ketoreductase domain of the mammalian fatty acid synthase from both Homo sapiens and Sus scrofa. Structural characterisation of YpFabG, and comparison with other bacterial FabGs and the mammalian fatty acid synthase, provides a strong platform for virtual screening of potential inhibitors, rational drug design, and the development of new antimicrobial agents to combat Y. pestis infections. PMID:26539719

  16. Growth and structure of pentacene films on graphite: Weak adhesion as a key for epitaxial film growth

    NASA Astrophysics Data System (ADS)

    Götzen, Jan; Käfer, Daniel; Wöll, Christof; Witte, Gregor

    2010-02-01

    The microstructure of pentacene films grown on the basal plane of graphite has been investigated. By combining various complementary techniques including scanning tunneling microscopy, atomic force microscopy, x-ray diffraction, thermal desorption spectroscopy, and x-ray absorption spectroscopy the molecular orientation, crystalline structure, and morphology of the films as well as their thermal stability have been characterized in detail as a function of the film thickness. Initial film growth leads to the formation of a commensurate monolayer consisting of flat-lying molecules while upon subsequent deposition epitaxially ordered (022)-oriented pentacene films are formed which adopt the Siegrist phase. The detailed analysis shows that this epitaxial growth of films with an essentially recumbent molecular orientation is brought about by a slight rotation of the molecules in the first layer around their long molecular axis upon deposition of overlying molecular layers. Such a structural modification is unusual and becomes possible by the rather weak adsorption energy on graphite. In contrast, a very different film structure including an upright orientation of molecules even in the first layer is found on nonperfect but rough graphite surfaces leading to the formation of (001)-oriented films which initially reveal the thin-film phase and continue to grow in the Campbell phase of pentacene.

  17. ?-Conotoxins Synthesized Using an Acid-cleavable Solubility Tag Approach Reveal Key Structural Determinants for NaV Subtype Selectivity*

    PubMed Central

    Peigneur, Steve; Paolini-Bertrand, Marianne; Gaertner, Hubert; Biass, Daniel; Violette, Aude; Stcklin, Reto; Favreau, Philippe; Tytgat, Jan; Hartley, Oliver

    2014-01-01

    Conotoxins are venom peptides from cone snails with multiple disulfide bridges that provide a rigid structural scaffold. Typically acting on ion channels implicated in neurotransmission, conotoxins are of interest both as tools for pharmacological studies and as potential new medicines. ?-Conotoxins act by inhibiting inactivation of voltage-gated sodium channels (Nav). Their pharmacology has not been extensively studied because their highly hydrophobic character makes them difficult targets for chemical synthesis. Here we adopted an acid-cleavable solubility tag strategy that facilitated synthesis, purification, and directed disulfide bridge formation. Using this approach we readily produced three native ?-conotoxins from Conus consors plus two rationally designed hybrid peptides. We observed striking differences in Nav subtype selectivity across this group of compounds, which differ in primary structure at only three positions: 12, 23, and 25. Our results provide new insights into the structure-activity relationships underlying the Nav subtype selectivity of ?-conotoxins. Use of the acid-cleavable solubility tag strategy should facilitate synthesis of other hydrophobic peptides with complex disulfide bridge patterns. PMID:25352593

  18. ?-Conotoxins synthesized using an acid-cleavable solubility tag approach reveal key structural determinants for NaV subtype selectivity.

    PubMed

    Peigneur, Steve; Paolini-Bertrand, Marianne; Gaertner, Hubert; Biass, Daniel; Violette, Aude; Stcklin, Reto; Favreau, Philippe; Tytgat, Jan; Hartley, Oliver

    2014-12-19

    Conotoxins are venom peptides from cone snails with multiple disulfide bridges that provide a rigid structural scaffold. Typically acting on ion channels implicated in neurotransmission, conotoxins are of interest both as tools for pharmacological studies and as potential new medicines. ?-Conotoxins act by inhibiting inactivation of voltage-gated sodium channels (Nav). Their pharmacology has not been extensively studied because their highly hydrophobic character makes them difficult targets for chemical synthesis. Here we adopted an acid-cleavable solubility tag strategy that facilitated synthesis, purification, and directed disulfide bridge formation. Using this approach we readily produced three native ?-conotoxins from Conus consors plus two rationally designed hybrid peptides. We observed striking differences in Nav subtype selectivity across this group of compounds, which differ in primary structure at only three positions: 12, 23, and 25. Our results provide new insights into the structure-activity relationships underlying the Nav subtype selectivity of ?-conotoxins. Use of the acid-cleavable solubility tag strategy should facilitate synthesis of other hydrophobic peptides with complex disulfide bridge patterns. PMID:25352593

  19. Structural Insights into the Quaternary Catalytic Mechanism of Hexameric Human Quinolinate Phosphoribosyltransferase, a Key Enzyme in de novo NAD Biosynthesis

    PubMed Central

    Youn, Hyung-Seop; Gyun Kim, Tae; Kim, Mun-Kyoung; Bu Kang, Gil; Youn Kang, Jung; Lee, Jung-Gyu; Yop An, Jun; Ryoung Park, Kyoung; Lee, Youngjin; Jun Im, Young; Hyuck Lee, Jun; Hyun Eom, Soo

    2016-01-01

    Quinolinate phosphoribosyltransferase (QPRT) catalyses the production of nicotinic acid mononucleotide, a precursor of de novo biosynthesis of the ubiquitous coenzyme nicotinamide adenine dinucleotide. QPRT is also essential for maintaining the homeostasis of quinolinic acid in the brain, a possible neurotoxin causing various neurodegenerative diseases. Although QPRT has been extensively analysed, the molecular basis of the reaction catalysed by human QPRT remains unclear. Here, we present the crystal structures of hexameric human QPRT in the apo form and its complexes with reactant or product. We found that the interaction between dimeric subunits was dramatically altered during the reaction process by conformational changes of two flexible loops in the active site at the dimer-dimer interface. In addition, the N-terminal short helix α1 was identified as a critical hexamer stabilizer. The structural features, size distribution, heat aggregation and ITC studies of the full-length enzyme and the enzyme lacking helix α1 strongly suggest that human QPRT acts as a hexamer for cooperative reactant binding via three dimeric subunits and maintaining stability. Based on our comparison of human QPRT structures in the apo and complex forms, we propose a drug design strategy targeting malignant glioma. PMID:26805589

  20. Structural Insights into the Quaternary Catalytic Mechanism of Hexameric Human Quinolinate Phosphoribosyltransferase, a Key Enzyme in de novo NAD Biosynthesis.

    PubMed

    Youn, Hyung-Seop; Kim, Tae Gyun; Kim, Mun-Kyoung; Kang, Gil Bu; Kang, Jung Youn; Lee, Jung-Gyu; An, Jun Yop; Park, Kyoung Ryoung; Lee, Youngjin; Im, Young Jun; Lee, Jun Hyuck; Eom, Soo Hyun

    2016-01-01

    Quinolinate phosphoribosyltransferase (QPRT) catalyses the production of nicotinic acid mononucleotide, a precursor of de novo biosynthesis of the ubiquitous coenzyme nicotinamide adenine dinucleotide. QPRT is also essential for maintaining the homeostasis of quinolinic acid in the brain, a possible neurotoxin causing various neurodegenerative diseases. Although QPRT has been extensively analysed, the molecular basis of the reaction catalysed by human QPRT remains unclear. Here, we present the crystal structures of hexameric human QPRT in the apo form and its complexes with reactant or product. We found that the interaction between dimeric subunits was dramatically altered during the reaction process by conformational changes of two flexible loops in the active site at the dimer-dimer interface. In addition, the N-terminal short helix α1 was identified as a critical hexamer stabilizer. The structural features, size distribution, heat aggregation and ITC studies of the full-length enzyme and the enzyme lacking helix α1 strongly suggest that human QPRT acts as a hexamer for cooperative reactant binding via three dimeric subunits and maintaining stability. Based on our comparison of human QPRT structures in the apo and complex forms, we propose a drug design strategy targeting malignant glioma. PMID:26805589

  1. Surface and Moho topography as key constraints for understanding the thermo-rheological structure and longevity of cratons and tectons

    NASA Astrophysics Data System (ADS)

    Burov, E. B.; Francois, T.

    2013-12-01

    Surface topography and Moho are the most robust observables that have been insufficiently exploited for containing the rheological and thermal structure and hence for understanding the longevity and eventual destruction of cratons and 'tectons'. Craton longevity has been often explained by their buoyancy and analysed by testing gravitational stability of cratonic mantle 'keels' as a function of the hypothesized plate thickness and thermo-rheological structure. Destruction of some cratons (e.g. North China) and data indicating little if no buoyancy of some tectons (e.g., Arabian shield) suggest that buoyancy is not the only factor of their stability, and previous studies show that their mechanical strength is as important as buoyancy. The upper bounds on this strength are provided by flexural studies demonstrating that Te values (equivalent elastic thickness) in cratons are highest in the world and may probably reach 150 km. Yet, the sensitivity of common methods is poor for Te values above 80 km while the lower bounds on the strength and the equivalent elastic thickness of cratons are still matter of debate. How this strength is partitioned between crust and mantle, and which set of rheological parameters pertain, remain major unknowns. We show that smooth low topography and 'frozen' heterogeneous crustal structure of cratons represent the missing constraints for understanding of craton longevity. The cratonic crust is characterized by isostatically misbalanced density heterogeneities, suggesting that the lithosphere has to be strong enough to keep them 'frozen' through the time without producing major gravitational instabilities and topographic undulations. Hence, to constrain thermo-rheological properties of cratons one should first investigate the stability of their topography and internal structure (constrained from seismic and gravity data). Our thermo-mechanical numerical experiments accounting for free surface boundary condition demonstrate that craton stability cannot be warranted by crustal strength only, and that strong dry olivine mantle rheology and cold thick lithosphere are needed for craton survival. We find fairly robust lower-bound limits on their thermo-rheological structure. In particular, the minimal Te needed for long-term stability of continents (cratons or tectons) is approximately 70 km.

  2. Design, Synthesis and Evaluation of Triazole-Pyrimidine Analogues as SecA Inhibitors.

    PubMed

    Cui, Jianmei; Jin, Jinshan; Chaudhary, Arpana Sagwal; Hsieh, Ying-Hsin; Zhang, Hao; Dai, Chaofeng; Damera, Krishna; Chen, Weixuan; Tai, Phang C; Wang, Binghe

    2016-01-01

    SecA, a key component of the bacterial Sec-dependent secretion pathway, is an attractive target for the development of new antimicrobial agents. Through a combination of virtual screening and experimental exploration of the surrounding chemical space, we identified a hit bistriazole SecA inhibitor, SCA-21, and studied a series of analogues by systematic dissections of the core scaffold. Evaluation of these analogues allowed us to establish an initial structure-activity relationship in SecA inhibition. The best compounds in this group are potent inhibitors of SecA-dependent protein-conducting channel activity and protein translocation activity at low- to sub-micromolar concentrations. They also have minimal inhibitory concentration (MIC) values against various strains of bacteria that correlate well with the SecA and protein translocation inhibition data. These compounds are effective against methicillin-resistant Staphylococcus aureus strains with various levels of efflux pump activity, indicating the capacity of SecA inhibitors to null the effect of multidrug resistance. Results from studies of drug-affinity-responsive target stability and protein pull-down assays are consistent with SecA as a target for these compounds. PMID:26607404

  3. Modification of Amphipathic Non-opioid Dynorphin A Analogues for Rat Brain Bradykinin Receptors

    PubMed Central

    Lee, Yeon Sun; Hall, Sara M.; Ramos-Colon, Cyf; Remesic, Michael; LeBaron, Lindsay; Nguyen, Ann; Rankin, David; Porreca, Frank; Lai, Josephine; Hruby, Victor J.

    2014-01-01

    It has been shown that under chronic pain or nerve injury conditions, up-regulated dynorphin A (Dyn A) interacts with bradykinin receptors (BRs) to cause hyperalgesia in the spinal cord. Thus BRs antagonist can modulate hyperalgesia by blocking Dyn A’s interaction with the BRs in the central nervous system. In our earlier structure-activity relationship (SAR) study, [des-Arg7]-Dyn A-(4-11) 13 was discovered as a minimum pharmacophore for rat brain BRs with its antagonist activity (anti-hyperalgesic effect) in in vivo tests using naïve or injured animals. We have pursued further modification on the [des-Arg7]-Dyn A analogues and identified a key insight into the pharmacophore of the rat brain BRs: amphipathicity. PMID:25434001

  4. Discovery of Desketoraloxifene Analogues as Inhibitors of Mammalian, Pseudomonas aeruginosa, and NAPE Phospholipase D Enzymes

    PubMed Central

    2015-01-01

    Phospholipase D (PLD) hydrolyses cellular lipids to produce the important lipid second messenger phosphatidic acid. A PLD enzyme expressed by Pseudomonas aeruginosa (PldA) has been shown to be important in bacterial infection, and NAPE-PLD has emerged as being key in the synthesis of endocannabinoids. In order to better understand the biology and therapeutic potential of these less explored PLD enzymes, small molecule tools are required. Selective estrogen receptor modulators (SERMs) have been previously shown to inhibit mammalian PLD (PLD1 and PLD2). By targeted screening of a library of SERM analogues, additional parallel synthesis, and evaluation in multiple PLD assays, we discovered a novel desketoraloxifene-based scaffold that inhibited not only the two mammalian PLDs but also structurally divergent PldA and NAPE-PLD. This finding represents an important first step toward the development of small molecules possessing universal inhibition of divergent PLD enzymes to advance the field. PMID:25384256

  5. Discovery of desketoraloxifene analogues as inhibitors of mammalian, Pseudomonas aeruginosa, and NAPE phospholipase D enzymes.

    PubMed

    Scott, Sarah A; Spencer, Cierra T; O'Reilly, Matthew C; Brown, Kyle A; Lavieri, Robert R; Cho, Chul-Hee; Jung, Dai-Il; Larock, Richard C; Brown, H Alex; Lindsley, Craig W

    2015-02-20

    Phospholipase D (PLD) hydrolyses cellular lipids to produce the important lipid second messenger phosphatidic acid. A PLD enzyme expressed by Pseudomonas aeruginosa (PldA) has been shown to be important in bacterial infection, and NAPE-PLD has emerged as being key in the synthesis of endocannabinoids. In order to better understand the biology and therapeutic potential of these less explored PLD enzymes, small molecule tools are required. Selective estrogen receptor modulators (SERMs) have been previously shown to inhibit mammalian PLD (PLD1 and PLD2). By targeted screening of a library of SERM analogues, additional parallel synthesis, and evaluation in multiple PLD assays, we discovered a novel desketoraloxifene-based scaffold that inhibited not only the two mammalian PLDs but also structurally divergent PldA and NAPE-PLD. This finding represents an important first step toward the development of small molecules possessing universal inhibition of divergent PLD enzymes to advance the field. PMID:25384256

  6. Five-membered ring formation in unimolecular reactions of peptides: a key structural element controlling low-energy collision-induced dissociation of peptides.

    PubMed

    Schlosser, A; Lehmann, W D

    2000-12-01

    Unimolecular fragmentation reactions of peptides in low-energy collision-induced dissociation are reviewed in the mechanistic context of five-membered ring formation. This structure of intermediates or of fragment ions is recognized as a key element that governs unimolecular peptide fragmentation within the structural framework determined by the peptide backbone and its side-chains. A collection of collision-induced dissociation reactions is presented covering (i) b-ion formation, (ii) the fragmentation of N-terminally acylated peptides, (iii) neutral loss of the C-terminal amino acid in alkali or silver cationized peptides, (iv) the fragmentation of isoAsp-containing peptides and (v) the fragmentation of negatively charged Asp- or Glu-containing peptides. It appears that for all possible nucleophile-electrophile interactions leading to a five-membered ring structure an associated unimolecular peptide fragmentation reaction can be observed. PMID:11180628

  7. POLYCHLORINATED BIPHENYLS AS HORMONALLY ACTIVE STRUCTURAL ANALOGUES

    EPA Science Inventory

    Among the environmental chemicals believed to have the potential to disrupt the endocrine systems of animals including humans, the polychlorinated biphenyls are a chemical class of considerable concern. Possible mechanisms by which these chemicals may interfere with endocrine fun...

  8. Synthesis and anti-tumor activity of carbohydrate analogues of the tetrahydrofuran containing acetogenins

    PubMed Central

    Bachan, Stewart; Tony, K. A.; Kawamura, Akira; Montenegro, Diego; Joshi, Anjali; Garg, Himanshu; Mootoo, David R.

    2013-01-01

    The tetrahydrofuran (THF) containing annonaceous acetogenins (AAs) are attractive candidates for drug development because of their potent cytotoxicity against a wide range of tumors and their relatively simple and robust structures. Replacement of the THF segment with a sugar residue may deliver analogues with improved tumor selectivity and pharmacokinetics and are therefore attractive for drug development. As a first test to the feasibility of such structures, a set of such monosaccharide analogues was synthesized and assayed against four human tumor cell lines, cervical (HeLa), breast (MDA-MB231), T-cell leukemia (Jurkat) and prostate (PC-3). Certain analogues showed low micromolar activity that was comparable to a structurally similar, naturally occurring mono-THF acetogenin. A preliminary examination of the structure-activity profile of these carbohydrate analogues suggests that they have a similar mechanism of action as their THF congeners. PMID:24045006

  9. Crystal Structure and Substrate Recognition of Cellobionic Acid Phosphorylase, Which Plays a Key Role in Oxidative Cellulose Degradation by Microbes.

    PubMed

    Nam, Young-Woo; Nihira, Takanori; Arakawa, Takatoshi; Saito, Yuka; Kitaoka, Motomitsu; Nakai, Hiroyuki; Fushinobu, Shinya

    2015-07-24

    The microbial oxidative cellulose degradation system is attracting significant research attention after the recent discovery of lytic polysaccharide mono-oxygenases. A primary product of the oxidative and hydrolytic cellulose degradation system is cellobionic acid (CbA), the aldonic acid form of cellobiose. We previously demonstrated that the intracellular enzyme belonging to glycoside hydrolase family 94 from cellulolytic fungus and bacterium is cellobionic acid phosphorylase (CBAP), which catalyzes reversible phosphorolysis of CbA into glucose 1-phosphate and gluconic acid (GlcA). In this report, we describe the biochemical characterization and the three-dimensional structure of CBAP from the marine cellulolytic bacterium Saccharophagus degradans. Structures of ligand-free and complex forms with CbA, GlcA, and a synthetic disaccharide product from glucuronic acid were determined at resolutions of up to 1.6 Å. The active site is located near the dimer interface. At subsite +1, the carboxylate group of GlcA and CbA is recognized by Arg-609 and Lys-613. Additionally, one residue from the neighboring protomer (Gln-190) is involved in the carboxylate recognition of GlcA. A mutational analysis indicated that these residues are critical for the binding and catalysis of the aldonic and uronic acid acceptors GlcA and glucuronic acid. Structural and sequence comparisons with other glycoside hydrolase family 94 phosphorylases revealed that CBAPs have a unique subsite +1 with a distinct amino acid residue conservation pattern at this site. This study provides molecular insight into the energetically efficient metabolic pathway of oxidized sugars that links the oxidative cellulolytic pathway to the glycolytic and pentose phosphate pathways in cellulolytic microbes. PMID:26041776

  10. Keys to Lipid Selection in Fatty Acid Amide Hydrolase Catalysis: Structural Flexibility, Gating Residues and Multiple Binding Pockets

    PubMed Central

    Palermo, Giulia; Bauer, Inga; Campomanes, Pablo; Cavalli, Andrea; Armirotti, Andrea; Girotto, Stefania; Rothlisberger, Ursula; De Vivo, Marco

    2015-01-01

    The fatty acid amide hydrolase (FAAH) regulates the endocannabinoid system cleaving primarily the lipid messenger anandamide. FAAH has been well characterized over the years and, importantly, it represents a promising drug target to treat several diseases, including inflammatory-related diseases and cancer. But its enzymatic mechanism for lipid selection to specifically hydrolyze anandamide, rather than similar bioactive lipids, remains elusive. Here, we clarify this mechanism in FAAH, examining the role of the dynamic paddle, which is formed by the gating residues Phe432 and Trp531 at the boundary between two cavities that form the FAAH catalytic site (the membrane-access and the acyl chain-binding pockets). We integrate microsecond-long MD simulations of wild type and double mutant model systems (Phe432Ala and Trp531Ala) of FAAH, embedded in a realistic membrane/water environment, with mutagenesis and kinetic experiments. We comparatively analyze three fatty acid substrates with different hydrolysis rates (anandamide > oleamide > palmitoylethanolamide). Our findings identify FAAHs mechanism to selectively accommodate anandamide into a multi-pocket binding site, and to properly orient the substrate in pre-reactive conformations for efficient hydrolysis that is interceded by the dynamic paddle. Our findings therefore endorse a structural framework for a lipid selection mechanism mediated by structural flexibility and gating residues between multiple binding cavities, as found in FAAH. Based on the available structural data, this exquisite catalytic strategy for substrate specificity seems to be shared by other lipid-degrading enzymes with similar enzymatic architecture. The mechanistic insights for lipid selection might assist de-novo enzyme design or drug discovery efforts. PMID:26111155

  11. Keys to Lipid Selection in Fatty Acid Amide Hydrolase Catalysis: Structural Flexibility, Gating Residues and Multiple Binding Pockets.

    PubMed

    Palermo, Giulia; Bauer, Inga; Campomanes, Pablo; Cavalli, Andrea; Armirotti, Andrea; Girotto, Stefania; Rothlisberger, Ursula; De Vivo, Marco

    2015-06-01

    The fatty acid amide hydrolase (FAAH) regulates the endocannabinoid system cleaving primarily the lipid messenger anandamide. FAAH has been well characterized over the years and, importantly, it represents a promising drug target to treat several diseases, including inflammatory-related diseases and cancer. But its enzymatic mechanism for lipid selection to specifically hydrolyze anandamide, rather than similar bioactive lipids, remains elusive. Here, we clarify this mechanism in FAAH, examining the role of the dynamic paddle, which is formed by the gating residues Phe432 and Trp531 at the boundary between two cavities that form the FAAH catalytic site (the "membrane-access" and the "acyl chain-binding" pockets). We integrate microsecond-long MD simulations of wild type and double mutant model systems (Phe432Ala and Trp531Ala) of FAAH, embedded in a realistic membrane/water environment, with mutagenesis and kinetic experiments. We comparatively analyze three fatty acid substrates with different hydrolysis rates (anandamide > oleamide > palmitoylethanolamide). Our findings identify FAAH's mechanism to selectively accommodate anandamide into a multi-pocket binding site, and to properly orient the substrate in pre-reactive conformations for efficient hydrolysis that is interceded by the dynamic paddle. Our findings therefore endorse a structural framework for a lipid selection mechanism mediated by structural flexibility and gating residues between multiple binding cavities, as found in FAAH. Based on the available structural data, this exquisite catalytic strategy for substrate specificity seems to be shared by other lipid-degrading enzymes with similar enzymatic architecture. The mechanistic insights for lipid selection might assist de-novo enzyme design or drug discovery efforts. PMID:26111155

  12. Analogue Sites for Mars Missions - A report from two workshops

    NASA Astrophysics Data System (ADS)

    Hipkin, V.; Voytek, M. A.; Glamoclija, M.

    2014-12-01

    Fieldwork, at terrestrial sites that are analogous in some way to Mars, has a key role in defining questions addressed by Mars missions. For MSL, the question is whether its landing site was habitable, and for Mars 2020, the question is how do we search for and what are signs of life in ancient habitable environments. Implementing these investigations by means of a rover mission on a distant planetary surface has challenges due to a limited set of tools and period of operations. Using this context of planetary missions is important in shaping how analog research can be used to advance planetary science. Following a successful 2010 AGU fall meeting session entitled "Analogue Sites for Mars Missions", two community workshops were held at The Woodlands, TX March 2011 and the Carnegie Institute of Washington in July 2013. These activities represent an ongoing dialogue with the analogue and mission communities. The AGU session solicited presentations of current analogue research relevant to MSL, at which time the landing site selection process was still considering four final sites. The 2011 Woodlands workshop solicited details on representative science questions and analogue sites by means of an abstract template. The output from The Woodlands workshop was an initial metric to assess the utility of analogue sites against specific science questions, as well as recommendations for future activities. The 2013 Carnegie workshop, followed up on some of the recommendations from 2011. Both on-line interactive dialogue and in person discussions targeted broad topics, including 'the advantages and problems of using a great terrestrial analog for field testing', and 'knowing what we currently do about Mars, what would be the best place on the planet to collect the first suite of samples to be returned to Earth? What would be appropriate analog sites on Earth?'. The results and recommendations from both workshops are summarized to publicize and stimulate this ongoing discussion.

  13. Structural analysis of human glutamine:fructose-6-phosphate amidotransferase, a key regulator in type 2 diabetes.

    PubMed

    Nakaishi, Yuichiro; Bando, Masahiko; Shimizu, Hiroshi; Watanabe, Kenji; Goto, Fumitaka; Tsuge, Hideaki; Kondo, Kazumi; Komatsu, Makoto

    2009-01-01

    Glutamine:fructose-6-phosphate amidotransferase (GFAT) is a rate-limiting enzyme in the hexoamine biosynthetic pathway and plays an important role in type 2 diabetes. We now report the first structures of the isomerase domain of the human GFAT in the presence of cyclic glucose-6-phosphate and linear glucosamine-6-phosphate. The C-terminal tail including the active site displays a rigid conformation, similar to the corresponding Escherichia coli enzyme. The diversity of the CF helix near the active site suggests the helix is a major target for drug design. Our study provides insights into the development of therapeutic drugs for type 2 diabetes. PMID:19059404

  14. Crystal Structure Analysis of Human Glutamine : Fructose 6-Phosphate Amidotransferase, a Key Regulator in Type 2 Diabetes

    NASA Astrophysics Data System (ADS)

    Nakaishi, Yuichiro; Bando, Masahiko

    Glutamine : fructose 6-phosphate amidotransferase (GFAT) is a rate-limiting enzyme in the hexoamine biosythetic pathway and plays an important role in type 2 diabetes. We now report the first structures of the isomerase domain of the human GFAT in the presence of cyclic glucose 6-phosphate and linear glucosamine 6-phosphate. The C-terminal tail including the active site displays a rigid conformation, similar to the corresponding Escherichia coli enzyme. The diversity of the CF helix near the active site suggests the helix is a major target for drug design. Our study provides insights into the development of therapeutic drugs for type 2 diabetes.

  15. Biological evaluation of a novel sorafenib analogue, t-CUPM

    PubMed Central

    Wecksler, Aaron T.; Hwang, Sung Hee; Liu, Jun-Yan; Wettersten, Hiromi I.; Morisseau, Christophe; Wu, Jian; Weiss, Robert H.; Hammock, Bruce D.

    2015-01-01

    Sorafenib (Nexavar) is currently the only FDA-approved small molecule targeted therapy for advanced hepatocellular carcinoma. The use of structural analogues and derivatives of sorafenib has enabled the elucidation of critical targets and mechanism(s) of cell death for human cancer lines. We previously performed a structure-activity relationship study on a series of sorafenib analogues designed to investigate the inhibition overlap between the major targets of sorafenib Raf-1 kinase and VEGFR-2, and an enzyme shown to be a potent off-target of sorafenib, soluble epoxide hydrolase. In the current work, we present the biological data on our lead sorafenib analogue, t-CUPM, demonstrating that this analogue retains cytotoxicity similar to sorafenib in various human cancer cell lines and strongly inhibits growth in the NCI-60 cell line panel. Co-treatment with the pan-caspase inhibitor, Z-VAD-FMK, failed to rescue the cell viability responses of both sorafenib and t-CUPM, and immunofluorescence microscopy shows similar mitochondrial depolarization and apoptosis-inducing factor release for both compounds. These data suggest that both compounds induce a similar mechanism of caspase-independent apoptosis in hepatoma cells. In addition, t-CUPM displays anti-proliferative effects comparable to sorafenib as seen by a halt in G0/G1 in cell cycle progression. The structural difference between sorafenib and t-CUPM significantly reduces inhibitory spectrum of kinases by this analogue, and pharmacokinetic characterization demonstrates a 20-fold better oral bioavailability of t-CUPM than sorafenib in mice. Thus, t-CUPM may have the potential to reduce the adverse events observed from the multikinase inhibitory properties and the large dosing regimens of sorafenib. PMID:25413440

  16. Biological evaluation of a novel sorafenib analogue, t-CUPM.

    PubMed

    Wecksler, Aaron T; Hwang, Sung Hee; Liu, Jun-Yan; Wettersten, Hiromi I; Morisseau, Christophe; Wu, Jian; Weiss, Robert H; Hammock, Bruce D

    2015-01-01

    Sorafenib (Nexavar) is currently the only FDA-approved small molecule targeted therapy for advanced hepatocellular carcinoma. The use of structural analogues and derivatives of sorafenib has enabled the elucidation of critical targets and mechanism(s) of cell death for human cancer lines. We previously performed a structure-activity relationship study on a series of sorafenib analogues designed to investigate the inhibition overlap between the major targets of sorafenib Raf-1 kinase and VEGFR-2, and an enzyme shown to be a potent off-target of sorafenib, soluble epoxide hydrolase. In the current work, we present the biological data on our lead sorafenib analogue, t-CUPM, demonstrating that this analogue retains cytotoxicity similar to sorafenib in various human cancer cell lines and strongly inhibits growth in the NCI-60 cell line panel. Co-treatment with the pan-caspase inhibitor, Z-VAD-FMK, failed to rescue the cell viability responses of both sorafenib and t-CUPM, and immunofluorescence microscopy shows similar mitochondrial depolarization and apoptosis-inducing factor release for both compounds. These data suggest that both compounds induce a similar mechanism of caspase-independent apoptosis in hepatoma cells. In addition, t-CUPM displays anti-proliferative effects comparable to sorafenib as seen by a halt in G0/G1 in cell cycle progression. The structural difference between sorafenib and t-CUPM significantly reduces inhibitory spectrum of kinases by this analogue, and pharmacokinetic characterization demonstrates a 20-fold better oral bioavailability of t-CUPM than sorafenib in mice. Thus, t-CUPM may have the potential to reduce the adverse events observed from the multikinase inhibitory properties and the large dosing regimens of sorafenib. PMID:25413440

  17. Synthesis of AZA analogues of TSAO.

    PubMed

    Nguyen Van Nhien, Albert; Tomassi, Cyrille; Len, Christophe; Marco-Contelles, José Luis; Postel, Denis

    2003-01-01

    TSAO derivatives which were first synthesized in 1992 have shown strong inhibitory effect and selectivity against HIV-1 (Camarasa, M.J.; Pérez-Pérez, M.J.; San-Félix, A.; Balzarini, J.; De Clercq, E. J. Med. Chem. 1992, 35, 2721-2727). The structure-activity relationship of these derivatives has shown strong binding between the amino acids constituting the reverse transcriptase and the different pharmacophore (tert-butyldimethylsilyl group, amino and sulfonate groups of the TSAO derivatives) (Camarasa, M.J.; San-Félix, A.; Pérez-Pérez, M.J.; Velázquez, S., Alvarez, R.; Chamorro, C.; Jimeno, M.L.; Pérez, C.; Gago, F.; De Clercq, E.; Balzarini, J. J. Carbohydr. Chem. 2000, 19, 6403-6406). We described the synthesis of an original TSAO analogue where, basically, the O-1'' atom is replaced by a nitrogen atom. PMID:14565316

  18. Synthesis and anticancer activity of nordihydroguaiaretic acid (NDGA) and analogues.

    PubMed

    McDonald, R W; Bunjobpon, W; Liu, T; Fessler, S; Pardo, O E; Freer, I K; Glaser, M; Seckl, M J; Robins, D J

    2001-12-01

    Nordihydroguaiaretic acid (NDGA) 1 is a constituent of the creosote bush Larrea divaricata and is well known to be a selective inhibitor of lipoxygenases. NDGA can also inhibit the platelet derived growth factor receptor and the protein kinase C intracellular signalling family, which both play an important role in proliferation and survival of cancers. Moreover, NDGA induces apoptosis in tumour xenografts. Although it is likely to have several targets of action, NDGA is well tolerated in animals. These encouraging results have prompted interest in the compound for clinical study. However, high concentrations of NDGA are required for efficacy and more potent analogues are required. We have synthesized five analogues of NDGA with different lengths of carbon bridge between the two catechol moieties in order to establish the spacing required for optimum anticancer effect and to compare their activities with NDGA. In order to ascertain if the catechol moieties are essential for anticancer activity, we prepared five analogues of NDGA containing only one hydroxyl group on each aromatic ring. NDGA 1, its racemic form 2, the catechol derivatives 5, 6 with five or six carbon atom bridges and the phenol analogues 8-11 with bridges of three to six carbon atoms all showed similar activity, with IC50 values of approximately 3-5 microM against the H-69 small cell lung cancer cell line. Analogues with shorter (3) or longer bridges (7, 12) were much less active. The most potent analogue was the biscatechol with a four-carbon bridge 4 which was > 10 times more active than NDGA and therefore represents a new lead compound in this area. Surprisingly, the tetramethyl ether 14 of this compound was slightly more active than NDGA, but the trihydroxy analogue 13 was less active than NDGA. The conformationally restricted analogue 15 was also less active than NDGA. In summary, simplification of the structure of NDGA by removal of the methyl groups has produced a new lead compound 4, which is >10 times more potent than NDGA as a proliferative inhibitor of H-69 small cell lung cancer cells. PMID:12375879

  19. Solution structure of the LIM-homeodomain transcription factor complex Lhx3/Ldb1 and the effects of a pituitary mutation on key Lhx3 interactions.

    PubMed

    Bhati, Mugdha; Lee, Christopher; Gadd, Morgan S; Jeffries, Cy M; Kwan, Ann; Whitten, Andrew E; Trewhella, Jill; Mackay, Joel P; Matthews, Jacqueline M

    2012-01-01

    Lhx3 is a LIM-homeodomain (LIM-HD) transcription factor that regulates neural cell subtype specification and pituitary development in vertebrates, and mutations in this protein cause combined pituitary hormone deficiency syndrome (CPHDS). The recently published structures of Lhx3 in complex with each of two key protein partners, Isl1 and Ldb1, provide an opportunity to understand the effect of mutations and posttranslational modifications on key protein-protein interactions. Here, we use small-angle X-ray scattering of an Ldb1-Lhx3 complex to confirm that in solution the protein is well represented by our previously determined NMR structure as an ensemble of conformers each comprising two well-defined halves (each made up of LIM domain from Lhx3 and the corresponding binding motif in Ldb1) with some flexibility between the two halves. NMR analysis of an Lhx3 mutant that causes CPHDS, Lhx3(Y114C), shows that the mutation does not alter the zinc-ligation properties of Lhx3, but appears to cause a structural rearrangement of the hydrophobic core of the LIM2 domain of Lhx3 that destabilises the domain and/or reduces the affinity of Lhx3 for both Ldb1 and Isl1. Thus the mutation would affect the formation of Lhx3-containing transcription factor complexes, particularly in the pituitary gland where these complexes are required for the production of multiple pituitary cell types and hormones. PMID:22848397

  20. Macrocyclic analogues of the diuretic insect neuropeptide helicokinin I show strong receptor-binding.

    PubMed

    Tran Van, Chien; Nennstiel, Dirk; Scherkenbeck, Jürgen

    2015-07-01

    Helicokinin I, a diuretic neuropeptide of the relevant cotton pest Helicoverpa zea represents a promising target for the design of insect neuropeptide mimetics. Using a ring-closing metathesis reaction, N-terminal bridged macrocyclic helicokinin I analogues with different rigidity were prepared and tested in a helicokinin receptor assay. A partially peptidomimetic helicokinin analogue, containing two structural modifications provides a deeper insight into the structural-requirements for receptor-binding. PMID:25960326

  1. The ketamine analogue methoxetamine and 3- and 4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor.

    PubMed

    Roth, Bryan L; Gibbons, Simon; Arunotayanun, Warunya; Huang, Xi-Ping; Setola, Vincent; Treble, Ric; Iversen, Les

    2013-01-01

    In this paper we determined the pharmacological profiles of novel ketamine and phencyclidine analogues currently used as 'designer drugs' and compared them to the parent substances via the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. The ketamine analogues methoxetamine ((RS)-2-(ethylamino)-2-(3-methoxyphenyl)cyclohexanone) and 3-MeO-PCE (N-ethyl-1-(3-methoxyphenyl)cyclohexanamine) and the 3- and 4-methoxy analogues of phencyclidine, (1-[1-(3-methoxyphenyl)cyclohexyl]piperidine and 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine), were all high affinity ligands for the PCP-site on the glutamate NMDA receptor. In addition methoxetamine and PCP and its analogues displayed appreciable affinities for the serotonin transporter, whilst the PCP analogues exhibited high affinities for sigma receptors. Antagonism of the NMDA receptor is thought to be the key pharmacological feature underlying the actions of dissociative anaesthetics. The novel ketamine and PCP analogues had significant affinities for the NMDA receptor in radioligand binding assays, which may explain their psychotomimetic effects in human users. Additional actions on other targets could be important for delineating side-effects. PMID:23527166

  2. Syntheses and biological activities of renin inhibitors containing statine analogues.

    PubMed

    Nishi, T; Saito, F; Nagahori, H; Kataoka, M; Morisawa, Y; Yabe, Y; Sakurai, M; Higashida, S; Shoji, M; Matsushita, Y

    1990-01-01

    Syntheses and biological activities of dipeptide renin inhibitors that contain statine analogues are described. The key steps of the synthetic approach to dipeptide renin inhibitors are the asymmetric synthesis of 2(R)-substituted-3-aminocarbonylpropionic acids and the diastereoselective syntheses of (3S,4S)-statine analogues. These inhibitors (2,14-40) inhibited human renin in the 3-140 nM range. Inhibitor ES 6864 (2) was found to be a highly potent inhibitor of human renin (IC50: 4.6 x 10(-9) M) and showed high enzyme specificity. Oral administration of ES 6864 at 3 mg/kg to conscious, sodium-depleted marmosets inhibited plasma renin activity (PRA) more than 80% after 1 h. PMID:2110866

  3. New Insight into the Transcarbamylase Family: The Structure of Putrescine Transcarbamylase, a Key Catalyst for Fermentative Utilization of Agmatine

    PubMed Central

    Polo, Luis Mariano; Gil-Ortiz, Fernando; Cantín, Angel; Rubio, Vicente

    2012-01-01

    Transcarbamylases reversibly transfer a carbamyl group from carbamylphosphate (CP) to an amine. Although aspartate transcarbamylase and ornithine transcarbamylase (OTC) are well characterized, little was known about putrescine transcarbamylase (PTC), the enzyme that generates CP for ATP production in the fermentative catabolism of agmatine. We demonstrate that PTC (from Enterococcus faecalis), in addition to using putrescine, can utilize L-ornithine as a poor substrate. Crystal structures at 2.5 Å and 2.0 Å resolutions of PTC bound to its respective bisubstrate analog inhibitors for putrescine and ornithine use, N-(phosphonoacetyl)-putrescine and δ-N-(phosphonoacetyl)-L-ornithine, shed light on PTC preference for putrescine. Except for a highly prominent C-terminal helix that projects away and embraces an adjacent subunit, PTC closely resembles OTCs, suggesting recent divergence of the two enzymes. Since differences between the respective 230 and SMG loops of PTC and OTC appeared to account for the differential preference of these enzymes for putrescine and ornithine, we engineered the 230-loop of PTC to make it to resemble the SMG loop of OTCs, increasing the activity with ornithine and greatly decreasing the activity with putrescine. We also examined the role of the C-terminal helix that appears a constant and exclusive PTC trait. The enzyme lacking this helix remained active but the PTC trimer stability appeared decreased, since some of the enzyme eluted as monomers from a gel filtration column. In addition, truncated PTC tended to aggregate to hexamers, as shown both chromatographically and by X-ray crystallography. Therefore, the extra C-terminal helix plays a dual role: it stabilizes the PTC trimer and, by shielding helix 1 of an adjacent subunit, it prevents the supratrimeric oligomerizations of obscure significance observed with some OTCs. Guided by the structural data we identify signature traits that permit easy and unambiguous annotation of PTC sequences. PMID:22363663

  4. Structure analysis of the flavoredoxin from Desulfovibrio vulgaris Miyazaki F reveals key residues that discriminate the functions and properties of the flavin reductase family.

    PubMed

    Shibata, Naoki; Ueda, Yasufumi; Takeuchi, Daisuke; Haruyama, Yoshihiro; Kojima, Shuichi; Sato, Junichi; Niimura, Youichi; Kitamura, Masaya; Higuchi, Yoshiki

    2009-09-01

    The crystal structure of flavoredoxin from Desulfovibrio vulgaris Miyazaki F was determined at 1.05 A resolution and its ferric reductase activity was examined. The aim was to elucidate whether flavoredoxin has structural similarity to ferric reductase and ferric reductase activity, based on the sequence similarity to ferric reductase from Archaeoglobus fulgidus. As expected, flavoredoxin shared a common overall structure with A. fulgidus ferric reductase and displayed weak ferric reductase and flavin reductase activities; however, flavoredoxin contains two FMN molecules per dimer, unlike A. fulgidus ferric reductase, which has only one FMN molecule per dimer. Compared with A. fulgidus ferric reductase, flavoredoxin forms three additional hydrogen bonds and has a significantly smaller solvent-accessible surface area. These observations explain the higher affinity of flavoredoxin for FMN. Unexpectedly, an electron-density map indicated the presence of a Mes molecule on the re-side of the isoalloxazine ring of FMN, and that two zinc ions are bound to the two cysteine residues, Cys39 and Cys40, adjacent to FMN. These two cysteine residues are close to one of the putative ferric ion binding sites of ferric reductase. Based on their structural similarities, we conclude that the corresponding site of ferric reductase is the most plausible site for ferric ion binding. Comparing the structures with related flavin proteins revealed key structural features regarding the discrimination of function (ferric ion or flavin reduction) and a unique electron transport system. PMID:19708087

  5. Crystal Structure and Identification of Two Key Amino Acids Involved in AI-2 Production and Biofilm Formation in Streptococcus suis LuxS

    PubMed Central

    Wang, Yang; Yi, Li; Wang, Shaohui; Fan, Hongjie; Ding, Chan; Mao, Xiang; Lu, Chengping

    2015-01-01

    Streptococcus suis has emerged as an important zoonotic pathogen that causes meningitis, arthritis, septicemia and even sudden death in pigs and humans. Quorum sensing is the signaling network for cell-to-cell communication that bacterial cells can use to monitor their own population density through production and exchange of signal molecules. S-Ribosylhomocysteinase (LuxS) is the key enzyme involved in the activated methyl cycle. Autoinducer 2 (AI-2) is the adduct of borate and a ribose derivative and is produced from S-adenosylhomocysteine (SAH). AI-2 can mediate interspecies communication and in some species facilitate the bacterial behavior regulation such as biofilm formation and virulence in both Gram-positive and Gram-negative bacteria. Here, we reported the overexpression, purification and crystallographic structure of LuxS from S. suis. Our results showed the catalytically active LuxS exists as a homodimer in solution. Inductively coupled plasma-mass spectrometry (ICP-MS) revealed the presence of Zn2+ in LuxS. Although the core structure shares the similar topology with LuxS proteins from other bacterial species, structural analyses and comparative amino acid sequence alignments identified two key amino acid differences in S. suis LuxS, Phe80 and His87, which are located near the substrate binding site. The results of site-directed mutagenesis and enzymology studies confirmed that these two residues affect the catalytic activity of the enzyme. These in vitro results were corroborated in vivo by expression of the LuxS variants in a S. suis ΔluxS strain. The single and two amino acid of LuxS variant decreased AI-2 production and biofilm formation significantly compared to that of the parent strain. Our findings highlight the importance of key LuxS residues that influence the AI-2 production and biofilm formation in S.suis. PMID:26484864

  6. Graphene analogues of layered metal selenides.

    PubMed

    Matte, H S S Ramakrishna; Plowman, Blake; Datta, Ranjan; Rao, C N R

    2011-10-28

    Graphene analogues of MoSe(2) and WSe(2) have been prepared by three different chemical methods and characterized by electron microscopy and other methods. Graphene analogues of these diselenides as well as of GaSe have also been obtained by liquid-phase exfoliation. Raman spectra of the graphene analogues show significant changes relative to those of the bulk samples. PMID:21776532

  7. FUNCTION GENERATOR FOR ANALOGUE COMPUTERS

    DOEpatents

    Skramstad, H.K.; Wright, J.H.; Taback, L.

    1961-12-12

    An improved analogue computer is designed which can be used to determine the final ground position of radioactive fallout particles in an atomic cloud. The computer determines the fallout pattern on the basis of known wind velocity and direction at various altitudes, and intensity of radioactivity in the mushroom cloud as a function of particle size and initial height in the cloud. The output is then displayed on a cathode-ray tube so that the average or total luminance of the tube screen at any point represents the intensity of radioactive fallout at the geographical location represented by that point. (AEC)

  8. Hydrocode modeling of the largest impact crater on Lutetia, a key to the inner structure of the asteroid

    NASA Astrophysics Data System (ADS)

    Oklay, N.; Vincent, J.-B.; Sierks, H.; Wünnemann, K.; Elbeshausen, D.

    2012-09-01

    The question whether the asteroid (21)Lutetia is differentiated or not is highly debated since ESA's spacecraft Rosetta flew by the asteroid on the 10th of July 2010. High resolution images from the OSIRIS camera system [1] and mass estimation from RSI experiment [2] lead to an average density of 3400 kg/m3, larger than what is normally expected for an asteroid (see [3] for typical densities). As we know the surface to be very porous (density 2400 kg/m3) for the first kilometers we expect much denser layers below, and some level of differentiation. So far no mineralogical evidence has been found to support or invalidate this hypothesis. The possibility has been investigated by many authors. The study of [4] showed that Lutetia is at the limit of differentiation. From what we know of this asteroid, only minor differences in its initial composition and location in the accretion disk would shift the balance towards a differentiated body or not. [5] investigated this problem by reconstructing the gravity field of Lutetia assuming different possible inner structures (no, partial, and full differentiation) and studied how the resulting gravity pattern on the surface would be compatible with the observed avalanches and other granular flows. They found that most of the visible flows require a gravity field that is more in agreement with a differentiated Lutetia, although this evidence is very tenuous. We tested the inner structure scenarios (Fig.1) proposed by [5] by performing impact simulations using iSALE hydrocode [6, 7, 8]. The same code is used by [9] to investigate the shape of two craters on Lutetia but without considering explicitly the influence of differentiation. We used our model to put some constraints on the density and layering of the first 5 to 10 km surface layer which can be responsible for the crater morphology [10]. We also discussed qualitatively the effects of different interior models on the shape (Fig.2) of the largest crater Massilia (˜55 km in diameter, ˜5 km in depth) observed on Lutetia. This current study is the continuation of the previously presented work. We compare now all morphological parameters of the craters obtained from our simulations with the real ones derived from the shape model produced by [11]. We look in details at the topographic profiles, diameter and depth, and the slopes distributions in the crater flanks, for several realistic interior models.

  9. Microbial community structure stability, a key parameter in monitoring the development of constructed wetland mesocosms during start-up.

    PubMed

    Ramond, Jean-Baptiste; Welz, Pamela J; Cowan, Don A; Burton, Stephanie G

    2012-01-01

    Constructed wetlands (CWs) are known to be effective for treating waste streams, and pilot-scale CWs are useful for assessing the impact of pollutants and their remediation. However, little is known with respect to the establishment of these mesocosm systems or the parameters which should be monitored in assessing system equilibration, i.e. when they present stabilised physical and biological patterns. The aim of this study was to evaluate the temporal aspects of CW equilibration as a basis for future studies of system response to amendment. Microbial biomass and hydraulic conductivity values were monitored and microbial community fingerprints were obtained using denaturing gradient gel electrophoresis (DGGE). This study showed that microbial community fingerprinting provides a valuable tool for assessing the time scales of equilibration, as it was the last parameter which stabilised during the equilibration period. Hydraulic conductivity was also an important parameter in determining the time scale for initiation of the equilibration process during the study. For a CW of the dimensions used (173 cm long/106 cm large/30 cm depth), community equilibration times demonstrated on the basis of similar microbial community structures were found to be on the order of 100 days. PMID:22027103

  10. Lithospheric flexure: the key to the structural evolution of large volcanic edifices on the terrestrial planets. (Invited)

    NASA Astrophysics Data System (ADS)

    McGovern, P. J.

    2009-12-01

    Large volcanic edifices, such as the majestic Hawaiian islands, the immense Olympus Mons on Mars, and the numerous, broad, but relatively short basaltic shields of Venus, constitute enormous excess masses at the surfaces of their respective planets. The lithosphere, the mechanically strong outer layer of a planet, responds to growing edifice loads on a regional scale by flexing, in a manner similar to a loaded beam in a building. The shape of lithospheric flexure and the resulting stress state exert critical influences on the structure of the evolving edifices, which in turn feed back into the flexural response. Flexural depression of the lithosphere forms topographic moats surrounding volcanoes; these depressions are partially to completely filled by landslide debris, volcaniclastic materials, and sediments (Hawaii, Marquesas, Reunion chains, Olympus Mons), or flat aprons of volcanic flows (Venusian volcanoes, Tharsis Montes on Mars). Flexure produces a "dipole" state of stress in the lithosphere beneath the edifice: extension at the bottom, and compression at the top. The orientation of the most compressive stress,?1, is therefore vertical in the lower lithosphere and horizontal in the upper lithosphere. The effects of this dipole were manifested physically in the Hawaiian earthquake pair of October 15, 2006 (see McGovern, GRL, 2007). By Anderson's criteria for intrusive magma ascent, the lower lithosphere stress state is conducive to magma ascent in vertical dikes, but in the upper lithosphere, ascending magma will get diverted into sub-horizontal sills. Finite element models of pressurization of magma chambers embedded in flexing lithospheres demonstrate this tendency: chambers in the upper (compressional) lithosphere fail near their middles under a stress state that favors sill formation (see Galgana et al., this volume). Thus, chambers are likely to assume oblate forms via lateral expansion, perhaps producing an extensive sill complex. Such complexes may express themselves at the surface by topographic slope breaks and annular zones of faulting (from both tectonic stresses and dikes emanating from the distal ends of the sills), as seen at Alba Patera on Mars and structures termed "coronae" on Venus. The state of compression in the upper lithosphere is generally transmitted into the edifice, unless the edifice is allowed to spread outwards along a basal decollement, as seen at the Hawaiian edifices and Olympus Mons. The absence of flexurally-induced compression at Hawaiian edifices accounts for the prominence of Hawaiian rift zones. Distinct Element models that account for movement-inhibiting effects of flexure show that the concave-up flank shape of Olympus Mons may be related to a flexure-spreading interaction (see McGovern and Morgan, Geology, 2009). Flexural stresses also affect magma ascent by influencing the pressure balance in dikes. Such considerations lead to a second criterion for magma ascent (Rubin, 1995): positive stress gradients in the lithosphere favor ascent. Models of flexure that account for both criteria predict a link between lithospheric thickness Te and edifice shape. Te modulates stress magnitudes and flexural wavelengths such that particular edifice shapes (conical, domical, and annular) correspond to particular ranges of Te (high, moderate, and low, respectively). Annular edifices may correspond to a subset of the coronae on Venus.

  11. Cysteine analogues potentiate glucose-induced insulin release in vitro

    SciTech Connect

    Ammon, H.P.; Hehl, K.H.; Enz, G.; Setiadi-Ranti, A.; Verspohl, E.J.

    1986-12-01

    In rat pancreatic islets, cysteine analogues, including glutathione, acetylcysteine, cysteamine, D-penicillamine, L-cysteine ethyl ester, and cysteine-potentiated glucose (11.1 mM) induced insulin secretion in a concentration-dependent manner. Their maximal effects were similar and occurred at approximately 0.05, 0.05, 0.1, 0.5, 1.0, 1.0 mM, respectively. At substimulatory glucose levels (2.8 mM), insulin release was not affected by these compounds. In contrast, thiol compounds, structurally different from cysteine and its analogues, such as mesna, tiopronin, meso-2,3-dimercaptosuccinic acid (DMSA), dimercaprol (BAL), beta-thio-D-glucose, as well as those cysteine analogues that lack a free-thiol group, including L-cystine, cystamine, D-penicillamine disulfide, S-carbocysteine, and S-carbamoyl-L-cysteine, did not enhance insulin release at stimulatory glucose levels (11.1 mM); cystine (5 mM) was inhibitory. These in vitro data indicate that among the thiols tested here, only cysteine and its analogues potentiate glucose-induced insulin secretion, whereas thiols that are structurally not related to cysteine do not. This suggests that a cysteine moiety in the molecule is necessary for the insulinotropic effect. For their synergistic action to glucose, the availability of a sulfhydryl group is also a prerequisite. The maximal synergistic action is similar for all cysteine analogues tested, whereas the potency of action is different, suggesting similarity in the mechanism of action but differences in the affinity to the secretory system.

  12. Conserved structure and varied expression reveal key roles of phosphoglucan phosphatase gene starch excess 4 in barley.

    PubMed

    Ma, Jian; Jiang, Qian-Tao; Wei, Long; Yang, Qiang; Zhang, Xiao-Wei; Peng, Yuan-Ying; Chen, Guo-Yue; Wei, Yu-Ming; Liu, Chunji; Zheng, You-Liang

    2014-12-01

    As one of the phosphoglucan phosphatases, starch excess 4 (SEX4) encoded by SEX4 gene has recently been intensively studied because of its vital role in the degradation of leaf starch. In this study, we isolated and chromosomally mapped barley SEX4, characterized its gene and protein structure, predicted the cis-elements of its promoter, and analysed its expression based on real-time quantitative PCR and publically available microarray data. The full length of barely SEX4 (HvSEX4) was 4,598 bp and it was mapped on the long arm of chromosome 4H (4HL). This gene contained 14 exons and 13 introns in all but two of the species analysed, Arabidopsis (13 exons and 12 introns) and Oryza brachyantha (12 exons and 11 introns). An exon-intron junction composed of intron 4 to intron 7 and exon 5 to exon 8 was highly conserved among the analysed species. SEX4 is characterized with conserved functional domains (dual specificity phosphatase domain and carbohydrate-binding module 48) and varied chloroplast transit peptide and C-terminal. Expression analyses indicated that: (1) SEX4 was mainly expressed in anthers of barley, young leaf and anthers of rice, and leaf of Arabidopsis; (2) it exhibited a diurnal pattern in barley, rice and Arabidopsis; (3) significant difference in the expression of SEX4 was not detected for either barley or rice under any of the investigated stresses; and (4) it was significantly down-regulated at middle stage and up-regulated at late stage under cold treatment, down-regulated at early stage under heat treatment, and up-regulated at late stage under salt treatment in Arabidopsis. The strong relationships detected in the current study between SEX4 and glucan, water dikinases (GWD) or phosphoglucan, water dikinases (PWD) were discussed. Collectively, our results provide insights into genetic manipulation of SEX4, especially in monocotyledon and uncovering the possible roles of SEX4 in plant development. PMID:25100144

  13. The Nisi Fault as a key structure for understanding the active deformation of the NW Peloponnese, Greece

    NASA Astrophysics Data System (ADS)

    Zygouri, V.; Koukouvelas, I. K.; Kokkalas, S.; Xypolias, P.; Papadopoulos, G. A.

    2015-05-01

    The previously unknown Nisi Fault in NW Peloponnese was ruptured during the 2008 Movri Mountain earthquake attaining a maximum offset of 25 cm. The fault is interpreted as a branch of a flower structure above a blind strike-slip fault. We investigate the Nisi Fault seismotectonic evolution using morphotectonic analysis in order to determine whether the landscape is affected by tectonic forcing and paleoseismology to determine earthquake recurrence interval and fault slip rates. We applied several geomorphic indices, such as the asymmetry factor (AF), the stream length-gradient index (SL), the valley floor width to valley height ratio (Vf), the mountain-front sinuosity (Smf), the drainage basin shape (Bs) and the hypsometric curve (Hc), in four large drainage basins of the study area. The results show that fault-related vertical motions and the associated tilting influenced the drainage geometry and the landscape development. Values of stream-gradient indices (SL) are relatively high close to the fault trace. Mountain-front sinuosity (Smf) mean values along the fault zones range from 1.12 to 1.23. Valley floor width to valley height ratios (Vf) mean values along the studied fault range between 0.21 and 2.50. Drainage basin shape (BS) mean values along the fault range from 1.04 to 3.72. Lateral fault growth was likely achieved by propagation primarily towards north-northwestward. The paleoseismic history of the fault, investigated by a trench and 14C dating of seven samples, indicates two morphogenic earthquakes in the last 1 kyr. Therefore, we suggest that the Nisi Fault displays a slip rate on the order of 1 mm/yr and a recurrence interval ranging between 300 and 600 years. From a seismotectonic point of view, the fault is classified as high activity rate, with abundant but discontinuous geomorphic evidence of its activity. Other similar faults affecting the western Peloponnese can be envisaged with a similar procedure. Additionally, the seismic history and surface expression of the Nisi Fault, resembles other faults of similar length in Greece and Italy. Particularly, a crucial issue in terms of seismic risk management is that neotectonic analysis has to be envisaged carefully on short in length faults, since these faults can be possibly related to strong earthquakes.

  14. Trehalose Analogues: Latest Insights in Properties and Biocatalytic Production

    PubMed Central

    Walmagh, Maarten; Zhao, Renfei; Desmet, Tom

    2015-01-01

    Trehalose (α-d-glucopyranosyl α-d-glucopyranoside) is a non-reducing sugar with unique stabilizing properties due to its symmetrical, low energy structure consisting of two 1,1-anomerically bound glucose moieties. Many applications of this beneficial sugar have been reported in the novel food (nutricals), medical, pharmaceutical and cosmetic industries. Trehalose analogues, like lactotrehalose (α-d-glucopyranosyl α-d-galactopyranoside) or galactotrehalose (α-d-galactopyranosyl α-d-galactopyranoside), offer similar benefits as trehalose, but show additional features such as prebiotic or low-calorie sweetener due to their resistance against hydrolysis during digestion. Unfortunately, large-scale chemical production processes for trehalose analogues are not readily available at the moment due to the lack of efficient synthesis methods. Most of the procedures reported in literature suffer from low yields, elevated costs and are far from environmentally friendly. “Greener” alternatives found in the biocatalysis field, including galactosidases, trehalose phosphorylases and TreT-type trehalose synthases are suggested as primary candidates for trehalose analogue production instead. Significant progress has been made in the last decade to turn these into highly efficient biocatalysts and to broaden the variety of useful donor and acceptor sugars. In this review, we aim to provide an overview of the latest insights and future perspectives in trehalose analogue chemistry, applications and production pathways with emphasis on biocatalysis. PMID:26084050

  15. The Valles natural analogue project

    SciTech Connect

    Stockman, H.; Krumhansl, J.; Ho, C.; McConnell, V.

    1994-12-01

    The contact between an obsidian flow and a steep-walled tuff canyon was examined as an analogue for a highlevel waste repository. The analogue site is located in the Valles Caldera in New Mexico, where a massive obsidian flow filled a paleocanyon in the Battleship Rock tuff. The obsidian flow provided a heat source, analogous to waste panels or an igneous intrusion in a repository, and caused evaporation and migration of water. The tuff and obsidian samples were analyzed for major and trace elements and mineralogy by INAA, XRF, X-ray diffraction; and scanning electron microscopy and electron microprobe. Samples were also analyzed for D/H and {sup 39}Ar/{sup 4O} isotopic composition. Overall,the effects of the heating event seem to have been slight and limited to the tuff nearest the contact. There is some evidence of devitrification and migration of volatiles in the tuff within 10 meters of the contact, but variations in major and trace element chemistry are small and difficult to distinguish from the natural (pre-heating) variability of the rocks.

  16. Developing Master Keys to Brain Pathology, Cancer and Aging from the Structural Biology of Proteins Controlling Reactive Oxygen Species and DNA Repair

    PubMed Central

    Perry, J. Jefferson P.; Fan, Li; Tainer, John A.

    2007-01-01

    This review is focused on proteins with key roles in pathways controlling either reactive oxygen species or DNA damage responses, both of which are essential for preserving the nervous system. An imbalance of reactive oxygen species or inappropriate DNA damage response likely causes mutational or cytotoxic outcomes, which may lead to cancer and/or aging phenotypes. Moreover, individuals with hereditary disorders in proteins of these cellular pathways have significant neurological abnormalities. Mutations in a superoxide dismutase, which removes oxygen free radicals, may cause the neurodegenerative disease amyotrophic lateral sclerosis. Additionally, DNA repair disorders that affect the brain to varying extents include ataxia-telangiectasia-like disorder, Cockayne syndrome or Werner syndrome. Here, we highlight recent advances gained through structural biochemistry studies on enzymes linked to these disorders and other related enzymes acting within the same cellular pathways. We describe the current understanding of how these vital proteins coordinate chemical steps and integrate cellular signaling and response events. Significantly, these structural studies may provide a set of master keys to developing a unified understanding of the survival mechanisms utilized after insults by reactive oxygen species and genotoxic agents, and also provide a basis for developing an informed intervention in brain tumor and neurodegenerative disease progression. PMID:17174478

  17. A Combination of Structural and Empirical Analyses Delineates the Key Contacts Mediating Stability and Affinity Increases in an Optimized Biotherapeutic Single-chain Fv (scFv).

    PubMed

    Tu, Chao; Terraube, Virginie; Tam, Amy Sze Pui; Stochaj, Wayne; Fennell, Brian J; Lin, Laura; Stahl, Mark; LaVallie, Edward R; Somers, Will; Finlay, William J J; Mosyak, Lydia; Bard, Joel; Cunningham, Orla

    2016-01-15

    Fully-human single-chain Fv (scFv) proteins are key potential building blocks of bispecific therapeutic antibodies, but they often suffer from manufacturability and clinical development limitations such as instability and aggregation. The causes of these scFv instability problems, in proteins that should be theoretically stable, remains poorly understood. To inform the future development of such molecules, we carried out a comprehensive structural analysis of the highly stabilized anti-CXCL13 scFv E10. E10 was derived from the parental 3B4 using complementarity-determining region (CDR)-restricted mutagenesis and tailored selection and screening strategies, and carries four mutations in VL-CDR3. High-resolution crystal structures of parental 3B4 and optimized E10 scFvs were solved in the presence and absence of human CXCL13. In parallel, a series of scFv mutants was generated to interrogate the individual contribution of each of the four mutations to stability and affinity improvements. In combination, these analyses demonstrated that the optimization of E10 was primarily mediated by removing clashes between both the VL and the VH, and between the VL and CXCL13. Importantly, a single, germline-encoded VL-CDR3 residue mediated the key difference between the stable and unstable forms of the scFv. This work demonstrates that, aside from being the critical mediators of specificity and affinity, CDRs may also be the primary drivers of biotherapeutic developability. PMID:26515064

  18. Ring closing metathesis reactions of α-methylene-β-lactams: application to the synthesis of a simplified phyllostictine analogue with herbicidal activity.

    PubMed

    Coe, Samuel; Pereira, Nicole; Geden, Joanna V; Clarkson, Guy J; Fox, David J; Napier, Richard M; Neve, Paul; Shipman, Michael

    2015-07-28

    Ring closing metathesis (RCM) reactions of α-methylene-β-lactams are used to construct strained 11- and 12-membered macrocycles that mimic key structural elements of phyllostictine A. The highest yield and stereoselectivity was achieved making 12-membered macrocycle Z-19 with use of a p-methoxyphenyl group on the lactam nitrogen. Interestingly, substrate concentration had an important influence on the stereochemical course of the reaction. A simplified analogue produced using this approach displays phytotoxic activity against Chlamydomonas reinhardtii suggesting that the α-methylene-β-lactam subunit is responsible, at least in part, for the herbicidal activity of phyllostictine A. PMID:26081012

  19. Heparinase I-specific disaccharide unit of heparin is a key structure but insufficient for exerting anti-prion activity in prion-infected cells.

    PubMed

    Teruya, Kenta; Wakao, Masahiro; Sato, Masaki; Hamanaka, Taichi; Nishizawa, Keiko; Funayama, Yukino; Sakasegawa, Yuji; Suda, Yasuo; Doh-ura, Katsumi

    2015-05-15

    Glycosaminoglycans reportedly play important roles in prion formation, but because of their structural complexity, the chemical structures affecting prion formation have not been fully evaluated. Here, we compared two types of low molecular weight heparins and found that heparinase I-sensitive structures influenced anti-prion activity in prion-infected cells. Surface plasmon resonance analyses showed significant binding of a representative heparinase I substrate disaccharide unit, GlcNS6S-IdoA2S, to recombinant prion protein (PrP) fragments, such as full-length PrP23-231 and N-terminal domain PrP23-89, but not to PrP89-230. This binding was competitively inhibited by heparin or pentosan polysulfate, but not by Cu(2+). These PrP binding profiles of the disaccharide unit are consistent with those previously reported for heparin. However, synthetic compounds comprising disaccharide unit alone or its multimers exhibited no anti-prion activity in prion-infected cells. Consequently, the findings suggest that the heparin disaccharide unit that binds to the N-terminal region of PrP is a key structure, but it is insufficient for exerting anti-prion activity. PMID:25839661

  20. Fibrinolytic enhancement with a prostaglandin analogue iloprost.

    PubMed

    Berridge, D C; Lonsdale, R; Jallihal, S; Westby, J C; Hopkinson, B R; Makin, G S

    1992-01-01

    Earlier workers have suggested a possible fibrinolytic effect using prostaglandin or prostaglandin analogues. Despite using maximum tolerated doses of the prostaglandin analogue Iloprost, we have been unable to demonstrate any significant effect on fibrinolysis in patients with stage IV peripheral vascular disease (Fontaine classification). PMID:1378686

  1. CO2 Capture with Enzyme Synthetic Analogue

    SciTech Connect

    Harry Cordatos

    2010-11-08

    Overview of an ongoing, 2 year research project partially funded by APRA-E to create a novel, synthetic analogue of carbonic anhydrase and incorporate it into a membrane for removal of CO2 from flue gas in coal power plants. Mechanism background, preliminary feasibility study results, molecular modeling of analogue-CO2 interaction, and program timeline are provided.

  2. The fluorite related modulated structures of the Gd{sub 2}(Zr{sub 2-x}Ce{sub x})O{sub 7} solid solution: An analogue for Pu disposition

    SciTech Connect

    Reid, D.P.; Stennett, M.C.; Hyatt, N.C.

    2012-07-15

    We present an overview of the Gd{sub 2}(Zr{sub 2-x}Ce{sub x})O{sub 7} phase diagram, of interest as a model system for ceramic disposition of Pu (with Ce as a Pu surrogate). The fluorite related structures of this solid solution were determined using a modulated structure approach, to identify the underlying cation and vacancy ordering mechanisms from analysis of key satellite reflections in selected zone axis electron diffraction patterns. This revealed the formation of four structure types: pyrochlore for x<0.25, defect fluorite for 0.5structure for x=1.00, and a C-type structure for x>1.50. X-ray absorption (XAS) and electron energy loss (EELS) spectra confirmed the presence of Ce{sup 4+} as the dominant species in compositions across this system, remaining analogous to Pu{sup 4+}. - Graphical abstract: Electron diffraction reveals the cation vacancy ordering mechanisms leading to fluorite related superstructures in the Gd{sub 2}(Zr{sub 2-x}Ce{sub x})O{sub 7} solid solution. Highlights: Black-Right-Pointing-Pointer The fluorite related solid solution Gd{sub 2}(Zr{sub 1-x}Ce{sub x})O{sub 7} was prepared by solid state synthesis. Black-Right-Pointing-Pointer Ce L{sub 3} edge XAS and Ce M{sub 4,5} EELS measurements show Ce substitutes as Ce{sup 4+}. Black-Right-Pointing-Pointer Cation and oxygen vacancy ordering results in four fluorite related structures.

  3. Synthesis and crystal structure of the synthetic analogue of mineral minyulite K[Al 2F(H 2O) 4(PO 4) 2]. Structural correlations with AlPO 4-CJ2

    NASA Astrophysics Data System (ADS)

    Dumas, Eddy; Taulelle, Francis; Frey, Grard

    2001-07-01

    The validation of our program of simulation for the prediction of unknown dehydrated structures needs accurate information of the mother hydrated structure at the starting point. This paper describes the synthesis (95C, 10 days, autogenous pressure) and the structure (space group Pba2; a=9.3477(2), b=9.7571(1), c=5.5280(1) , V=503.91 3, Z=2) of the synthetic homologue of two-dimensional mineral minyulite K[Al 2F(H 2O) 4(PO 4) 2]. The 27Al, 19F and 31P solid state NMR characteristics are reported, as well as the thermal decomposition which confirms the prediction of a collapse of the structure. Finally, structural correlations between minyulite and AlPO 4-CJ2 are given.

  4. Synthesis and neuroprotective activity of dictyoquinazol A and analogues.

    PubMed

    Lizarme, Yuvixza; Wangsahardja, Jonatan; Marcolin, Gabriella M; Morris, Jonathan C; Jones, Nicole M; Hunter, Luke

    2016-04-01

    A flexible and efficient synthesis of the neuroprotective alkaloid, dictyoquinazol A, is reported. Several structural analogues of the target molecule were produced, and the neuroprotective activity of this series of compounds was investigated using three different cell-based models of stroke. Several of the new compounds were found to have superior activity compared to the natural product. This work has established a new molecular scaffold that holds promise for a novel pharmaceutical treatment for stroke. PMID:26906473

  5. Marine Pyrrolocarbazoles and Analogues: Synthesis and Kinase Inhibition

    PubMed Central

    Deslandes, Sébastien; Chassaing, Stefan; Delfourne, Evelyne

    2009-01-01

    Granulatimide and isogranulatimide are alkaloids obtained from marine sources which have been shown to inhibit cell-cycle G2-checkpoint, targeting more particularly checkpoint 1 kinase (Chk1). At a structural level, they possess a characteristic pyrrolocarbazole framework also shared by the well-known rebeccamycin and staurosporine microbial metabolites which have been described to inhibit topoisomerase I and diverse kinases, respectively. This review reports precisely on the synthesis and kinase inhibitory activities of pyrrolocarbazole-based analogues of granulatimide. PMID:20098609

  6. Transition States and transition state analogue interactions with enzymes.

    PubMed

    Schramm, Vern L

    2015-04-21

    Enzymatic transition states have lifetimes of a few femtoseconds (fs). Computational analysis of enzyme motions leading to transition state formation suggests that local catalytic site motions on the fs time scale provide the mechanism to locate transition states. An experimental test of protein fs motion and its relation to transition state formation can be provided by isotopically heavy proteins. Heavy enzymes have predictable mass-altered bond vibration states without altered electrostatic properties, according to the Born-Oppenheimer approximation. On-enzyme chemistry is slowed in most heavy proteins, consistent with altered protein bond frequencies slowing the search for the transition state. In other heavy enzymes, structural changes involved in reactant binding and release are also influenced. Slow protein motions associated with substrate binding and catalytic site preorganization are essential to allow the subsequent fs motions to locate the transition state and to facilitate the efficient release of products. In the catalytically competent geometry, local groups move in stochastic atomic motion on the fs time scale, within transition state-accessible conformations created by slower protein motions. The fs time scale for the transition state motions does not permit thermodynamic equilibrium between the transition state and stable enzyme states. Isotopically heavy enzymes provide a diagnostic tool for fast coupled protein motions to transition state formation and mass-dependent conformational changes. The binding of transition state analogue inhibitors is the opposite in catalytic time scale to formation of the transition state but is related by similar geometries of the enzyme-transition state and enzyme-inhibitor interactions. While enzymatic transition states have lifetimes as short as 10(-15) s, transition state analogues can bind tightly to enzymes with release rates greater than 10(3) s. Tight-binding transition state analogues stabilize the rare but evolved enzymatic geometry to form the transition state. Evolution to efficient catalysis optimized this geometry and its stabilization by a transition state mimic results in tight binding. Release rates of transition state analogues are orders of magnitude slower than product release in normal catalytic function. During catalysis, product release is facilitated by altered chemistry. Compared to the weak associations found in Michaelis complexes, transition state analogues involve strong interactions related to those in the transition state. Optimum binding of transition state analogues occurs when the complex retains the system motions intrinsic to transition state formation. Conserved dynamic motion retains the entropic components of inhibitor complexes, improving the thermodynamics of analogue binding. PMID:25848811

  7. Contact zones and hydrothermal systems as analogues to repository conditions

    SciTech Connect

    Wollenberg, H.A.; Flexser, S.

    1984-10-01

    Radioactive waste isolation efforts in the US are currently focused on examining basalt, tuff, salt, and crystalline rock as candidate rock types to encompass waste repositories. As analogues to near-field conditions, the distributions of radio- and trace-elements have been examined across contacts between these rocks and dikes and stocks that have intruded them. The intensive study of the Stripa quartz monzonite has also offered the opportunity to observe the distribution of uranium and its daughters in groundwater and its relationship to U associated with fracture-filling and alteration minerals. Investigations of intrusive contact zones to date have included (1) a tertiary stock into Precambrian gneiss, (2) a stock into ash flow tuff, (3) a rhyodacite dike into Columbia River basalt, and (4) a kimberlite dike into salt. With respect to temperature and pressure, these contact zones may be considered "worst-case scenario" analogues. Results indicate that there has been no appreciable migration of radioelements from the more radioactive intrusives into the less radioactive country rocks, either in response to the intrusions or in the fracture-controlled hydrological systems that developed following emplacement. In many cases, the radioelements are locked up in accessory minerals, suggesting that artificial analogues to these would make ideal waste forms. Emphasis should now shift to examination of active hydrothermal systems, studying the distribution of key elements in water, fractures, and alteration minerals under pressure and temperature conditions most similar to those expected in the near-field environment of a repository. 14 refs.

  8. Fully analogue photonic reservoir computer.

    PubMed

    Duport, François; Smerieri, Anteo; Akrout, Akram; Haelterman, Marc; Massar, Serge

    2016-01-01

    Introduced a decade ago, reservoir computing is an efficient approach for signal processing. State of the art capabilities have already been demonstrated with both computer simulations and physical implementations. If photonic reservoir computing appears to be promising a solution for ultrafast nontrivial computing, all the implementations presented up to now require digital pre or post processing, which prevents them from exploiting their full potential, in particular in terms of processing speed. We address here the possibility to get rid simultaneously of both digital pre and post processing. The standalone fully analogue reservoir computer resulting from our endeavour is compared to previous experiments and only exhibits rather limited degradation of performances. Our experiment constitutes a proof of concept for standalone physical reservoir computers. PMID:26935166

  9. Fully analogue photonic reservoir computer

    PubMed Central

    Duport, François; Smerieri, Anteo; Akrout, Akram; Haelterman, Marc; Massar, Serge

    2016-01-01

    Introduced a decade ago, reservoir computing is an efficient approach for signal processing. State of the art capabilities have already been demonstrated with both computer simulations and physical implementations. If photonic reservoir computing appears to be promising a solution for ultrafast nontrivial computing, all the implementations presented up to now require digital pre or post processing, which prevents them from exploiting their full potential, in particular in terms of processing speed. We address here the possibility to get rid simultaneously of both digital pre and post processing. The standalone fully analogue reservoir computer resulting from our endeavour is compared to previous experiments and only exhibits rather limited degradation of performances. Our experiment constitutes a proof of concept for standalone physical reservoir computers. PMID:26935166

  10. Fully analogue photonic reservoir computer

    NASA Astrophysics Data System (ADS)

    Duport, François; Smerieri, Anteo; Akrout, Akram; Haelterman, Marc; Massar, Serge

    2016-03-01

    Introduced a decade ago, reservoir computing is an efficient approach for signal processing. State of the art capabilities have already been demonstrated with both computer simulations and physical implementations. If photonic reservoir computing appears to be promising a solution for ultrafast nontrivial computing, all the implementations presented up to now require digital pre or post processing, which prevents them from exploiting their full potential, in particular in terms of processing speed. We address here the possibility to get rid simultaneously of both digital pre and post processing. The standalone fully analogue reservoir computer resulting from our endeavour is compared to previous experiments and only exhibits rather limited degradation of performances. Our experiment constitutes a proof of concept for standalone physical reservoir computers.

  11. Syntheses and Biological Evaluation of Costunolide, Parthenolide, and Their Fluorinated Analogues.

    PubMed

    Yang, Zhong-Jin; Ge, Wei-Zhi; Li, Qiu-Ying; Lu, Yaxin; Gong, Jian-Miao; Kuang, Bei-Jia; Xi, Xiaonan; Wu, Haiting; Zhang, Quan; Chen, Yue

    2015-09-10

    Inspired by the biosynthesis of sesquiterpene lactones (SLs), herein we report the asymmetric total synthesis of the germacrane ring (24). The synthetic strategy features a selective aldol reaction between β,γ-unsaturated chiral sulfonylamide 15a and aldehyde 13, as well as the intramolecular α-alkylation of sulfone 21 to construct a 10-membered carbocylic ring. The key intermediate 24 can be used to prepare the natural products costunolide and parthenolide (PTL), which are the key precursors for transformation into other SLs. Furthermore, the described synthetic sequences are amenable to the total synthesis of SL analogues, such as trifluoromethylated analogues 32 and 45. Analogues 32 and 45 maintained high activities against a series of cancer cell lines compared to their parent PTL and costunolide, respectively. In addition, 32 showed enhanced tolerance to acidic media compared with PTL. To our surprise, PTL and 32 showed comparable half-lives in rat plasma and in the presence of human liver microsomes. PMID:26226279

  12. Cryo-EM reveals the conformation of a substrate analogue in the human 20S proteasome core

    PubMed Central

    da Fonseca, Paula C.A.; Morris, Edward P.

    2015-01-01

    The proteasome is a highly regulated protease complex fundamental for cell homeostasis and controlled cell cycle progression. It functions by removing a wide range of specifically tagged proteins, including key cellular regulators. Here we present the structure of the human 20S proteasome core bound to a substrate analogue inhibitor molecule, determined by electron cryo-microscopy (cryo-EM) and single-particle analysis at a resolution of around 3.5?. Our map allows the building of protein coordinates as well as defining the location and conformation of the inhibitor at the different active sites. These results open new prospects to tackle the proteasome functional mechanisms. Moreover, they also further demonstrate that cryo-EM is emerging as a realistic approach for general structural studies of proteinligand interactions. PMID:26133119

  13. Cryo-EM reveals the conformation of a substrate analogue in the human 20S proteasome core

    NASA Astrophysics Data System (ADS)

    da Fonseca, Paula C. A.; Morris, Edward P.

    2015-07-01

    The proteasome is a highly regulated protease complex fundamental for cell homeostasis and controlled cell cycle progression. It functions by removing a wide range of specifically tagged proteins, including key cellular regulators. Here we present the structure of the human 20S proteasome core bound to a substrate analogue inhibitor molecule, determined by electron cryo-microscopy (cryo-EM) and single-particle analysis at a resolution of around 3.5 Å. Our map allows the building of protein coordinates as well as defining the location and conformation of the inhibitor at the different active sites. These results open new prospects to tackle the proteasome functional mechanisms. Moreover, they also further demonstrate that cryo-EM is emerging as a realistic approach for general structural studies of protein-ligand interactions.

  14. Identification of key structural elements for neuronal calcium sensor-1 function in the regulation of the temperature-dependency of locomotion in C. elegans

    PubMed Central

    2013-01-01

    Background Intracellular Ca2+ regulates many aspects of neuronal function through Ca2+ binding to EF hand-containing Ca2+ sensors that in turn bind target proteins to regulate their function. Amongst the sensors are the neuronal calcium sensor (NCS) family of proteins that are involved in multiple neuronal signalling pathways. Each NCS protein has specific and overlapping targets and physiological functions and specificity is likely to be determined by structural features within the proteins. Common to the NCS proteins is the exposure of a hydrophobic groove, allowing target binding in the Ca2+-loaded form. Structural analysis of NCS protein complexes with target peptides has indicated common and distinct aspects of target protein interaction. Two key differences between NCS proteins are the size of the hydrophobic groove that is exposed for interaction and the role of their non-conserved C-terminal tails. Results We characterised the role of NCS-1 in a temperature-dependent locomotion assay in C. elegans and identified a distinct phenotype in the ncs-1 null in which the worms do not show reduced locomotion at actually elevated temperature. Using rescue of this phenotype we showed that NCS-1 functions in AIY neurons. Structure/function analysis introducing single or double mutations within the hydrophobic groove based on information from characterised target complexes established that both N- and C-terminal pockets of the groove are functionally important and that deletion of the C-terminal tail of NCS-1 did not impair its ability to rescue. Conclusions The current work has allowed physiological assessment of suggestions from structural studies on the key structural features that underlie the interaction of NCS-1 with its target proteins. The results are consistent with the notion that full length of the hydrophobic groove is required for the regulatory interactions underlying NCS-1 function whereas the C-terminal tail of NCS-1 is not essential. This has allowed discrimination between two potential modes of interaction of NCS-1 with its targets. PMID:23981466

  15. Towards bottom-up nanopatterning of Prussian blue analogues

    PubMed Central

    Trannoy, Virgile; Faustini, Marco; Grosso, David; Mazerat, Sandra; Brisset, Franois; Dazzi, Alexandre

    2014-01-01

    Summary Ordered nanoperforated TiO2 monolayers fabricated through solgel chemistry were used to grow isolated particles of Prussian blue analogues (PBA). The elaboration of the TiO2/CoFe PBA nanocomposites involves five steps. The samples were characterized by scanning electron microscopy (SEM), atomic force microscopy (AFM), infrared spectroscopy and X-ray photoelectron spectroscopy (XPS) all along the synthesis process. Selected physico-chemical parameters have been varied in order to determine the key steps of the synthesis process and to optimize it. This study is an important step towards the full control of the fabrication process. PMID:25383305

  16. Astrobiology Field Research in Moon/Mars Analogue Environments: Preface

    NASA Technical Reports Server (NTRS)

    Foing, B. H.; Stoker, C.; Ehrenfreund, P.

    2011-01-01

    Extreme environments on Earth often provide similar terrain conditions to landing/operation sites on Moon and Mars. Several field campaigns (EuroGeoMars2009 and DOMMEX/ILEWG EuroMoonMars from November 2009 to March 2010) were conducted at the Mars Desert Research Station (MDRS) in Utah. Some of the key astrobiology results are presented in this special issue on Astrobiology field research in Moon/Mars analogue environments relevant to investigate the link between geology, minerals, organics and biota. Preliminary results from a multidisciplinary field campaign at Rio Tinto in Spain are presented.

  17. Synthesis and bioactivity of ?-substituted fosmidomycin analogues targeting 1-deoxy-D-xylulose-5-phosphate reductoisomerase.

    PubMed

    Chofor, Ren; Sooriyaarachchi, Sanjeewani; Risseeuw, Martijn D P; Bergfors, Terese; Pouyez, Jenny; Johny, Chinchu; Haymond, Amanda; Everaert, Annelien; Dowd, Cynthia S; Maes, Louis; Coenye, Tom; Alex, Alexander; Couch, Robin D; Jones, T Alwyn; Wouters, Johan; Mowbray, Sherry L; Van Calenbergh, Serge

    2015-04-01

    Blocking the 2-C-methyl-d-erythrithol-4-phosphate (MEP) pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodium or Mycobacterium spp. growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Here we introduced aryl or aralkyl substituents at the ?-position of the hydroxamate analogue of 2. While direct addition of a ?-aryl moiety resulted in poor inhibition, longer linkers between the carbon backbone and the phenyl ring were generally associated with better binding to the enzymes. X-ray structures of the parasite Dxr-inhibitor complexes show that the "longer" compounds generate a substantially different flap structure, in which a key tryptophan residue is displaced, and the aromatic group of the ligand lies between the tryptophan and the hydroxamate's methyl group. Although the most promising new Dxr inhibitors lack activity against Escherichia coli and Mycobacterium smegmatis, they proved to be highly potent inhibitors of Plasmodium falciparum in vitro growth. PMID:25781377

  18. Quinlobelane: A water-soluble lobelane analogue and inhibitor of VMAT2

    PubMed Central

    Vartak, Ashish P.; Deaciuc, A. Gabriela; Dwoskin, Linda P.; Crooks, Peter A.

    2013-01-01

    Replacing the phenyl groups in the structure of the VMAT2 inhibitor, lobelane with either pyridyl, quinolyl or indolyl groups affords novel analogues with improved water solubility. The synthetic methodologies reported herein also underscore the paucity of hydrogenation methods that offer selectivity in the synthesis of the different classes of heteroaromatic lobelane analogues. The quinolyl group was the only replacement for the phenyl group in lobelane that retained VMAT2 inhibition. PMID:20494575

  19. Variation effect on the insecticide activity of DDT analogues. A chemometric approach

    NASA Astrophysics Data System (ADS)

    Itoh, S.; Nagashima, U.

    2002-08-01

    We investigated a variation effect on the insecticide activity of DDT analogues by using the first principles electronic structure calculations and the neural network analysis. It has been found that the charge distribution at the specific atomic sites in the DDT molecule is related to their toxicity. This approach can contribute to designing a new insecticide and a new harmlessness process of the DDT analogues.

  20. Structural Studies of Cinnamoyl-CoA Reductase and Cinnamyl-Alcohol Dehydrogenase, Key Enzymes of Monolignol Biosynthesis[C][W

    PubMed Central

    Pan, Haiyun; Zhou, Rui; Louie, Gordon V.; Mühlemann, Joëlle K.; Bomati, Erin K.; Bowman, Marianne E.; Dudareva, Natalia; Dixon, Richard A.; Noel, Joseph P.; Wang, Xiaoqiang

    2014-01-01

    The enzymes cinnamoyl-CoA reductase (CCR) and cinnamyl alcohol dehydrogenase (CAD) catalyze the two key reduction reactions in the conversion of cinnamic acid derivatives into monolignol building blocks for lignin polymers in plant cell walls. Here, we describe detailed functional and structural analyses of CCRs from Medicago truncatula and Petunia hybrida and of an atypical CAD (CAD2) from M. truncatula. These enzymes are closely related members of the short-chain dehydrogenase/reductase (SDR) superfamily. Our structural studies support a reaction mechanism involving a canonical SDR catalytic triad in both CCR and CAD2 and an important role for an auxiliary cysteine unique to CCR. Site-directed mutants of CAD2 (Phe226Ala and Tyr136Phe) that enlarge the phenolic binding site result in a 4- to 10-fold increase in activity with sinapaldehyde, which in comparison to the smaller coumaraldehyde and coniferaldehyde substrates is disfavored by wild-type CAD2. This finding demonstrates the potential exploitation of rationally engineered forms of CCR and CAD2 for the targeted modification of monolignol composition in transgenic plants. Thermal denaturation measurements and structural comparisons of various liganded and unliganded forms of CCR and CAD2 highlight substantial conformational flexibility of these SDR enzymes, which plays an important role in the establishment of catalytically productive complexes of the enzymes with their NADPH and phenolic substrates. PMID:25217505

  1. Synthesis, biological activity, and conformational study of N-methylated allatostatin analogues inhibiting juvenile hormone biosynthesis.

    PubMed

    Xie, Yong; Zhang, Li; Zhang, Chuanliang; Wu, Xiaoqing; Deng, Xile; Yang, Xinling; Tobe, Stephen S

    2015-03-25

    An allatostatin (AST) neuropeptide mimic (H17) is a potential insect growth regulator, which inhibits the production of juvenile hormone (JH) by the corpora allata. To determine the effect of conformation of novel AST analogues and their ability to inhibit JH biosynthesis, eight insect AST analogues were synthesized using H17 as the lead compound by N-methylation scanning, which is a common strategy for improving the biological properties of peptides. A bioassay using JH production by corpora allata of the cockroach Diploptera punctata in