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Total Synthesis and Evaluation of Phostriecin and Key Structural Analogues  

PubMed Central

Full details of the total synthesis of phostriecin (2), the assignment of its relative and absolute stereochemistry, and the resultant structural reassignment of the natural product previously represented as sultriecin (1), a phosphate versus sulfate monoester, are detailed. Studies with authentic material confirmed that phostriecin, but not sultriecin, is an effective and selective inhibitor of protein phosphatase 2A (PP2A) defining a mechanism of action responsible for its antitumor activity. The extension of the studies to the synthesis and evaluation of a series of key synthetic analogues is disclosed that highlights the importance of the natural product phosphate monoester (vs sulfate or free alcohol, inactive and >250-fold), the ?,?-unsaturated lactone (12-fold), and the hydrophobic Z,Z,E-triene tail (C12–C22, ca. 200-fold) including the unique importance of its unsaturation (50-fold, and no longer PP2A selective).

Burke, Christopher P.; Swingle, Mark R.; Honkanen, Richard E.; Boger, Dale L.



Key residues in octyl-tridecaptin A1 analogues linked to stable secondary structures in the membrane.  


Tridecaptin A1 is a linear antimicrobial lipopeptide comprised of 13 amino acids, including three diaminobutyric acid (Dab) residues. It displays potent activity against Gram-negative bacteria, including multidrug-resistant strains. Using solid-phase peptide synthesis, we performed an alanine scan of a fully active analogue, octyl-tridecaptin A1 , to determine key residues responsible for activity. The synthetic analogues were tested against ten organisms, both Gram-positive and Gram-negative bacteria. Modification of D-Dab8 abolished activity, and marked decreases were observed with substitution of D-allo-Ile12 and D-Trp5. Circular dichroism showed that octyl-tridecaptin A1 adopts a secondary structure in the presence of model phospholipid membranes, which was weakened by D-Dab8-D-Ala, D-allo-Ile12-D-Ala, and D-Trp5-D-Ala substitutions. The antimicrobial activity of the analogues is directly correlated to their ability to adopt a stable secondary structure in a membrane environment. PMID:24816483

Cochrane, Stephen A; Findlay, Brandon; Vederas, John C; Ratemi, Elaref S



Structural characterization of native autoinducing peptides and abiotic analogues reveals key features essential for activation and inhibition of an AgrC quorum sensing receptor in Staphylococcus aureus.  


Staphylococcus aureus is a major human pathogen that uses quorum sensing (QS) to control virulence. Its QS system is regulated by macrocyclic peptide signals (or autoinducing peptides (AIPs)) and their cognate transmembrane receptors (AgrCs). Four different specificity groups of S. aureus have been identified to date (groups I-IV), each of which uses a different AIP:AgrC pair. Non-native ligands capable of intercepting AIP:AgrC binding, and thereby QS, in S. aureus have attracted considerable interest as chemical tools to study QS pathways and as possible antivirulence strategies for the treatment of infection. We recently reported a set of analogues of the group-III AIP that are capable of strongly modulating the activity of all four AgrC receptors. Critical to the further development of such ligands is a detailed understanding of the structural features of both native AIPs and non-native analogues that are essential for activity. Herein, we report the first three-dimensional structural analysis of the known native AIP signals (AIPs-I-IV) and several AIP-III analogues with varied biological activities using NMR spectroscopy. Integration of these NMR studies with the known agonism and antagonism profiles of these peptides in AgrC-III revealed two key structural elements that control AIP-III (and non-native peptide) activity: (1) a tri-residue hydrophobic "knob" essential for both activation and inhibition and (2) a fourth anchor point on the exocyclic tail needed for receptor activation. These results provide strong structural support for a mechanism of AIP-mediated AgrC activation and inhibition in S. aureus , and should facilitate the design of new AgrC ligands with enhanced activities (as agonists or antagonists) and simplified chemical structures. PMID:24219181

Tal-Gan, Yftah; Ivancic, Monika; Cornilescu, Gabriel; Cornilescu, Claudia C; Blackwell, Helen E



Structural analogues of ZAPA as GABAA agonists.  


Structural analogues of ZAPA, Z-3-[(aminoiminomethyl)thio]prop-2-enoic acid, an isothiouronium analogue of GABA, are potent GABAA agonists as seen in the isolated guinea-pig ileum and in the facilitation of [3H]diazepam binding to rat brain membranes. Compounds with guanidino or amidine groups replacing the amino functionality of GABA were also found to be active. The highest activity was displayed by the isothiouronium salts in which the conformational flexibility of the molecule is restricted by a Z-substituted carbon-carbon double bond. A series of bis-isothiouronium compounds was prepared from aliphatic alpha, omega-bis-thioureas as mixtures of E and Z adducts. Maximum GABAA agonist activity for this series was found with a C6-C8 carbon chain, and the results were consistent with an interaction at the GABAA receptor with only one end of the molecule, rather than the more potent effect expected of a molecule bridging two active sites. GABAA antagonist/partial agonist activity was observed on the guinea pig isolated ileum for a number of different analogue types, with the most potent being bis-isothiouronium derivatives. None of the substituted derivatives of ZAPA was as active as ZAPA itself, and maximum GABAA activity was found in the n-pentyl and n-hexyl analogues. PMID:9153000

Allan, R D; Dickenson, H W; Johnston, G A; Kazlauskas, R; Mewett, K N



Rational Design, Synthesis, and Evaluation of Key Analogues of CC-1065 and the Duocarmycins  

PubMed Central

The design, synthesis, and evaluation of a predictably more potent analogue of CC-1065 entailing the substitution replacement of a single skeleton atom in the alkylation subunit are disclosed and was conducted on the basis of design principles that emerged from a fundamental parabolic relationship between chemical reactivity and cytotoxic potency. Consistent with projections, the MeCTI (7-methyl-1,2,8,8a-tetrahydrocyclopropa[c]thieno[3,2-e]indol-4-one) alkylation subunit as well as its isomer iso-MeCTI (6-methyl-1,2,8,8a-tetrahydrocyclopropa[c]thieno[2,3-e]indol-4-one) were found to be 5–6 times more stable than the MeCPI alkylation subunit found in CC-1065 and slightly more stable than even the DSA alkylation subunit found in duocarmycin SA placing it at the point of optimally balanced stability and reactivity for this class of antitumor agents. Their incorporation into the key analogues of the natural products provided derivatives that surpassed the potency of MeCPI derivatives (3–10 fold) matching or slightly exceeding the potency of the corresponding DSA derivatives consistent with projections made based on the parabolic relationship. Notable of these, MeCTI-TMI proved to be as potent or slightly more potent than the natural product duocarmycin SA (DSA-TMI, IC50 = 5 vs 8 pM) and MeCTI-PDE2 proved to be 3-fold more potent than the natural product CC-1065 (MeCPI-PDE2, IC50 = 7 vs 20 pM). Both exhibited efficiencies of DNA alkylation that correlate with this enhanced potency without impacting the intrinsic selectivity characteristic of this class of antitumor agents.

Tichenor, Mark S.; MacMillan, Karen S.; Stover, James S.; Wolkenberg, Scott E.; Pavani, Maria G.; Zanella, Lorenzo; Zaid, Abdel N.; Spalluto, Gianpiero; Rayl, Thomas J.; Hwang, Inkyu



Rational design, synthesis, and evaluation of key analogues of CC-1065 and the duocarmycins.  


The design, synthesis, and evaluation of a predictably more potent analogue of CC-1065 entailing the substitution replacement of a single skeleton atom in the alkylation subunit are disclosed and were conducted on the basis of design principles that emerged from a fundamental parabolic relationship between chemical reactivity and cytotoxic potency. Consistent with projections, the 7-methyl-1,2,8,8a-tetrahydrocyclopropa[c]thieno[3,2-e]indol-4-one (MeCTI) alkylation subunit and its isomer 6-methyl-1,2,8,8a-tetrahydrocyclopropa[c]thieno[2,3-e]indol-4-one (iso-MeCTI) were found to be 5-6 times more stable than the MeCPI alkylation subunit found in CC-1065 and slightly more stable than even the DSA alkylation subunit found in duocarmycin SA, placing it at the point of optimally balanced stability and reactivity for this class of antitumor agents. Their incorporation into the key analogues of the natural products provided derivatives that surpassed the potency of MeCPI derivatives (3-10-fold), matching or slightly exceeding the potency of the corresponding DSA derivatives, consistent with projections made on the basis of the parabolic relationship. Notable of these, MeCTI-TMI proved to be as potent as or slightly more potent than the natural product duocarmycin SA (DSA-TMI, IC50 = 5 vs 8 pM), and MeCTI-PDE2 proved to be 3-fold more potent than the natural product CC-1065 (MeCPI-PDE2, IC50 = 7 vs 20 pM). Both exhibited efficiencies of DNA alkylation that correlate with this enhanced potency without impacting the intrinsic selectivity characteristic of this class of antitumor agents. PMID:17948994

Tichenor, Mark S; MacMillan, Karen S; Stover, James S; Wolkenberg, Scott E; Pavani, Maria G; Zanella, Lorenzo; Zaid, Abdel N; Spalluto, Gianpiero; Rayl, Thomas J; Hwang, Inkyu; Baraldi, Pier Giovanni; Boger, Dale L



Relationship between antimold activity and molecular structure of cinnamaldehyde analogues.  


A quantitative structure-activity relationship (QSAR) modeling of the antimold activity of cinnamaldehyde analogues against of Aspergillus niger and Paecilomyces variotii was presented. The molecular descriptors of cinnamaldehyde analogues were calculated by the CODESSA program, and these descriptors were selected by best multi-linear regression method (BMLR). Satisfactory multilinear regression models of Aspergillus niger and Paecilomyces variotii were obtained with R(2)=0.9099 and 0.9444, respectively. The models were also satisfactorily validated using internal validation and leave one out validation. The QSAR models provide the guidance for further synthetic work. PMID:23374870

Zhang, Yuanyuan; Li, Shujun; Kong, Xianchao



Antimicrobial Activities of Jadomycin B and Structurally Related Analogues  

Microsoft Academic Search

Natural products are leads for new antibiotics as a result of their structural complexity and diversity. We have isolated a series of structurally related polyketide-derived natural products from Streptomyces venezuelae ISP5230. The most active of these jadomycin analogues showed good activity against a variety of staphylococci, including methicillin-resistant Staphylococcus aureus. Natural products, or natural-product derivatives, comprise the majority of clinically

David L. Jakeman; Srinivasulu Bandi; Cathy L. Graham; Taryn R. Reid; Jason R. Wentzell; Susan E. Douglas



Polychlorinated biphenyls as hormonally active structural analogues  

SciTech Connect

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.

McKinney, J.D. (Environmental Protection Agency, Research Triangle Park, NC (United States)); Waller, C.L. (Washington Univ., St. Louis, MO (United States))



Resveratrol and Resveratrol Analogues—Structure—Activity Relationship  

Microsoft Academic Search

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\\u000a prevention of heart disease and significant anti-inflammatory effects, resveratrol might inhibit tumor cell growth and even\\u000a play a role in the aging process. We here describe the structure-activity relationship of resveratrol and analogues of resveratrol\\u000a regarding the

Thomas Szekeres; Monika Fritzer-Szekeres; Philipp Saiko; Walter Jäger



New synthetic route to granulatimide and its structural analogues.  


The Stille coupling reaction of stannylindole 12 with 4-iodoimidazole 13 (or 24) in the presence of PdCl(2)(PPh(3))(2) gave the corresponding indole-imidazole coupling product 14 (or 25), thereby affording a new synthetic approach to the alkaloid granulatimide (7), isolated from the Brazilian ascidian Didemnum granulatum, as well as its structural analogues, 10-methylgranulatimide (23), 17-methylgranulatimide (30), 10,17-dimethylgranulatimide (31). PMID:12045354

Yoshida, Takuji; Nishiyachi, Masakazu; Nakashima, Nobuyuki; Murase, Masayuki; Kotani, Eiichi



Structure-activity studies of antitumor agent irofulven (hydroxymethylacylfulvene) and analogues.  


Many analogues of the antitumor agent irofulven have been readily prepared by replacing the allylic hydroxyl with a variety of nucleophiles. Analogues of acylfulvene (the precursor to irofulven) were also prepared by Michael reaction with acrolein. The toxicity of the analogues was determined, as well as preclinical antitumor activity. Several analogues exhibited good activity in mouse xenografts. Structural requirements for activity are discussed. PMID:11529745

McMorris, T C; Yu, J; Lira, R; Dawe, R; MacDonald, J R; Waters, S J; Estes, L A; Kelner, M J



Are structural analogues to bisphenol a safe alternatives?  


Background: Bisphenol A (BPA) is a chemical with widespread human exposure suspected of causing low-dose effects. Thus, a need for developing alternatives to BPA exists. Structural analogues of BPA have already been detected in foods and humans. Due to the structural analogy of the alternatives, there is a risk of effects similar to BPA. Objectives: The aim was to elucidate and compare the hazards of bisphenol B (BPB), bisphenol E (BPE), bisphenol F (BPF), bisphenol S (BPS) and 4-cumylphenol (HPP) to BPA. Methods: In vitro studies on steroidogenesis, receptor activity, and biomarkers of effect, as well as Quantitative Structure-Activity Relationship (QSAR) modeling. Results: All test compounds caused the same qualitative effects on estrogen receptor and androgen receptor activities, and most of the alternatives exhibited potencies within the same range as BPA. Hormone profiles for the compounds indicated a specific mechanism of action on steroidogenesis which generally lead to decreased androgen, and increased estrogen and progestagen levels. Differential effects on corticosteroid synthesis were observed suggesting a compound-specific mechanism. Overall, BPS was less estrogenic and antiandrogenic than BPA, but BPS showed the largest efficacy on 17?-hydroxyprogesterone  (17?-OH progesterone). Finally, there were indications of DNA damage, carcinogenicity, oxidative stress, effects on metabolism, and skin sensitization of one or more of the test compounds. Conclusions: Interference with the endocrine system was the predominant effect of the test compounds. A substitution of BPA with these structural analogues should be carried out with caution. PMID:24563381

Rosenmai, Anna Kjerstine; Dybdahl, Marianne; Pedersen, Mikael; Alice van Vugt-Lussenburg, Barbara Medea; Wedebye, Eva Bay; Taxvig, Camilla; Vinggaard, Anne Marie



Modelling Trust Structures for Public Key Infrastructures  

Microsoft Academic Search

The development of Public Key Infrastructures (PKIs) is highly desirable to support secure digital transactions and communica- tions throughout existing networks. It is important to adopt a particular trust structure or PKI model at an early stage as this forms a basis for the PKI's development. Many PKI models have been proposed but use only natural language descriptions. We apply

Marie Henderson; Robert S. Coulter; Ed Dawson; Eiji Okamoto



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

PubMed Central

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.

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



Functional and structural characteristics of anticancer peptide Pep27 analogues  

PubMed Central

Background A secreted peptide Pep27 initiates the cell death program in S. pneumoniae through signal transduction. This study was undertaken to evaluate the relation between the structure and cytotoxic activity of Pep27 and its analogues on cancer cells. Results Pep27anal2 characterized substituting (2R?W), (4E?W), (11S?W) and (13Q?W) in native Pep27, exhibited greater hydrophobicity and anticancer activity than Pep27 and other analogues. The IC50 values of Pep27anal2 were approximately 10 – 30 ?M in a number of cell lines (AML-2, HL-60, Jurkat, MCF-7 and SNU-601). Confocal microscopy showed that Pep27anal2-FITC was localized in the plasma membrane, and then moving from the membrane to subcellular compartments with the initiation of membrane blebbing. Flow cytometric analysis using propidium iodide and Annexin V also revealed that Pep27anal2 induced apoptosis with minor membrane damage. Electron microscopy revealed that Pep27 induced apoptosis in Jurkat cells. The anticancer activity of Pep27anal2 was neither abrogated by pan-caspase inhibitor (Z-VAD-fmk) nor related to cytochrome c release from mitochondria. The 3D solution structures of these two Pep27 peptides revealed that both form a random coil conformation in water; however, they adopted stable ?-helical conformations in solutions. Conclusion The results indicate that Pep27anal2 can penetrate the plasma membrane, and then induce apoptosis in both caspase-and cytochrome c-independent manner. The hydrophobicity of Pep27anal2 appears to play an important role in membrane permeabilization and/or anticancer properties. The structure-functional relationships of these peptides are also discussed. It is proposed that Pep27anal2 is a potential candidate for anticancer therapeutic agents.

Lee, Dong Gun; Hahm, Kyung-Soo; Park, Yoonkyung; Kim, Hai-Young; Lee, Weontae; Lim, Sung-Chul; Seo, Youn-Kyung; Choi, Cheol-Hee



Modern freshwater microbialite analogues for ancient dendritic reef structures  

NASA Technical Reports Server (NTRS)

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.

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



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


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

Manna, Debasish; Roy, Gouriprasanna; Mugesh, Govindasamy



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

PubMed Central

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.

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



Butitaxel analogues: synthesis and structure-activity relationships.  


N-Acyl analogues 8, 9, and 12-26 of butitaxel (3) were prepared in one or two steps from amines 5 and 6 through Schotten-Baumann acylation. Seventeen novel analogues, consisting of aliphatic carbamates, alicyclic amides, and heteroaromatic amides, were synthesized. They were evaluated for their in vitro ability to stimulate the formation of microtubules, their cytotoxicity toward B16 melanoma cells, and their solubility in water. The most potent analogue found in this study was N-debenzoyl-N-(2-thenoyl)butitaxel (20), possessing ca. 2-fold better tubulin assembly properties and cytotoxic activity against B16 melanoma cells than paclitaxel. Compound 20 was ca. 25 times more water soluble than paclitaxel. PMID:9003522

Ali, S M; Hoemann, M Z; Aubé, J; Georg, G I; Mitscher, L A; Jayasinghe, L R



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)

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 (55°53'N; 63°18'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.

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.



Control of ethylene activity in various plant systems by structural analogues of 1-methylcyclopropene  

Microsoft Academic Search

Two structural analogues of 1-methylcyclopropene (1-MCP), 1-ethylcyclopropene (1-ECP) and 1-propylcyclopropene (1-PCP) were found to inhibit ethylene action and thereby the responses to ethylene in various plant systems. When applied prior to exposure to ethylene, the analogues considerably delayed ethylene-induced ripening of avocado and tomato fruits, delayed citrus leaf explants abscission and reversed ethylene-induced swelling and inhibition of elongation in etiolated

Xuqiao Feng; Akiva Apelbaum; Edward C. Sisler; Raphael Goren



Membrane structure and interactions of a short Lycotoxin I analogue.  


Lycotoxin I and Lycotoxin II are natural anti-microbial peptides that were identified in the venom of the Wolf Spider Lycosa carolinensis. These peptides were found to be potent growth inhibitors for bacteria (Escherichia coli) and yeast (Candida glabrata) at micromolar concentrations. Recently, shortened analogues of LycoI and LycoII have been reported to have decreased haemolytic effects. A shorter Lyco-I analogue studied, LycoI 1-15 (H-IWLTALKFLGKHAAK-NH2), was active only above 10 microM, but was also the least haemolytic. On the basis of these findings, we became interested in obtaining a deeper insight into the membrane activity of LycoI 1-15, as this peptide may represent the first major step for the future development of selective, i.e. non-haemolytic, Lycotoxin-based antibiotics. The interaction of this peptide with liposomes of different composition was studied by microcalorimetry [differential scanning calorimetry (DSC) and isothermal titration calorimetry (ITC)] and CD. The results obtained from the calorimetric and spectroscopic techniques were jointly discussed in an attempt to further understand the interaction of this peptide with model membranes. PMID:18098329

Adão, R; Seixas, R; Gomes, P; Pessoa, J Costa; Bastos, M



Structure-activity relationships for vitamin d3-based aromatic a-ring analogues as hedgehog pathway inhibitors.  


A structure-activity relationship study for a series of vitamin D3-based (VD3) analogues that incorporate aromatic A-ring mimics with varying functionality has provided key insight into scaffold features that result in potent, selective Hedgehog (Hh) pathway inhibition. Three analogue subclasses containing (1) a single substitution at the ortho or para position of the aromatic A-ring, (2) a heteroaryl or biaryl moiety, or (3) multiple substituents on the aromatic A-ring were prepared and evaluated. Aromatic A-ring mimics incorporating either single or multiple hydrophilic moieties on a six-membered ring inhibited the Hh pathway in both Hh-dependent mouse embryonic fibroblasts and cultured cancer cells (IC50 values 0.74-10 ?M). Preliminary studies were conducted to probe the cellular mechanisms through which VD3 and 5, the most active analogue, inhibit Hh signaling. These studies suggested that the anti-Hh activity of VD3 is primarily attributed to the vitamin D receptor, whereas 5 affects Hh inhibition through a separate mechanism. PMID:24730984

Deberardinis, Albert M; Madden, Daniel J; Banerjee, Upasana; Sail, Vibhavari; Raccuia, Daniel S; De Carlo, Daniel; Lemieux, Steven M; Meares, Adam; Hadden, M Kyle



Synthesis, biological activity and solution structure of new analogues of the antimicrobial Gramicidin S.  


Gramicidin S (GS) is a cyclo-decapeptide antibiotic isolated from Bacillus brevis. The structural studies have shown that GS forms a two-stranded antiparallel ?-sheet imposed by two II' ?-turns. Despite its wide Gram+ and Gram- antimicrobial spectrum, GS is useless in therapy because of its high hemotoxicity in humans. It was found, however, that the analogues of GS-14 (GS with 14 amino acid residues) attained a better antimicrobial selectivity when their amphipatic moments were perturbed. In this study, we report effects of similar perturbations imposed on GS cyclo-decapeptide analogues. Having solved their structures by NMR/molecular dynamics and having tested their activities/selectivities, we have concluded that the idea of perturbation of the amphipatic moment does not work for GS-10_0 analogues. An innovative approach to the synthesis of head-to-tail cyclopeptides was used. PMID:21308877

Kamysz, El?bieta; Mickiewicz, Beata; Kamysz, Wojciech; Bieli?ska, Sylwia; Rodziewicz-Motowid?o, Sylwia; Ciarkowski, Jerzy



Structure-antiviral activity relationships of cecropin A-magainin 2 hybrid peptide and its analogues.  


In order to elucidate the structure-antiviral activity relationship of cecropin A (1-8)-magainin 2 (1-12) (termed CA-MA) hybrid peptide, several analogues with amino acid substitutions were synthesized. In a previous study, it was shown that serine at position 16 in CA-MA hybrid peptide was very important for antimicrobial activity. Analogues were designed to increase the hydrophobic property by substituting a hydrophobic amino acid residue (S --> A, V, F or W, position 16) in the CA-MA hybrid peptide. In this study, the structure-antiviral activity relationships of CA-MA and its analogues were investigated. In particular, substitution of Ser with a hydrophobic amino acid, Val, Phe or Trp at position 16 caused a dramatic increase in the virus-cell fusion inhibitory activity. These results suggested that the hydrophobicity at position 16 in the hydrophobic region of CA-MA is important for potent antiviral activity. PMID:15160842

Lee, Dong Gun; Park, Yoonkyung; Jin, Ingnyol; Hahm, Kyung-Soo; Lee, Hyang-Hee; Moon, Young-Hee; Woo, Eun-Rhan



Structure activity relationship of uridine 5?-diphosphate analogues at the human P2Y6 receptor  

PubMed Central

The structure activity relationships and molecular modeling of the uracil nucleotide-activated P2Y6 receptor have been studied. A series of UDP analogues bearing substitutions of the ribose moiety, the uracil ring, and the diphosphate group was synthesized and assayed for activity at the human P2Y6 receptor. The uracil ring was modified at the 4-position, with the synthesis of 4-substituted-thiouridine-5?-diphosphate analogues, as well as at positions 3 and 5. The effect of modifications at the level of the phosphate chain was studied by preparing a cyclic 3?,5?-diphosphate analogue, a 3?-diphosphate analogue and several dinucleotide diphosphates. 5-Iodo-UDP 32 (EC50 0.15 ?M) was equipotent to UDP, while substitutions of the 2?-hydroxyl (amino, azido) greatly reduce potency. 2- and 4-Thio analogues, 20 and 21, respectively, were also relatively potent in comparison to UDP. However, most other modifications greatly reduced potency. Molecular modeling indicates that the ?-phosphate of 5?-UDP and analogs is essential for the establishment of electrostatic interactions with two of the three conserved cationic residues of the receptor. Among 4-thioether derivatives, a 4-ethylthio analogue 23 displayed an EC50 of 0.28 ?M, indicative of favorable interactions predicted for a small 4-alkylthio moiety with the aromatic ring of Y33 in TM1. The activity of analogue 19 in which the ribose was substituted with a 2-oxabicyclohexane ring in a rigid (S) conformation (P= 126°, 1?-exo) was consistent with molecular modeling. These results provide a better understanding of molecular recognition at the P2Y6 receptor and will be helpful in designing selective and potent P2Y6 receptor ligands

Besada, Pedro; Shin, Dae Hong; Costanzi, Stefano; Ko, Hyojin; Mathe, Christophe; Gagneron, Julien; Gosselin, Gilles; Maddileti, Savitri; Harden, T. Kendall; Jacobsona, Kenneth A.



Structure-activity relationship studies of illudins: analogues possessing a spiro-cyclobutane ring.  


Bicyclic and tricyclic analogues of anticancer sesquiterpene illudin S have been synthesized. These contain a spiro-cyclobutane instead of spiro-cyclopropane structure. The cytotoxicity of the former is less than that of the corresponding cyclopropane-containing compounds. PMID:14656090

McMorris, Trevor C; Cong, Qiang; Kelner, Michael J



Studies on the novel ?-glucosidase inhibitory activity and structure–activity relationships for andrographolide analogues  

Microsoft Academic Search

A series of analogues of andrographolide were synthesized and evaluated as novel ?-glucosidase inhibitors. Among them compound 23, 15-p-methoxylbenzylidene 14-deoxy-11,12-didehydroandrographolide, was a potent inhibitor against ?-glucosidase whose IC50 value was 16?M. The structure–activity relationships were also discussed.

Gui-Fu Dai; Hai-Wei Xu; Jun-Feng Wang; Feng-Wu Liu; Hong-Min Liu



Structural elucidation of a tadalafil analogue found as an adulterant of a herbal product  

Microsoft Academic Search

A tadalafil analogue and hydroxyhomosildenafil were isolated from a herbal product marketed for erectile dysfunction. The structure of the tadalafil analogue was elucidated using LC-UV, high resolution MS, ESI-MS\\/MS, IR, and NMR. The compound was determined to be (6R,12aR)-2-amino-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydropyrazino[1?,2?:1,6] pyrido[3,4-b]indole-1,4-dione. This compound should be included as a target compound when screening for adulterants in herbal products. This is the first

Peng Zou; Peiling Hou; Min-Yong Low; Hwee-Ling Koh



Inhibition of neuronal membrane GABAB receptor binding by GABA structural analogues.  


1. A number of compounds structurally related to GABA were tested as inhibitors of baclofen-sensitive GABAB receptor binding to membranes from mouse brain. 2. In addition to two known inhibitors--baclofen and 5-aminovaleric acid--two analogues were shown to possess inhibitory activity. These compounds were 4-aminobutyryl-DL-alanine hydrobromide (IC50 = 3 microM) and trans-2-(aminomethyl)cyclopropane carboxylic acid (IC50 = 90 microM). 3. Both drugs also exhibited affinity for GABAA binding sites. 4. Further experiments are needed to establish if these analogues exert agonist or antagonist action at the GABAB receptor. PMID:2832226

Tunnicliff, G; Rogier, C J; Youngs, T L



Isolation and structural elucidation of a new sildenafil analogue from a functional coffee.  


A sildenafil analogue was detected in a functional coffee sample labelled to have male sexual performance enhancement effects. This analogue was isolated and purified by flash chromatography and preparative high-performance liquid chromatography. Its structure was elucidated using high-resolution mass spectrometry; electrospray ionization-tandem mass spectrometry; and nuclear magnetic resonance spectroscopy, ultraviolet spectroscopy, and infrared spectroscopy. Compared with sildenafil, instead of an N-methylpiperazinyl moiety, ring opening of the piperazine ring with the loss of a carbon atom resulted in a substituted benzenesulfonamide. The chemical name of this analogue is N-[2-(dimethylamino)ethyl]-4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonamide. It is named descarbonsildenafil because it has one less carbon atom when compared with sildenafil. PMID:22825675

Li, Lin; Low, Min-Yong; Ge, Xiaowei; Bloodworth, Bosco C; Koh, Hwee-Ling



Structural requirement for the rapid movement of charged molecules across membranes. Experiments with tetraphenylborate analogues.  

PubMed Central

Charge-pulse experiments were performed in the presence of structural analogues of tetraphenylborate (TPB) on membranes made of dioleoyl phosphatidylethanolamine and dioleoyl phosphatidylcholine. The analysis of the experimental results using a previously proposed model allowed the calculation of the partition coefficient, beta, and of the translocation rate constant, kappa i. The temperature dependence of the partition coefficients was used to calculate the thermodynamics of the adsorption of the lipophilic ions to the membranes. The analysis of the translocation rate constants obtained at different temperatures yielded detailed information on the free energy of the TPB-analogues within artificial lipid bilayer membranes, and on the activation energy of the translocation rate constants. The adsorption of the different TPB-analogues to the membranes was only slightly affected by their structure, whereas a dramatic influence of the structure on the free energy of the lipophilic ions within the membranes was observed. The free energy of the ions in the membranes decreased from triphenylcyanoborate (TPCB) to tetrakis(3-trifluoromethylphenyl)borate (TTFPB) by more than 31 kJ/mol (7.4 kcal/mol). This could be concluded from the observed increase in the translocation rate constant by almost six orders of magnitude. The change of the free energy in the membrane was used for the estimation of an effective radius of the TPB-analogues with respect to TPB.

Benz, R



Structure--antiadenoviral activity of nitrogen containing macroheterocycles and their analogues.  


The search for the inhibitors of adenoviruses has been performed among the substances of new class NCM (nitrogen containing macroheterocycles) and their analogues that have high potential of pharmacological properties. We have found a number of NCM and their derivatives that inhibit the reproduction of adenoviruses to various degrees. For the prediction of NCM structure with antiadenoviral activity we have performed the computer modeling using QSAR approach on the basis of simplex representation of molecular structure (SiRMS). PMID:17388122

Dyachenko, N S; Nosach, L N; Povnitsa, O Y; Kuz'min, V E; Artemenko, A G; Lozitskaya, R N; Basok, S S; Alexeeva, I V; Zhovnovataya, V L; Vanden Eynde, J J



Thiazole constrained analogues of the thevinones: synthesis and structure.  


A simple synthesis of ring-constrained endoethenomorphinans possessing 2'-substituted thiazole ring 4-6 has been achieved by regio- and stereoselective Diels-Alder reaction of thiazolomorphinandienes 1-3 and methyl vinyl ketone in high yield (72, 64 and 87%, respectively). The structure of cycloaddition products was determined by high resolution mass spectrometry (HRMS), IR, 1D and 2D NMR techniques. Double-pulsed field gradient spin-echo-nOe and HMBC were found to be particularly powerful and indispensable tools in the exact structural elucidation of the presented new class of spatially constrained thevinones. PMID:19431155

Sipos, Attila; Skaliczki, Tímea; Berényi, Sándor; Antus, Sándor



Characterization and use of an unprecedentedly bright and structurally non-perturbing fluorescent DNA base analogue.  


This article presents the first evidence that the DNA base analogue 1,3-diaza-2-oxophenoxazine, tC(O), is highly fluorescent, both as free nucleoside and incorporated in an arbitrary DNA structure. tC(O) is thoroughly characterized with respect to its photophysical properties and structural performance in single- and double-stranded oligonucleotides. The lowest energy absorption band at 360 nm (epsilon = 9000 M(-1) cm(-1)) is dominated by a single in-plane polarized electronic transition and the fluorescence, centred at 465 nm, has a quantum yield of 0.3. When incorporated into double-stranded DNA, tC(O) shows only minor variations in fluorescence intensity and lifetime with neighbouring bases, and the average quantum yield is 0.22. These features make tC(O), on average, the brightest DNA-incorporated base analogue so far reported. Furthermore, it base pairs exclusively with guanine and causes minimal perturbations to the native structure of DNA. These properties make tC(O) a promising base analogue that is perfectly suited for e.g. photophysical studies of DNA interacting with macromolecules (proteins) or for determining size and shape of DNA tertiary structures using techniques such as fluorescence anisotropy and fluorescence resonance energy transfer (FRET). PMID:18003656

Sandin, Peter; Börjesson, Karl; Li, Hong; Mårtensson, Jerker; Brown, Tom; Wilhelmsson, L Marcus; Albinsson, Bo



Measuring sub-Planck structural analogues in chronocyclic phase space  

NASA Astrophysics Data System (ADS)

Phase space quasi-probability distributions of certain quantum states reveal structure on a scale that is small compared to the Planck area. Using an analog between the wavefunction of a single photon and the electric field of a classical ultrashort optical pulse we show that spectral shearing interferometry enables measurement of such structure directly, thereby extending an idea of Krzysztof Wódkiewicz and others. In particular, we use multiple-shear spectral interferometry to fully characterize a pulse consisting of two sub-pulses which are temporally and spectrally disjoint, without a relative-phase ambiguity. This enables us to compute the Wigner distribution of the pulse. This spectrographic representation of the pulse field features fringes that are tilted with respect to both the time- and frequency axes, showing that in general the shortest sub-Planck distances may not be in the directions of the canonical (and easily experimentally accessible) directions. Further, independent of this orientation, evidence of the sub-Planck scale of the structure may be extracted directly from the measured signal.

Austin, Dane R.; Witting, Tobias; Wyatt, Adam S.; Walmsley, Ian A.



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


Mandelate racemase (MR, EC 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

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



The solution structure of a superpotent B-chain-shortened single-replacement insulin analogue.  

PubMed Central

This paper reports on an insulin analogue with 12.5-fold receptor affinity, the highest increase observed for a single replacement, and on its solution structure, determined by NMR spectroscopy. The analogue is [D-AlaB26]des-(B27-B30)-tetrapeptide-insulin-B26-amide. C-terminal truncation of the B-chain by four (or five) residues is known not to affect the functional properties of insulin, provided the new carboxylate charge is neutralized. As opposed to the dramatic increase in receptor affinity caused by the substitution of D-Ala for the wild-type residue TyrB26 in the truncated molecule, this very substitution reduces it to only 18% of that of the wild-type hormone when the B-chain is present in full length. The insulin molecule in solution is visualized as an ensemble of conformers interrelated by a dynamic equilibrium. The question is whether the "active" conformation of the hormone, sought after in innumerable structure/function studies, is or is not included in the accessible conformational space, so that it could be adopted also in the absence of the receptor. If there were any chance for the active conformation, or at least a predisposed state to be populated to a detectable extent, this chance should be best in the case of a superpotent analogue. This was the motivation for the determination of the three-dimensional structure of [D-AlaB26]des-(B27-B30)-tetrapeptide-insulin-B26-amide. However, neither the NMR data nor CD spectroscopic comparison of a number of related analogues provided a clue concerning structural features predisposing insulin to high receptor affinity. After the present study it seems more likely than before that insulin will adopt its active conformation only when exposed to the force field of the receptor surface.

Kurapkat, G.; Siedentop, M.; Gattner, H. G.; Hagelstein, M.; Brandenburg, D.; Grotzinger, J.; Wollmer, A.



Antioxidant, prooxidant and cytotoxic activity of hydroxylated resveratrol analogues: structure–activity relationship  

Microsoft Academic Search

Resveratrol (trans-3,4?,5-trihydroxystilbene), a naturally occurring hydroxystilbene, is considered an essential antioxidative constituent of red wine possessing chemopreventive properties. However, resveratrol and even more its metabolite piceatannol were reported to have also cytostatic activities. In order to find out whether this is related to antioxidative properties of those compounds, we synthesized five other polyhydroxylated resveratrol analogues and studied structure–activity relationships between

Marek Murias; Walter Jäger; Norbert Handler; Thomas Erker; Zsuzsanna Horvath; Thomas Szekeres; Hans Nohl; Lars Gille



Conformations of Acyclonucleosides: Crystal Structure of 9-(4-Hydroxybutyl)Guanine, an Analogue of Acyclovir  

Microsoft Academic Search

9-(4-Hydroxybutyl)guanine is an analogue of acyclovir in which the ether oxygen is replaced by a methylene group. Crystals of the monohydrate belong to the monoclinic space group P21\\/n with a = 4.350 (1), b = 10.859 (1), c = 23.684 (4) Å, ? = 90.65 (1)°. X-ray intensity data were measured with a diffractometer and the structure was determined by

George I. Birnbaum; Nils Gunnar Johansson; David Shugar



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

Microsoft Academic Search

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

Hyunjung Kim; Krzysztof Kaczmarski; Georges Guiochon



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

Microsoft Academic Search

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

Hyunjung Kim; Krzysztof Kaczmarski; Georges A Guiochon



The Beta Environmental Fine Structure (BEFS): The XAFS Nuclear Analogue  

SciTech Connect

The Beta Environmental Fine Structure (BEFS) effect is an oscillatory modulation on the otherwise smooth spectrum of electrons emitted by beta-decaying nuclei. The existence of this effect was theoretically proposed in 1991, for condensed emitters, in analogy with XAFS. In BEFS the electron, playing the role of the XAFS photoelectron, originates directly from the nucleus and an anti-neutrino is emitted at the same time. We present evidence for BEFS oscillations observed in Silver Perrhenate (AgReO4) low-temperature (0.1K) microbolometers, together with a XAFS-like analysis that allowed for the first time a direct measurement of the anti-neutrino angular momentum. We discuss the physical analogies and differences between BEFS and XAFS and the implications for the next generation experiments aimed at measuring the neutrino mass on purely kinematic grounds. Moreover, we briefly discuss the potential and the limits of BEFS-based techniques with respect to the classical XAFS.

Monfardini, A. [ITC-IRST and INFN sez. Padova, Via Sommarive, 18 I-38050 Povo (Italy); Benedek, G. [Dipartimento di Scienza dei Materiali dell'Universita di Milano-Bicocca, Via Cozzi 53, I-20125 Milan (Italy); Istituto Nazionale di Fisica Nucleare (INFN) sez. Milano-Bicocca, Piazza delle Scienze 3, I-20126 Milan (Italy); Cremonesi, O.; Nucciotti, A.; Sisti, M. [Istituto Nazionale di Fisica Nucleare (INFN) sez. Milano-Bicocca, Piazza delle Scienze 3, I-20126 Milan (Italy); Dipartimento di Fisica dell'Universita di Milano-Bicocca, Piazza delle Scienze 3, I-20126 Milan (Italy); Filipponi, A. [Dipartimento di Fisica dell'Universita dell'Aquila, Via Vetoio, I-67010 Coppito di L'Aquila (Italy)



The pyrogenicity of the synthetic adjuvant muramyl dipeptide and two structural analogues.  


The pyrogenic efect of the synthetic adjuvant N-acetylmuramyl-L-alanine-D-isoglutamine, also known as muramyl dipeptide (MDP), was studied in rabbits. MDP induced biphasic fevers in rabbits, but two structural analogues, N-acetylmuramyl-L-alanine-D-glutamic acid (MDPA) and the dimethylester of MDPA, were 10 times less pyrogenic. This finding was supported by studies in which MDP and its analogues released leukocytic pyrogen (LP) from rabbit phagocytic cells in vitro. In addition, MDP released LP from human phagocytes. Human phagocytes, however, required a 10-fold greater concentration of MDP than did rabbit cells. The structural analogues were similarly less effective than the parent molecule in releasing LP from human cells. All preparations of MDP were negative in the limulus amebocyte lysate test and failed to show pyrogenic cross-tolerance with bacterial endotoxin. Thus MDP, which is a pyrogenic molecule, is also able to release LP from rabbit phagocytes and to a lesser degree from human phagocytes, but does not cause gelation of limulus amebocyte lysate. PMID:368262

Dinarello, C A; Elin, R J; Chedid, L; Wolff, S M



Choleretic activity of phloracetophenone in rats: structure-function studies using acetophenone analogues.  


The relationship between the chemical structure and choleretic activity of phloracetophenone (2,4,6-trihydroxyacetophenone) was investigated in adult male rats. Fourteen acetophenone analogues, with different substituents on the benzene nucleus, were intraduodenally administered and bile samples were collected via a bile fistula. All of the compounds tested immediately induced choleresis. For the same number of substituents on the benzene ring, hydroxy analogues induced a greater choleresis. The number and position of hydroxy substituents on the benzene nucleus play an important role in determining choleretic activity and biliary secretion of bile acid, but had no relation to biliary excretion of cholesterol. The choleretic activity of the hydroxylated compounds was inversely related to hydrophobicity, as inferred by thin-layer chromatography (TLC). Among the hydroxylated acetophenone analogues, 2,4,6-trihydroxyacetophenone was identified as the most potent, with a choleretic activity of 231.8+/-6.1 microl/mmol/min. It induced both a high bile flow rate and a high bile salt output and led to lower plasma cholesterol levels. This bile had a low lithogenic potential. The results suggest that a structural requirement for high choleretic activity of 2,4,6-trihydroxyacetophenone is a substituent hydroxy group at 4-position. Additional hydroxy groups at 2- and 6-positions are essential for the induction of higher an output of bile acid, and possibly, other solid materials. PMID:10650163

Piyachaturawat, P; Chai-ngam, N; Chuncharunee, A; Komaratat, P; Suksamrarn, A



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

NASA Astrophysics Data System (ADS)

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.

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


Phalloidin synthetic analogues: structural requirements in the interaction with F-actin.  


Synthetic derivatives of phalloidin have been investigated in solution by circular dichroism (CD) and NMR spectroscopy. They differ from natural phalloidin (PHD). bicyclo(Ala1-D-Thr2-Cys3-cis-4-hydroxy-Pro4-Ala5-2-mercapto-Trp6-(OH)2Leu7)(S-3 --> 6), in that they are modified at positions 2, 3, and 7. Among these synthetic analogues, structural differences and varying degrees of atropisomerism are found. By comparing the respective molecular models obtained by restrained molecular dynamics (RMD) simulations based on experimental NMR data, structural features that may be responsible for the different biological behavior become apparent. Our results indicate that the structural changes that result from an inversion of chirality of residue 3 lead to a complete loss of toxicity. Conversely, toxicity is less affected by the structural changes that stem from an inversion of chirality of residue 2. Moreover, unlike the other phallotoxins, when the thioether unit bridges to the opposite face of the main peptide ring, in contrast to the situation in other phallotoxins, large structural changes are observed as well as a total loss of activity. Molecular models of the synthetic phalloidin analogues have been used to investigate the necessary structural requirements for the interaction with F-actin. To this end, the F-actin/PHD model of M. Lorenz et al. was employed; docking experiments of our molecular models in the PHD binding site are presented. PMID:11757659

Falcigno, L; Costantini, S; D'Auria, G; Bruno, B M; Zobeley, S; Zanotti, G; Paolillo, L



Chromone-fused cytosine analogues: synthesis, biological activity, and structure-activity relationship.  


The preparation of a series of novel chromone-fused cytosine analogues, i.e., chromeno[2,3-d]pyrimidines has been carried out from substituted 2-amino-4-oxo-4H-chromene-3-carbonitriles with urea, thiourea, and guanidine under different reaction conditions. These chromone-fused cytosine analogues were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv strain and different microbial pathogenic strains in cell culture for their structure-activity relationships, respectively. Among the synthesized compounds, 2d, 3a, and 4e showed better results against Mycobacterium tuberculosis H37Rv. The compounds 2a, 2b, and 3a showed potential antibacterial activity against E. coli and P. aeruginosa, while the majority of compounds were found to be active against S. aureus as compared to ampicillin. The synthesized cytosine analogues having an imine (-C&dbnd;NH) have been less sensitive to the bacterial and fungal strains but have a more beneficial effect on Mycobacterium tuberculosis H37Rv. PMID:24660882

Haveliwala, Dhaval D; Kamdar, Nimesh R; Mistry, Prashant T; Patel, Saurabh K



Cytotoxic Activity and Structure Activity Relationship of Ceramide Analogues in Caki-2 and HL-60 Cells.  


B13, a ceramide analogue, is a ceramidase inhibitor and induces apoptosis to give potent anticancer activity. A series of thiourea B13 analogues was evaluated for their in vitro cytotoxic activities against human renal cancer Caki-2 and leukemic cancer HL-60 in the MTT assay. Some compounds (12, 15, and 16) showed stronger cytotoxicity than B13 and C6-ceramide against both tumor cell lines, and compound (12) gave the most potent activity with IC(50) values of 36 and 9 µM, respectively. Molecular modeling of thiourea B13 analogues was carried out by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). We obtained highly reliable and predictive CoMSIA models with cross-validated q(2) values of 0.707 and 0.753 and CoMSIA contour maps to show the structural requirements for potent activity. These data suggest that the amide group of B13 could be replaced by thiourea, that the stereochemistry of 1,3-propandiol may not be essential for activity and that long alkyl chains increase cytotoxicity. PMID:21311687

Kim, Yong Jin; Kim, Eun Ae; Sohn, Uy Dong; Yim, Chul Bu; Im, Chaeuk



Synthesis of the antiproliferative agent hippuristanol and its analogues from hydrocortisone via Hg(II)-catalyzed spiroketalization: structure-activity relationship.  


An efficient synthesis of hippuristanol (1), a marine-derived highly potent antiproliferative steroidal natural product, and nine closely related analogues has been accomplished from the commercially available hydrocortisone utilizing Hg(II)-catalyzed spiroketalization of 3-alkyne-1,7-diol motif as a key strategy. This practical synthetic sequence furnished 1 in 11% overall yield from hydrocortisone in 15 linear steps. Modifications to the parent molecule 1 encompassed changing the functional groups on rings A and E. Each analogue was screened for their effects on inhibition of cap-dependent translation, and the assay results were used to establish structure-activity relationships. These results suggest that the stereochemistry and all substituents of spiroketal portion (rings E and F) and C3-? and C11-? hydroxyl functional groups on rings A and C, respectively, are critical for the inhibitory activity of natural product 1. PMID:24588834

Somaiah, Ragam; Ravindar, Kontham; Cencic, Regina; Pelletier, Jerry; Deslongchamps, Pierre



Possibility of usage of aminostigmine structural analogue for the treatment of toxic cognitive disorders.  


We studied the effects of 2-(hexyl(methyl)amino)methyl)pyridyl-3-dimethyl carbamate (OPDC), a structural analogue of aminostigmine oxalate, on memory formation in rats with toxic scopolamine-induced amnesia. It was shown that OPDC in non-toxic doses ((1)/215 LD50) has significant anti-amnesic action. Ipidacrine and galantamine in the doses similar to toxic doses ((1)/17 and (1)/6 of LD50, respectively) induced the retention of memory trace. Administration of aminostigmine ((1)/11 of LD50) induced unstable anti-amnesic effect in the model of scopolamine-induced amnesia. PMID:24771374

Fateev, I V; Subbotina, S N; Kurpyakova, A F; Tyunin, M A



Mechanisms of heparanase inhibition by the heparan sulfate mimetic PG545 and three structural analogues?  

PubMed Central

The tetrasaccharide heparan sulfate (HS) mimetic PG545, a clinical anti-cancer candidate, is an inhibitor of the HS-degrading enzyme heparanase. The kinetics of heparanase inhibition by PG545 and three structural analogues were investigated to understand their modes of inhibition. The cholestanol aglycon of PG545 significantly increased affinity for heparanase and also modified the inhibition mode. For the tetrasaccharides, competitive inhibition was modified to parabolic competition by the addition of the cholestanol aglycon. For the trisaccharides, partial competitive inhibition was modified to parabolic competition. A schematic model to explain these findings is presented.

Hammond, Edward; Handley, Paul; Dredge, Keith; Bytheway, Ian



Structural characterization of angiotensin I-converting enzyme in complex with a selenium analogue of captopril  

PubMed Central

Human somatic angiotensin I-converting enzyme (ACE), a zinc-dependent dipeptidyl carboxypeptidase, is central to the regulation of the renin–angiotensin aldosterone system. It is a well-known target for combating hypertension and related cardiovascular diseases. In a recent study by Bhuyan and Mugesh [Org. Biomol. Chem. (2011) 9, 1356–1365], it was shown that the selenium analogues of captopril (a well-known clinical inhibitor of ACE) not only inhibit ACE, but also protect against peroxynitrite-mediated nitration of peptides and proteins. Here, we report the crystal structures of human testis ACE (tACE) and a homologue of ACE, known as AnCE, from Drosophila melanogaster in complex with the most promising selenium analogue of captopril (SeCap) determined at 2.4 and 2.35 Å resolution, respectively. The inhibitor binds at the active site of tACE and AnCE in an analogous fashion to that observed for captopril and provide the first examples of a protein–selenolate interaction. These new structures of tACE–SeCap and AnCE–SeCap inhibitor complexes presented here provide important information for further exploration of zinc coordinating selenium-based ACE inhibitor pharmacophores with significant antioxidant activity. Database Structural data for the two SeCap complexes with ACE and AnCE have been deposited with the RCSB Protein Data Bank under the codes 2YDM and 3ZQZ, respectively.

Akif, Mohd; Masuyer, Geoffrey; Schwager, Sylva L U; Bhuyan, Bhaskar J; Mugesh, Govindasamy; Isaac, R Elwyn; Sturrock, Edward D; Acharya, K Ravi



Dissecting the chemical interactions and substrate structural signatures governing RNA polymerase II trigger loop closure by synthetic nucleic acid analogues  

PubMed Central

The trigger loop (TL) of RNA polymerase II (Pol II) is a conserved structural motif that is crucial for Pol II catalytic activity and transcriptional fidelity. The TL remains in an inactive open conformation when the mismatched substrate is bound. In contrast, TL switches from an inactive open state to a closed active state to facilitate nucleotide addition upon the binding of the cognate substrate to the Pol II active site. However, a comprehensive understanding of the specific chemical interactions and substrate structural signatures that are essential to this TL conformational change remains elusive. Here we employed synthetic nucleotide analogues as ‘chemical mutation’ tools coupling with ?-amanitin transcription inhibition assay to systematically dissect the key chemical interactions and structural signatures governing the substrate-coupled TL closure in Saccharomyces cerevisiae Pol II. This study reveals novel insights into understanding the molecular basis of TL conformational transition upon substrate binding during Pol II transcription. This synthetic chemical biology approach may be extended to understand the mechanisms of other RNA polymerases as well as other nucleic acid enzymes in future studies.

Xu, Liang; Butler, Kyle Vincent; Chong, Jenny; Wengel, Jesper; Kool, Eric T.; Wang, Dong



Synthesis of charybdotoxin and of two N-terminal truncated analogues. Structural and functional characterisation.  


Charybdotoxin and two N-terminal truncated peptides, corresponding to the 2-37 and 7-37 sequences, were obtained by stepwise solid-phase synthesis using N alpha-t-butyloxycarbonyl and benzyltype side-chain protection. While this strategy was generally useful, the S-acetamidomethyl protecting group used for the six cysteines was not completely stable under HF treatment and its subsequent removal by mercury(II) treatment was neither complete nor devoid of side reactions. The completely deprotected native and truncated sequences were folded efficiently in the presence of glutathione and were finally purified by high-pressure liquid chromatography with overall yields of 4.0-5.0%. Each protein was characterised chemically, structurally and functionally. 1H-NMR spectroscopy was used and a complete assignment of all the protons of the three synthetic proteins was achieved. NMR data show that synthetic charybdotoxin is indistinguishable from the natural protein. The two truncated proteins contain the same elements of secondary structure and a similar overall three-dimensional structure, in agreement with circular dichroic measurements. The shortest analogue, however, may have local structural perturbations and/or higher flexibility. Biological activity on dog epithelial Ca(2+)-activated K+ channels and on rat brain synaptosomal voltage-dependent K+ channels show that synthetic charybdotoxin was as potent as the natural toxin on both channels. For both channels, deletion of the first amino acid, 5-oxoproline (pyroglutamic acid) decreased only slightly the potency of the inhibitor, while deletion of the entire 1-6 segment reduced potency much more. We conclude that the N-terminal region of charybdotoxin plays a functional role in tuning the toxin's biological activity but is not essential for the folding and stability of the structure. The structure of the shortest analogue represents an interesting example of how a well organised and stable alpha/beta fold can be engineered with only 31 amino acid residues. PMID:7693459

Vita, C; Bontems, F; Bouet, F; Tauc, M; Poujeol, P; Vatanpour, H; Harvey, A L; Menez, A; Toma, F



Metallic fluoride complexes as phosphate analogues for structural and mechanistic studies of phosphoryl group transfer enzymes.  


There have been intensive efforts to try to understand the details of phosphoryl transfer reactions extending from nonenzymatic (or enzyme model) systems to the mechanisms of the enzyme catalysed reactions. As phosphate analogues, few metallic fluorides AlFx, BeFx and MgFx affect the activity of a variety of phosphoryl transfer enzymes, and it is accepted that these small inorganic complexes are useful chemical probes for structural and mechanistic studies in enzymology because they are able to mimic phosphoryl group in ground state (BeFx) as well as in transition state (AlFx,MgFx). Al3+ and Be2+ tend to form stable complexes with different fluoride anions (x = 1 to 4) spontaneously in aqueous solution but Mg2+ does not. BeFx geometry is strictly tetrahedral resembling the phosphate ground state when bound to an acyl group of protein active site (phosphorylated acyl groups are unstable otherwise), or the Michaelis complex when BeFx concominantly with nucleoside diphosphate replaces g-phosphate group in nucleoside triphosphate sites. AlFx and MgFx are identified as enzymatic analogues of phosphoryl transition state where both are able to form different coordination geometries within the enzyme active sites: trigonal bipyramidal (AlF3 and MgF3-) or octahedral (AlF4- or MgF42-). The geometry and charge of MgF3- are the best suited to mimicking the trigonal planar PO3- moiety of phosphoryl transfer transition state but MgF3- does not, unlike aluminum and beryllium fluoride complexes, exists in solution and can be assembled and stabilized in suitable active site only. Therefore it is particularly interesting to characterize as a potentially highly accurate transition state analogue and may be the best reagent of choice for studying phosphoryl transfer reactions in future. PMID:24061722

Goli?nik, Marko



Inhibitory effects of caffeine analogues on neoplastic transformation: structure-activity relationship  

PubMed Central

Some xanthine analogues, including 1,3,7-trimethylxanthine (caffeine) and 1,3-dimethylxanthine (theophylline), have been shown to exert anticancer activities in both cell culture and animal models. The present study focused on the relationship of structure and activity of 50 different caffeine analogues in preventing epidermal growth factor (EGF)-induced malignant transformation of mouse epidermal JB6 promotion-sensitive (P+) Cl41 (JB6 P+) cells. Results indicated that the inhibition of cell transformation by the 1,3,7-trialkylxanthines depends on the number of carbons at the alkyl groups R1 and R3, but not R7. Notably, 1-ethyl-3-hexylxanthine (xanthine 70) was the most effective compound for inhibiting EGF-induced neoplastic transformation among the 50 xanthine analogues tested. The 50% inhibition of cell transformation (ICT50) value for xanthine 70 was 48- or 75-fold less than the ICT50 value of caffeine or theophylline, respectively. Further study revealed that xanthine 70 (5–40 ?M) dose dependently inhibited EGF-induced transactivation of activator protein 1 (AP-1), whereas theophylline or caffeine (up to 500 ?M) had no effect on AP-1 activity. In addition, xanthine 70 (10 ?M) inhibited 12-O-tetradecanoylphorbol-13-acetate- or H-Ras-induced neoplastic transformation in JB6 P+ cells by 78.2 or 62.0%, respectively. Collectively, these results indicated that the number of carbons at R1 and R3 is important for the antitumor-promoting activity of the trialkylxanthines and xanthine 70 might be a promising anticancer agent.

Rogozin, Evgeny A.; Lee, Ki Won; Kang, Nam Joo; Yu, Haoyu; Nomura, Masaaki; Miyamoto, Ken-Ichi; Conney, Allan H.; Bode, Ann M.; Dong, Zigang



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

PubMed Central

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.

Wang, Chaozhan; Neugebauer, Ute; Burck, Jochen; Myllykoski, Matti; Baumgartel, Peter; Popp, Jurgen; Kursula, Petri



Cellular localization of dieldrin and structure-activity relationship of dieldrin analogues in dopaminergic cells.  


The incidence of Parkinson's 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 structure-activity 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

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



Synthesis, cytotoxicity against human oral cancer KB cells and structure-activity relationship studies of trienone analogues of curcuminoids.  


A general method for the synthesis of substituted (1E,4E,6E)-1,7-diphenylhepta-1,4,6-trien-3-ones, based on the aldol condensations of substituted 4-phenylbut-3-en-2-ones and substituted 3-phenylacrylaldehydes, was achieved. The natural trienones 4 and 5 have been synthesized by this method, together with the trienone analogues 9-20. These analogues were evaluated for their cytotoxic activity against human oral cancer KB cell line. The structure-activity relationship study has indicated that the analogues with the 1,4,6-trien-3-one function are more potent than the curcuminoid-type function. Analogues with meta-oxygen function on the aromatic rings are more potent than those in the ortho- and para-positions. Free phenolic hydroxy group is more potent than the corresponding methyl ether analogues. Among the potent trienones, compounds 11, 18 and 20 were more active than the anticancer drug ellipticine. All compounds were also evaluated against the non-cancerous Vero cells and it was found that compounds 11, 12 and 17 were much less toxic than curcumin (1); they showed high selectivity indices of 35.46, 33.46 and 31.68, respectively. These analogues are regarded as the potent trienones for anti-oral cancer study. PMID:24857542

Chuprajob, Thipphawan; Changtam, Chatchawan; Chokchaisiri, Ratchanaporn; Chunglok, Warangkana; Sornkaew, Nilubon; Suksamrarn, Apichart



The Grid File: An Adaptable, Symmetric Multi-Key File Structure  

Microsoft Academic Search

Traditional file structures that provide multi-key access to records, for example inverted files, are extensions of file structures originally designed for single-key access. They manifest various deficiencies, in particular for multi-key access to highly dynamic files. We study the dynamic aspects of file structures that treat all keys symmetrically, that is, avoid the distinction between primary key and secondary keys.

Jürg Nievergelt; Hans Hinterberger; Kenneth C. Sevcik



Structural correlation of some heterocyclic chalcone analogues and evaluation of their antioxidant potential.  


A series of six novel heterocyclic chalcone analogues 4(a-f) has been synthesized by condensing 2-acetyl-5-chlorothiophene with benzaldehyde derivatives in methanol at room temperature using a catalytic amount of sodium hydroxide. The newly synthesized compounds are characterized by IR, mass spectra, elemental analysis and melting point. Subsequently; the structures of these compounds were determined using single crystal X-ray diffraction. All the synthesized compounds were screened for their antioxidant potential by employing various in vitro models such as DPPH free radical scavenging assay, ABTS radical scavenging assay, ferric reducing antioxidant power and cupric ion reducing antioxidant capacity. Results reflect the structural impact on the antioxidant ability of the compounds. The IC? values illustrate the mild to good antioxidant activities of the reported compounds. Among them, 4f with a p-methoxy substituent was found to be more potent as antioxidant agent. PMID:24077177

Kumar, C S Chidan; Loh, Wan-Sin; Ooi, Chin Wei; Quah, Ching Kheng; Fun, Hoong-Kun



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

SciTech Connect

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.

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



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

SciTech Connect

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.

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



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

PubMed Central

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 ?-stacking interactions between adjacent adenine and guanine bases and 2 conserved tyrosines. An arginine at one end of the ?-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 H2O nucleophile. Catalytic forces originate primarily from leaving group activation evident in both RTA and SAP in complex with transition state analogues.

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



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

NASA Astrophysics Data System (ADS)

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.

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



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

PubMed Central

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.

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



[Effect of a synthetic analogue of bacterial anabiosis autoinducers hexylresorcinol on the stability of membrane structures].  


The effect of hexylresorcinol (HR), a chemical analogue of microbial anabiosis autoinducers of the alkylhydroxybenzene (AHB) group, on the stability of biological membranes and monolamellar liposomes formed of egg phosphatidylcholine (ePC) was studied. According to spectrophotometry and electron microscopy studying of HR-loaded liposomes in the presence of a surface-active agent Tween 20, the critical ratio between HR and ePC for liposome preservation was found to be close to equimolar. The trends in HR influence on membrane structural organization and stability confirmed in experiments on liposomes were also reproduced on intact bacterial cells explaining non-species-specific effect of AHBs. The demonstrated high efficiency of AHB biocides may be used in material and equipment protection against biocorrosion. PMID:19382705

Lo?lo, N G; Muliukin, A L; Kozlova, A N; Kaplun, A P; Sorokin, V V; Borzenkov, I A; Nikolaev, Iu A; Kaprel'iants, A S; El'-Registan, G I



Impact of synkinematic sedimentation on the geometry and dynamics of compressive growth structures: Insights from analogue modelling  

NASA Astrophysics Data System (ADS)

Analogue sandbox models have been set up to study the impact of synkinematic deposits on the geometry and evolution of single thrusts and folds according to different sedimentation modes (a slow or rapid sedimentation rate that is constant or changing in space and time) and rheological profiles (thin or thick sedimentary series, with or without a basal décollement level). A first series of experiments documents the influence of synkinematic deposits according to their sedimentation rate and the rheology of the prekinematic materials. A second series investigates the influence of changes in the sedimentation rate through time. A third one considers the influence of changes in the sedimentation rate in space. All these experiments suggest that the geometry and evolution of single compressive growth structures vary according to the sedimentation rate. The number and dip of their frontal thrust segments change with the ratio R between the sedimentation rate at the footwall of the faults and the uplift rate of their hanging wall. The latter is then more or less uplifted depending on the dip of the thrusts. As a result, the overall structure has either a fault-bend fold or a fault-propagation fold geometry. These rules are verified when the ratio R changes in space or through time. In addition, the rheological profile of the models also affects the geometry and evolution of compressive growth structures. Their structural style, as well as the synsedimentary splitting and steepening of the associated thrusts, varies according to the occurrence and strength of the brittle and ductile layers. According to this modelling study, the ratio R and its changes in space and time, along with the rheology of the deformed materials, are key parameters to better understand the geometrical and kinematical complexities of natural growth thrusts and folds and to improve their interpretation.

Barrier, Laurie; Nalpas, Thierry; Gapais, Denis; Proust, Jean-Noël



Information Theoretic Secret Key Generation: Structured Codes and Tree Packing  

ERIC Educational Resources Information Center

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,…

Nitinawarat, Sirin



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

Microsoft Academic Search

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),

Hyunjung Kim; Georges A Guiochon



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

PubMed Central

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.

Gupta, Malaya; Majumder, Upal Kanti



Morpho-structural criteria for the identification of volcano deformation processes from analogue modeling  

NASA Astrophysics Data System (ADS)

The morphology of volcanoes provides important information about edifice evolution. Volcanoes can deform by gravitational instability and intrusions. This deformation can compromise volcano structural stability, promoting flank collapse even at dormant edifices. Identification of past/active deformation processes is therefore important not only for the understanding of volcano evolution but also for volcanic hazards. Both deformation due to the flank spreading of a volcano over its weak core and due to the intrusion of a cryptodome in the volcano edifice can produce faulting and changes in the morphology of volcano flanks. These morpho-structural changes in the volcano open the possibility to identify potential deformed and unstable volcanoes using remote sensing techniques and DEMs. We have used analogue models of flank spreading and intrusion processes to make progress in the morpho-structural identification of deformation features which can provide criteria for distinguishing processes. We have geometrically and mechanically scaled two different sets of experiments using a sand-plaster mixture for volcano materials, silicone putty for weak core rocks and Golden Syrup for magma intrusions. For monitoring changes in the volcano morphology we have used a Kinect sensor (Microsoft), which provides us vertical displacements of volcano flanks several times per second with a 1 mm precision. We have synchronized the Kinect sensor with a digital camera for monitoring the spatio-temporal evolution of tectonic structures together with morphology. All experiments produce asymmetrical changes in volcano morphology, developing convex-concave geometries in the deformed flank. However, the spatial relationships of structures with changes in volcano flank curvature are different for the two processes, as noted by previous authors. The morphometric tools developed for analyzing volcano topography allow us to identify intrusion processes due to volcano volume increase. We have compared the results of our experiments with known examples of deformed volcanoes due to intrusions (eg., St Helens) and flank spreading (eg. Casita) and we confirmed that the criteria developed from modeling works well in the natural cases. We consider that further experiments are necessary to fully explore the capacity of application of morphometric tools to analogue modeling of volcano deformation processes, since our first results show a promising research avenue for the remote identification and evaluation of volcano deformation processes in remote volcanoes worldwide.

Rincon, Marta; Marquez, Alvaro; van Wyk de Vries, Benjamin; Herrera, Raquel; Granja Bruña, Jose Luis; Llanes, Pilar



Structure of the Isobar Analogue States (ias), Double Isobar Analogue States (dias), and Configuration States (cs) in Halo Nuclei  

NASA Astrophysics Data System (ADS)

Structure of the excited states and resonances with different isospin quantum numbers in halolike nuclei is discussed. It is shown that IAS, DIAS, and CS can simultaneously have nn, np, and pp halo components in their wave functions.

Izosimov, I. N.



Bispidine analogues of Cisplatin, Carboplatin, and oxaliplatin. Synthesis, structures, and cytotoxicity.  


Bispidine (3,7-diazabicyclo[3.3.1]nonane, C7H14N2) analogues of cisplatin, carboplatin, and oxaliplatin have been prepared. (C7H14N2)PtCl2·DMF (1b), obtained from (1,5-hexadiene)PtCl2 and bispidine in DMF, is dimeric in the solid state. Dissolving 1b in hot N-methylformamide allows crystallization of the solvent-free polymeric (C7H14N2)PtCl2 (1a). Recrystallization of 1a,b from hot water yields the trihydrate (C7H14N2)PtCl2·3H2O (1c). Reaction of 1 with Ag2(cbdca) (cbdca = 1,1-cyclobutanedicarboxylate) in water affords the pentahydrate (C7H14N2)Pt{C4H6(CO2)2}·5H2O (2b), which loses water in vacuo to give (C7H14N2)Pt{C4H6(CO2)2} (2a). Reaction of 1 with AgNO3 in water, followed by addition of Na2C2O4, affords the water-free polymeric (C7H14N2)Pt(C2O4) (3). All complexes have been structurally characterized, revealing various patterns of N-H···Cl and N-H···O hydrogen bonds. In the hydrates 1c and 2b the complexes are embedded in intricate three-dimensional water networks. Complexes 1a, 2a, and 3 have been tested for their cytotoxicity against human cancer cell lines K562 (chronic myeloid leukemia), A2780 (ovarian cancer), and its platinum-resistant subline A2780 CisR and are compared to their parent analogues. The new complexes show significant cytotoxic activity along with a low platinum resistance factor. PMID:24665859

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



Structure, aromaticity, stability, and energetic performance of the analogues and derivatives of s-heptazine.  


s-heptazine is one of the most attractive polycyclic C-N precursors for graphitic carbon nitride materials (CNx). In this paper in order to find the relationships between the structure, aromaticity, and stability for this novel compound, its analogues with three conjoint six-membered rings (I???V) and derivatives with different substituents (VI-1???VI-5) were investigated using the density functional theory method. Aromaticity was predicted using the magnetic criterion iso-chemical shielding surface in the Z direction (ICSSzz) obtained with the gauge-independent atomic orbital (GIAO) method. Stability was estimated by the band gap and the topological properties obtained from the atoms in molecules theory. Results show that replacement of the CH groups with the nitrogen atoms in the tricyclic core enhances both the aromaticity and the stability. s-heptazine (VI) that has the maximum number of N atoms among analogues I???VI possesses the largest aromaticity and the best stability. Substitutions of -NH2, -NHNH2, and -N3 groups increase not only the aromaticity but also the stability; -NO2 increases the aromaticity while decreases the stability; -CN decreases both the aromaticity and the stability. Furthermore, the energetic performance of VI-1???VI-5 was evaluated according to the estimated specific impulse (Is). The obtained Is has the order of VI-5?>?VI-4?>?VI-3?>?VI?>?VI-1?>?VI-2. The Is of VI-5 is higher than that of HMX (1, 3, 5, 7-tetranitro-1, 3, 5, 7-tetraazacyclooctane). PMID:25038634

Yang, Junqing; Gong, Xuedong; Wang, Guixiang



Antigelling and antisickling bisphenyl oligopeptides and peptide analogues have similar structural features.  


Single-crystal X-ray diffraction was used to determine the three-dimensional structures of two antigelling oligopeptides, L-lysyl-L-phenylalanyl-L-phenylalanine and L-phenylalanylglycylglycyl-D-phenylalanine, and two antisickling peptide analogues, L-phenylalanine benzyl ester and N-phenylacetyl-L-phenylalanine. Although these bisphenyl compounds are chemically quite different from one another, they demonstrate unusual structural similarities: The molecules have compact conformations in which the two phenyl rings are positioned approximately 5 A apart with interplanar angles approaching 90 degrees, thereby making intramolecular edge-to-face interactions. In addition, the polar atoms, nitrogen and oxygen, are in close proximity without forming intramolecular hydrogen bonds. The relative spatial distribution of polar and nonpolar atoms renders the structures compact and amphipathic. The intramolecular edge-to-face interaction between two aromatic rings, which brings a hydrogen atom with relative positive charge near the pi-electron cloud with relative negative charge, is enthalpically favorable and maintains the molecules in a compact and amphipathic conformation. Nonbonded potential energy calculations were used to characterize the energetics of the aromatic-aromatic interaction, and they showed that the observed geometry is stabilized enthalpically by a favorable interaction on the order of -1 to -2 kcal/mol. Structural differences between the two antisickling and the two antigelling agents suggest that molecular volume limits red cell membrane passage. These data provide a molecular structural framework from which to design and synthesize amphipathic bisphenyl compounds that both bind to deoxy sickle cell hemoglobin and cross the erythrocyte membrane. PMID:3663644

Burley, S K; Wang, A H; Votano, J R; Rich, A



Transition state analogue structures of human phosphoglycerate kinase establish the importance of charge balance in catalysis.  


Transition state analogue (TSA) complexes formed by phosphoglycerate kinase (PGK) have been used to test the hypothesis that balancing of charge within the transition state dominates enzyme-catalyzed phosphoryl transfer. High-resolution structures of trifluoromagnesate (MgF(3)(-)) and tetrafluoroaluminate (AlF(4)(-)) complexes of PGK have been determined using X-ray crystallography and (19)F-based NMR methods, revealing the nature of the catalytically relevant state of this archetypal metabolic kinase. Importantly, the side chain of K219, which coordinates the alpha-phosphate group in previous ground state structures, is sequestered into coordinating the metal fluoride, thereby creating a charge environment complementary to the transferring phosphoryl group. In line with the dominance of charge balance in transition state organization, the substitution K219A induces a corresponding reduction in charge in the bound aluminum fluoride species, which changes to a trifluoroaluminate (AlF(3)(0)) complex. The AlF(3)(0) moiety retains the octahedral geometry observed within AlF(4)(-) TSA complexes, which endorses the proposal that some of the widely reported trigonal AlF(3)(0) complexes of phosphoryl transfer enzymes may have been misassigned and in reality contain MgF(3)(-). PMID:20397725

Cliff, Matthew J; Bowler, Matthew W; Varga, Andrea; Marston, James P; Szabó, Judit; Hounslow, Andrea M; Baxter, Nicola J; Blackburn, G Michael; Vas, Mária; Waltho, Jonathan P



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

NASA Astrophysics Data System (ADS)

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.

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



Synthesis and structure-activity relationship studies of novel tubulysin U analogues--effect on cytotoxicity of structural variations in the tubuvaline fragment.  


Tubulysins are cytotoxic natural products with promising anti-cancer properties, originally isolated from myxobacterial cultures. Structurally, tubulysins are tetrapeptides, incorporating three unusual (Mep, Tuv and Tup) and one proteinogenic amino acid (Ile). Here we describe the synthesis and structure-activity relationship studies of novel tubulysin U and V analogues, with variations in the central Tuv fragment, which is known to be of paramount importance for tubulysins' potency and hence cytotoxicity, but has seldom been modified in previous studies. Specifically, we replaced the natural iso-propyl and acetoxy functionalities with other structurally related groups. In general, the new analogues showed much lower potency relative to native tubulysin U. However, one of the synthetic analogues (1f) having a MOM function replacing the acetyl group exhibited a 22 nM IC50 on the HT-29 cell line which is comparable to the IC(50) displayed by tubulysin U (3.8 nM). Furthermore, the synthetic methodology reported herein was found to be flexible enough to deliver different core-modified tubulysin analogues and hence may be regarded as a scalable and convenient strategy for the chemical generation of novel tubulysin analogues. PMID:23411563

Shankar, Sreejith P; Jagodzinska, Monika; Malpezzi, Luciana; Lazzari, Paolo; Manca, Ilaria; Greig, Iain R; Sani, Monica; Zanda, Matteo



1,2-dithiole-3-thione and its structural analogue oltipraz are potent inhibitors of dibenz.  


Dithiolethiones are currently one of the most promising classes of cancer chemopreventive agents that exhibit antitumorigenic properties at numerous organ sites against several classes of carcinogens. In the current study, we examined the effects of 2 dithiolethiones, 1,2-dithiole-3-thione (D3T) and its structural analogue oltipraz, on DNA adduction induced by the potent mammary carcinogen dibenzo-[a,l]pyrene (DBP) in vivo. Female Sprague-Dawley rats were provided dietary D3T and oltipraz (500 ppm each) for I week followed by a single intragastric dose of DBP (8 micromol/kg body weight) and killed 5 days later. D3T inhibited DBP-DNA adduction from 78% to 82% in all tissues examined, while oltipraz was equally effective in the lung and liver but less effective in the mammary glands, inhibiting DBP-DNA adduction by nearly 60%. These data coupled with their broad anti-tumor specificity support the use of D3T and oltipraz as cancer-preventive agents in clinical trials. PMID:11149412

Smith, W A; Arif, J M; Gupta, R C



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

SciTech Connect

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.

Kim, Hyunjung [University of Tennessee, Knoxville (UTK); Kaczmarski, Krzysztof [University of Tennessee and Rzeszow University of Technology, Poland; Guiochon, Georges A [ORNL



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


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

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



Synthesis and structure–activity relationships of andrographolide analogues as novel cytotoxic agents  

Microsoft Academic Search

Andrographolide 1, the cytotoxic agent of the plant Andrographis paniculata was subjected to semi-synthetic studies leading to the preparation of a number of potent and novel analogues. Of the analogues synthesized, while 8,17-epoxy andrographolide 6 retained the cytotoxic activity of 1, ester derivatives of 6 exhibited considerable improvement in activity. Lower activity was observed when the epoxy moiety in the

Srinivas Nanduri; Vijay Kumar Nyavanandi; Siva Sanjeeva Rao Thunuguntla; Sridevi Kasu; Mahesh Kumar Pallerla; P. Sai Ram; Sriram Rajagopal; R. Ajaya Kumar; Rajagopalan Ramanujam; J. Moses Babu; Krishnamurthi Vyas; A. Sivalakshmi Devi; G. Om Reddy; Venkateswarlu Akella



Crystal Structure of Baeyer?Villiger Monooxygenase MtmOIV, the Key Enzyme of the Mithramycin Biosynthetic Pathway  

SciTech Connect

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 kDa homodimeric 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. MtmOIV's structure was determined by X-ray crystallography using molecular replacement to a resolution of 2.9 A. 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 identifies several residues that participate in cofactor 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.

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



Research Article Crystal structure of Enterobacter cloacae 908R class C bb-lactamase bound to iodo-acetamido-phenyl boronic acid, a transition-state analogue  

Microsoft Academic Search

The structures of the class C b-lactamase from Enterobacter cloacae 908R alone and in complex with a boronic acid transition-state analogue were determined by X-ray crystallography at 2.1 and 2.3 Å, respectively. The structure of the enzyme resembles those of other class C b-lactamases. The structure of the complex with the tran- sition-state analogue, iodo-acetamido-phenyl boronic acid, shows that the

J. Wouters; E. Fonzé; M. Vermeire; J.-M. Frèreb; P. Charlier


Crystal structure of Enterobacter cloacae 908R class C ß-lactamase bound to iodo-acetamido-phenyl boronic acid, a transition-state analogue  

Microsoft Academic Search

The structures of the class C ß-lactamase from Enterobacter cloacae 908R alone and in complex with a boronic acid transition-state analogue were determined by X-ray crystallography at 2.1 and 2.3 Å, respectively. The structure of the enzyme resembles those of other class C ß-lactamases. The structure of the complex with the transition-state analogue, iodo-acetamido-phenyl boronic acid, shows that the inhibitor

J. Wouters; E. Fonzé; M. Vermeire; J.-M. Frère; P. Charlier



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

SciTech Connect

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.

Kim, Hyunjung [University of Tennessee, Knoxville (UTK); Guiochon, Georges A [ORNL



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


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(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. PMID:16194108

Kim, Hyunjung; Guiochon, Georges



Self-assembly of a molecular crown as a structural analogue of calix[4]arene to modify Keggin anions.  


Four Ag(I) ions are linked by four 5-phenyl-1H-tetrazole (Hptz) units to form a molecular crown [Ag4(ptz)4] as a structural analogue of calix[4]arene, which are further supported by Keggin anions to build a 2D layer containing two kinds of cycles, [Ag8(ptz)4(HPW(V)2W(VI)10O40)]·2H2O (1). PMID:23698455

Tian, Aixiang; Lin, Xiaoling; Ying, Jun; Zhang, Juwen; Lin, Hongyan; Liu, Guocheng; Zhao, Dan; Li, Na; Wang, Xiuli



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

Microsoft Academic Search

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

Hyunjung Kim; Georges A Guiochon



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

PubMed Central

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.

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



Synthesis of 13C- and 14C-labeled dinucleotide mRNA cap analogues for structural and biochemical studies  

PubMed Central

Herein we describe the first simple and short method for specific labeling of mono- and trimethylated dinucleotide mRNA cap analogues with 13C and 14C isotopes. The labels were introduced within the cap structures either at the N7 for monomethylguanosine cap or N7 and N2 position for trimethylguanosine cap. The compounds designed for structural and biochemical studies will be useful tools for better understanding the role of the mRNA cap structures in pre-mRNA splicing, nucleocytoplasmic transport, translation initiation and mRNA degradation.

Piecyk, Karolina; Davis, Richard E.; Jankowska-Anyszka, Marzena



Structure-activity relationship of S-trityl-L-cysteine analogues as inhibitors of the human mitotic kinesin Eg5.  


The human kinesin Eg5 is a potential drug target for cancer chemotherapy. Eg5 specific inhibitors cause cells to block in mitosis with a characteristic monoastral spindle phenotype. Prolonged metaphase block eventually leads to apoptotic cell death. S-trityl-L-cysteine (STLC) is a tight-binding inhibitor of Eg5 that prevents mitotic progression. It has proven antitumor activity as shown in the NCI 60 tumor cell line screen. It is of considerable interest to define the minimum chemical structure that is essential for Eg5 inhibition and to develop more potent STLC analogues. An initial structure-activity relationship study on a series of STLC analogues reveals the minimal skeleton necessary for Eg5 inhibition as well as indications of how to obtain more potent analogues. The most effective compounds investigated with substitutions at the para-position of one phenyl ring have an estimated K i (app) of 100 nM in vitro and induce mitotic arrest with an EC 50 of 200 nM. PMID:18266314

Debonis, Salvatore; Skoufias, Dimitrios A; Indorato, Rose-Laure; Liger, François; Marquet, Bernard; Laggner, Christian; Joseph, Benoît; Kozielski, Frank



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


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

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



Structures and excitation energies of Zn–tetraarylporphyrin analogues: A theoretical study  

Microsoft Academic Search

The photophysical properties of ?-substituted Zn–tetraarylporphyrin (ZnTAP) analogues used as dyes in dye-sensitized solar cells were studied using density functional theory (DFT). Singlet-excitation energy calculations of ZnTAP analogues were performed using time-dependent DFT with B3LYP, B3PW91, PBE0 exchange–correlation functionals at 6-31G(d) and 6-31+G(d) basis sets using B3LYP\\/6-31G(d) geometries. The PBE0 functional at 6-31+G(d) basis set provided a better correlation with

Mannix P. Balanay; Dong Hee Kim



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


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

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



A Ground Penetrating Radar Lunar Analogue Field Campaign in the Haughton Impact Structure, Canada  

NASA Astrophysics Data System (ADS)

Ground-Penetrating Radar (GPR) has been widely cited as an important scientific instrument for future Moon and Mars surface exploration missions. In support of GPR technique testing for lunar subsurface exploration, a series of overlapping 3D GPR surveys were conducted over impact melt rocks in the 39 Ma, 23 km diameter Haughton impact structure, Devon Island, Nunavut, Canada. The target consisted of calcite-dominated clast-rich impact melt rock with permafrost at depths less than one metre. The target rocks were chosen as a physical analogue to lunar electrical conditions: the electrical permittivity and conductivity in ice produce a better match for lunar electrical conditions than liquid water bearing sites. Using commercially available equipment, 50, 100 and 200 MHz GPR surveys were conducted in a high-resolution grid 30m by 30m totalling nearly 14 km of GPR lines. Lines ran in both X and Y directions with the following line spacings: 50 cm for 50 MHz for a total of 122 lines; 50 cm with a subset at 25 cm at 100 MHz totalling 162 lines; and subsets of the grid were done at 25 and 10 cm line spacings at 200 MHz totalling 182 lines. CMP surveys at each frequency were performed to provide velocity information for the active and permafrost layers with results ranging from 0.068 to 0.088 m/ns. Physical samples were obtained to confirm the electrical properties of the survey site for use in comparative modelling. Initial data show some shallow dipping features which vanish at depths of approximately 7, 4 and 2.5 metres at 50, 100 and 200 MHz respectively. These data are compared to a 100 MHz transect of nearby non-brecciated dolomitic limestone which shares a weathering processes and is compositionally similar. In the non-brecciated materials, clear reflectors are visible beyond a depth of 8 metres at 100 MHz. Thus, preliminary results show higher effective attenuation in the breccia than can be explained by conductivity alone. This suggests that the brecciated and melted medium is increasing signal attenuation due to scattering processes. This additional attenuation has implications for the usefulness of GPR as an exploration method in lunar mediums, particularly in seeing through regolith and impact breccias. Additional modelling and field surveys at other terrestrial impact structures are planned to confirm these results.

Unrau, T.; Tiampo, K. F.; Pratt, R. G.; Osinski, G.




EPA Science Inventory

Consideration of Reaction Intermediates in Structure- Activity Relationships: A Key to Understanding and Prediction A structure-activity relationship (SAR) represents an empirical means for generalizing chemical information relative to biological activity, and is frequent...


Structural stator spacers-the key to silent electrical machines  

Microsoft Academic Search

This paper presents a powerful new design aspect to reduce acoustic noise and vibration of electro-magnetic origin for electrical machines, by introducing improved slot wedges referred to as “structural stator spacers”. These spacers, by using a very stiff dielectric and nonmagnetic material, a modified shape and small modifications to the stator laminations not only secure the windings and reduce windage

P. O. Rasmussen; J. Andreasen; J. M. Pijanowski



Physiological evidence for the discrimination of L-arginine from structural analogues by the zebrafish olfactory system.  


Although it is generally assumed that fish are capable of discriminating amino acid odorants on the basis of differences in side-chain structure, less is known about their ability to discriminate amino acids with modifications to alpha-carboxyl and alpha-amino groups. In this study, the ability of the zebrafish olfactory system to detect and presumably discriminate analogues of the basic amino acid Arg was assessed, by using cross-adaptation and activity-dependent labeling techniques. Electrophysiological recordings established that esterification (L-arginine methyl ester; AME) or deletion (agmatine or amino-4-guanidobutane; AGB) of the alpha-carboxyl group yielded odorants more potent than Arg, whereas deletion of the alpha-amino group (L-argininic acid; AA) yielded a less potent analogue. In cross-adaptation experiments, no test-competitor odorant combination yielded complete cross-adaptation, suggesting the detection of these Arg analogues by multiple odorant receptors (ORs) with partially nonoverlapping specificities. Activity-dependent immunocytochemical labeling of olfactory receptor neurons supported this conclusion. AGB, an ion-channel-permeant probe (and odorant), labeled 4.9 +/- 0.4% (n = 24) of sensory epithelium, whereas the addition of Arg, 1-ethylguanidine sulfate, L-alpha-amino-beta-guanidinopropionate, or AME to AGB resulted in a significant elevation of labeling (8-14%). This study provides evidence that the olfactory system has the potential to discriminate among amino acid odorants with modified alpha-carboxyl and alpha-amino groups. PMID:10601449

Lipschitz, D L; Michel, W C



Structure-activity relationships of a series of analogues of the RFamide-related peptide 26RFa.  


26RFa is a new member of the RFamide peptide family that has been identified as the endogenous ligand of the orphan GPCR GPR103. As the C-terminal heptapeptide (26RFa((20-26))) mimics the action of the native peptide on food intake and gonadotropin secretion in rodents, we have synthesized a series of analogues of 26RFa((20-26)) and measured their potency to induce [Ca(2+)](i) mobilization in G?(16)-hGPR103-transfected CHO cells. Systematic replacement of each residue by an alanine (Ala scan) and its D-enantiomer (D scan) showed that the last three C-terminal residues were very sensitive to the substitutions while position 23 tolerated rather well both modifications. Most importantly, replacement of Ser(23) by a norvaline led to an analogue, [Nva(23)]26RFa((20-26)), that was 3-fold more potent than the native heptapeptide. These new pharmacological data, by providing the first information regarding the structure-activity relationships of 26RFa analogues, should prove useful for the rational design of potent GPR103 receptor ligands with potential therapeutic application. PMID:21623631

Le Marec, Olivier; Neveu, Cindy; Lefranc, Benjamin; Dubessy, Christophe; Boutin, Jean A; Do-Régo, Jean-Claude; Costentin, Jean; Tonon, Marie-Christine; Tena-Sempere, Manuel; Vaudry, Hubert; Leprince, Jérôme



Structure-Activity Analysis of Diffusible Lipid Electrophiles Associated with Phospholipid Peroxidation: 4-Hydroxynonenal and 4-Oxononenal Analogues  

PubMed Central

Electrophile-mediated disruption of cell signal-ing is involved in the pathogenesis of several diseases including atherosclerosis and cancer. Diffusible and membrane bound lipid electrophiles are known to modify DNA and protein substrates and modulate cellular pathways including ER stress, antioxidant response, DNA damage, heat shock, and apoptosis. Herein we report on a structure?activity relationship for several electrophilic analogues of 4-hydroxynonenal (HNE) and 4-oxononenal (ONE) with regard to toxicity and anti-inflammatory activity. The analogues studied were the oxidation products of HNE and ONE, HNEA/ONEA, the in vivo hydrolysis products of oxidized phosphatidylcholine, COOH-HNE/COOH-ONE, and their methyl esters, COOMe-HNE/ONE. The reactivity of each compound toward N-acetylcysteine was determined and compared to the toxicity toward a human colorectal carcinoma cell line (RKO) and a human monocytic leukemia cell line (THP-1). Further analysis was performed in differentiated THP-1 macrophages to assess changes in macrophage activation and pro-inflammatory signaling in response to each lipid electrophile. HNE/ONE analogues inhibited THP-1 macrophage production of the pro-inflammatory cytokines, IL-6, IL-1?, and TNF?, after lipopolysaccharide (LPS)/IFN? activation. Inhibition of cytokine production was observed at submicromolar concentrations of several analogues with as little as 30 min of exposure. Phagocytosis of fluorescent beads was also inhibited by lipid electrophile treatment. Lipid electrophiles related to HNE/ONE are both toxic and anti-inflammatory, but the anti-inflammatory effects in human macrophages are observed at nontoxic concentrations. Neither toxicity nor anti-inflammatory activity are strongly correlated to the reactivity of the model nucleophile, N-acetylcysteine.



Structural visualization of key steps in human transcription initiation.  


Eukaryotic transcription initiation requires the assembly of general transcription factors into a pre-initiation complex that ensures the accurate loading of RNA polymerase II (Pol II) at the transcription start site. The molecular mechanism and function of this assembly have remained elusive due to lack of structural information. Here we have used an in vitro reconstituted system to study the stepwise assembly of human TBP, TFIIA, TFIIB, Pol II, TFIIF, TFIIE and TFIIH onto promoter DNA using cryo-electron microscopy. Our structural analyses provide pseudo-atomic models at various stages of transcription initiation that illuminate critical molecular interactions, including how TFIIF engages Pol II and promoter DNA to stabilize both the closed pre-initiation complex and the open-promoter complex, and to regulate start--initiation complexes, combined with the localization of the TFIIH helicases XPD and XPB, support a DNA translocation model of XPB and explain its essential role in promoter opening. PMID:23446344

He, Yuan; Fang, Jie; Taatjes, Dylan J; Nogales, Eva



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


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

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



PABA/NO as an anticancer lead: analogue synthesis, structure revision, solution chemistry, reactivity toward glutathione, and in vitro activity.  


PABA/NO is a diazeniumdiolate of structure Me(2)NN(O)=NOAr (where Ar is a 5-substituted-2,4-dinitrophenyl ring whose 5-substituent is N-methyl-p-aminobenzoic acid). It has shown activity against human ovarian cancer xenografts in mice rivaling that of cisplatin, but it is poorly soluble and relatively unstable in water. Here we report structure-based optimization efforts resulting in three analogues with improved solubility and stability in aqueous solution. We sought to explain PABA/NO's physicochemical uniqueness among these four compounds, whose aminobenzoic acid precursors differ structurally only in the presence or absence of the N-methyl group and/or the position of the carboxyl moiety (meta or para). Studies revealed that PABA/NO's N-methyl-p-aminobenzoic acid substituent is bound to the dinitrobenzene ring via its carboxyl oxygen while the other three are linked through the aniline nitrogen. This constitutes a revision of the previously published PABA/NO structure. All four analogues reacted with GSH to produce bioactive nitric oxide (NO), but PABA/NO was the most reactive. Consistent with PABA/NO's potent suppression of A2780 human ovarian cancer xenograft growth in mice, it was the most potent of the four in the OVCAR-3 cell line. PMID:16451080

Saavedra, Joseph E; Srinivasan, Aloka; Buzard, Gregory S; Davies, Keith M; Waterhouse, David J; Inami, Keiko; Wilde, Thomas C; Citro, Michael L; Cuellar, Matthew; Deschamps, Jeffrey R; Parrish, Damon; Shami, Paul J; Findlay, Victoria J; Townsend, Danyelle M; Tew, Kenneth D; Singh, Shivendra; Jia, Lee; Ji, Xinhua; Keefer, Larry K



A comparison of the antiatherogenic effects of probucol and of a structural analogue of probucol in low density lipoprotein receptor-deficient rabbits.  

PubMed Central

The efficacies of probucol and a close structural analogue as antioxidants in the prevention of atherogenesis in LDL receptor-deficient rabbits were compared. The antioxidant potency of the analogue in vitro was equal to that of probucol. Its biological availability was much greater: almost comparable concentrations in total plasma were achieved by feeding 1% probucol (wt/wt) and 0.05% analogue (wt/wt). Total plasma concentrations were comparable, but the concentration of probucol within the LDL fraction was about twice that of the analogue. Probucol slowed lesion progression by almost 50%, confirming earlier reports; the analogue, however, showed no detectable inhibitory effect on atherogenesis. Resistance of LDL to oxidation was measured at the end of the study by incubating it with Cu2+ and measuring the rate of diene conjugation. Probucol prolonged diene conjugation lag time from the control value of 130 min to values > 1,000 min. The analogue approximately tripled the lag time (mean, 410 min) and yet failed to slow the atherogenic process. The results suggest that LDL resistance to oxidation must reach some threshold level before there is significant protection against atherogenesis. However, probucol has additional biological effects, possibly not shared by the analogue, that could contribute to its antiatherogenic potential. Images

Fruebis, J; Steinberg, D; Dresel, H A; Carew, T E



Synthesis and structure-activity relationships of constrained heterocyclic analogues of combretastatin A4.  


A series of combretastatin A4 (CA4) analogues with a lactam or lactone ring fused to the trimethoxyphenyl or the B-phenyl moiety were synthesized in an efficient and stereoselective manner by using a domino Heck-Suzuki-Miyaura coupling reaction. The vascular-disrupting potential of these conformationally restricted CA4 analogues was assessed by various in?vitro assays: inhibition of tubulin polymerization, modification of endothelial cell morphology, and disruption of endothelial cell cords. Compounds were also evaluated for their growth inhibitory effects against murine and human tumor cells. B-ring-constrained derivatives that contain an oxindole ring (in contrast to compounds with a benzofuranone ring) as well as analogues bearing a six-membered lactone core fused to the trimethoxyphenyl ring are endowed with significant biological activity. The most potent compound of this series (oxindole 9?b) is of particular interest, as it combines chemical stability and a biological activity profile characteristic of a vascular-disrupting agent. PMID:21732536

Arthuis, Martin; Pontikis, Renée; Chabot, Guy G; Seguin, Johanne; Quentin, Lionel; Bourg, Stéphane; Morin-Allory, Luc; Florent, Jean-Claude



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

SciTech Connect

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.

Galas, M.C.; Lignon, M.F.; Rodriguez, M.; Mendre, C.; Fulcrand, P.; Laur, J.; Martinez, J. (Centre de Pharmacologie-Endocrinologie, Montpellier (France))



Cisplatin and its analogues induce a significant change in the higher-order structure of long duplex DNA  

NASA Astrophysics Data System (ADS)

It has recently become clear that a long DNA with a size of more than several tens of kilo base-pairs (kbp) exhibits a large on/off change in conformation between elongated coil and folded compact states. To explore the possible effect of anticancer drugs on the conformation of large DNA, we observed single DNA molecules with regard to changes in their higher-order structure upon the addition of cisplatin and its derivatives, diamminedinitratoplatinum(II) and tetrammineplatinum(II). We found that these cisplatin analogues significantly affected the conformation of individual DNA molecules by inducing a folding transition.

Katsuda, Yousuke; Yoshikawa, Yuko; Sato, Takaji; Saito, Yoshihiro; Chikuma, Masahiko; Suzuki, Mari; Yoshikawa, Kenichi



Divalent and oxabridged neonicotinoids constructed by dialdehydes and nitromethylene analogues of imidacloprid: design, synthesis, crystal structure, and insecticidal activities.  


A series of divalent and oxabridged neonicotinoids were synthesized by reactions of nitromethylene analogues of imidacloprid and dialdehydes, and their structures were confirmed by (1)H NMR, (13)C NMR, high-resolution mass spectroscopy, and X-ray diffraction analysis. The bioassays indicated that some of them were endowed with excellent insecticidal activities against cowpea aphid ( Aphis craccivora ), armyworm ( Pseudaletia separata Walker), and brown planthopper ( Nilaparvata lugens ). Divalent neonicotinoid 6 and oxabridged 8a had higher activities than imidacloprid against cowpea aphids and armyworm; furthermore, the activity of 8a was 40.4-fold higher than that of imidacloprid against imidacloprid-resistant brown planthopper. PMID:20000569

Shao, Xusheng; Fu, Hua; Xu, Xiaoyong; Xu, Xinglei; Liu, Zewen; Li, Zhong; Qian, Xuhong



An analogue-sensitive approach identifies basal body rotation and flagellum attachment zone elongation as key functions of PLK in Trypanosoma brucei  

PubMed Central

Polo-like kinases are important regulators of cell division, playing diverse roles in mitosis and cytoskeletal inheritance. In the parasite Trypanosoma brucei, the single PLK homologue TbPLK is necessary for the assembly of a series of essential organelles that position and adhere the flagellum to the cell surface. Previous work relied on RNA interference or inhibitors of undefined specificity to inhibit TbPLK, both of which have significant experimental limitations. Here we use an analogue-sensitive approach to selectively and acutely inhibit TbPLK. T. brucei cells expressing only analogue-sensitive TbPLK (TbPLKas) grow normally, but upon treatment with inhibitor develop defects in flagellar attachment and cytokinesis. TbPLK cannot migrate effectively when inhibited and remains trapped in the posterior of the cell throughout the cell cycle. Using synchronized cells, we show that active TbPLK is a direct requirement for the assembly and extension of the flagellum attachment zone, which adheres the flagellum to the cell surface, and for the rotation of the duplicated basal bodies, which positions the new flagellum so that it can extend without impinging on the old flagellum. This approach should be applicable to the many kinases found in the T. brucei genome that lack an ascribed function.

Lozano-Nunez, Ana; Ikeda, Kyojiro N.; Sauer, Thomas; de Graffenried, Christopher L.



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

PubMed Central

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.

Huang, Yanzhao; Xiao, Yi



Secrecy improvement in confidential coherence modulation by means of a new keying structure  

Microsoft Academic Search

In this paper, we present a new keying structure which enhances the secrecy of an already relatively secure coherence modulation method we developed recently. The originality of the method consists in using an encrypting key composed of a large amplitude – low frequency part and a low amplitude – high frequency part. These two components ensure that the spectrum, as

B. Wacogne; W. Elflein; C. Pieralli; P. Mollier; H. Porte; D. A. Jackson



Extent of salmeterol-mediated reassertion of relaxation in guinea-pig trachea pretreated with aliphatic side chain structural analogues.  

PubMed Central

1. Salmeterol is a potent, selective and long acting beta 2-adrenoceptor agonist. In vitro, salmeterol exerts 'reassertion' relaxation of airways smooth muscle. Reassertion relaxation refers to the capacity of salmeterol to cause repeated functional antagonism of induced contraction when airway smooth muscle is intermittently exposed to, then washed free from, beta-adrenoceptor antagonists such as sotalol. The mechanism(s) underlying reassertion relaxation are unknown but may relate to high affinity binding of the long aliphatic side chain of salmeterol to an accessory site, distinct from the agonist recognition site, in or near the beta 2-adrenoceptor (exosite binding hypothesis). 2. In order to test the exosite hypothesis, three pure analogues of salmeterol, each exactly preserving the molecular structure of the aliphatic side chain but with zero or low efficacy at the beta 2-adrenoceptor were synthesized. The effect of pre-incubating guinea-pig tracheal smooth muscle with these analogues on salmeterol-induced reassertion relaxation was determined. 3. Computer Assisted Molecular Modelling of these molecules revealed that each of them exactly preserved the low energy linear conformation of the aliphatic side chain of salmeterol. Measurement of lipophilicity (octanol:water partition coefficient; log P) and direct partition into synthetic membranes (membrane partition coefficient; Kpmem) showed that all compounds had high affinity for lipids and membranes. In particular the biophysical properties of CGP 59162 (log P 1.89, Kpmem 16500) were very similar to salmeterol (log P 1.73, Kpmem 16800). 4. Two of the analogues, CGP 54103 and D 2543 (1 microM), which are structural mimics of the side chain of salmeterol, differing slightly in their length, did not prevent either the initial relaxation induced by salmeterol (0.1 microM) or the reassertion relaxation; however, it was not possible to determine whether either of these molecules occupied the beta 2-adrenoceptor. 5. The third analogue, CGP 59162, which has the substituents on the active saligenin head group of salmeterol in transposed positions, itself exerted a weak beta 2-adrenoceptor-mediated relaxation antagonized by ICI 118551 (beta 2-selective antagonist) but not CGP 20712 (beta 1-selective antagonist) and, at higher concentrations CGP 59162 caused reassertion relaxation suggesting that it may occupy and activate the beta 2-adrenoceptor in a manner analogous to salmeterol. 6. CGP 59162, at concentrations up to ten fold molar excess, did not prevent or reduce salmeterol-induced reassertion relaxation. 7. In conclusion these data are not consistent with the existence of a distinct 'exosite' recognising the aliphatic side chain of salmeterol mediating reassertion. Images Figure 3

Bergendal, A.; Linden, A.; Skoogh, B. E.; Gerspacher, M.; Anderson, G. P.; Lofdahl, C. G.



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

NASA Astrophysics Data System (ADS)

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.

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



Use of keyed character string data structures and operators in models of primate groups.  


Many primate populations exhibit forms of organization that are both complex and highly dynamic. A prototype of a general purpose primate population computer modelling system has been developed; this modelling system provides data structures and operators that facilitate computer representation of many static and dynamic features of primate population organization. In this system, primate group structures are represented by text strings known as key strings. A key string begins with a label or key character that identifies its population element type. The label character is followed by data fields contained between bounds marker characters. Nested key strings can be used to concisely represent many of the structural features of social groups in different primate species. Changes in group structures are accomplished by key string insertion, deletion and move operations. Models of structures and processes in island, rhesus monkey and hamadryas baboon populations built with this prototype modelling system are discussed. In these pilot applications, use of key string data structures and operators greatly simplifies many aspects of model construction. PMID:3840219

Olivier, T J



Binding of bilirubin and its structural analogues to hepatic microsomal bilirubin UDP glucuronyltransferase  

SciTech Connect

Hepatic glucuronidation of the asymmetrical natural bilirubin molecule results in formation of two different positional isomers, bilirubin C-8 monoglucuronide and bilirubin C-12 monoglucuronide. In view of the existence of multiple isoforms of UDPglucuronyltransferase, which is the microsomal enzyme system responsible for bilirubin esterification, the authors performed kinetic analysis of microsomal glucuronidation of bilirubin and a number of its structural congeners to determine whether synthesis of the two monoglucuronide isomers involved two distinct substrate-binding sites or reflected two different modes of binding to a single catalytic site. Both isomers were found in all tested species (man, rat, guinea pig, sheep), but there were marked species differences in the C-8/C-12 ratio of monoglucuronide found in bile or formed by liver microsomes. Correspondence between in vivo and in vitro results for such regioselectivity of glucuronidation was excellent in each species. On the basis of these results of kinetic analysis of bilirubin esterification at variable pigment substrate concentrations and inhibition studies with alternative substrates, the authors postulate that both natural monoglucuronide isomers are synthesized at a single binding site. Possible mechanisms responsible for the markedly regioselective esterification of bilirubin by rat and sheep liver were investigated by study of glucuronidation of selected structural analgoues of the pigment. Collectively, their findings suggest that the molecular from(s) of bilirubin able to engage in catalytically effective binding to UDPglucuronyltransferase does (do) not correspond with intramolecularly hydrogen-bonded conformers and that the nature of the ..beta..-substituents of the outer pyrromethenone rings is a key determinant of glucuronidation rate.

Vanstapel, F.; Blanckaert, N.



Structural characteristics of chloroquine-bridged ferrocenophane analogues of ferroquine may obviate malaria drug-resistance mechanisms.  


Five compounds displaying an unprecedented binding mode of chloroquine to ferrocene through the bridging of the cyclopentadienyl rings were studied alongside their monosubstituted ferrocene analogues and organic fragments. The antiplasmodial activity was evaluated against strains of the malaria parasite (Plasmodium falciparum). While the chloroquine-bridged ferrocenyl derivatives were less active than their five monosubstituted ferrocenyl analogues, they retained activity in the drug-resistant strains. The biological and physical properties were correlated to antiplasmodial activity. Intramolecular hydrogen bonding was associated with increased antiplasmodial action, but it is not the determining factor. Instead, balance between lipophilicity and hydrophilicity had a greater influence. It was found that calculated partition coefficient (log P) values of 4.5-5.0 and topological polar surfaces area (tPSA) values of ?26.0 Å(2) give the best balance. The particular conformation, compact size, and lipophilicity/hydrophilicity balance observed in the bridged compounds provide them with the structural characteristics needed to escape the mechanisms responsible for resistance. PMID:23327489

Salas, Paloma F; Herrmann, Christoph; Cawthray, Jacqueline F; Nimphius, Corinna; Kenkel, Alexander; Chen, Jessie; de Kock, Carmen; Smith, Peter J; Patrick, Brian O; Adam, Michael J; Orvig, Chris



Design, synthesis and structure-activity relationship of new arginine vasopressin analogues containing proline derivatives in position 2.  


In this study, we present the synthesis and pharmacological properties of new analogues of arginine vasopressin modified in the N-terminal part of the molecule with proline derivatives: indoline-2-carboxylic acid (Ica) and (2S,4R)-4-(naphthalene-2-ylmethyl)pyrrolidine-2-carboxylic acid. All the peptides were tested for pressor, antidiuretic and in vitro uterotonic activities. We also determined their binding affinity to the human oxytocin receptor. The Ica(2) substitution resulted in two moderately potent and selective antioxytocic agents: [Mpa(1), Ica(2), D-Arg(8)]VP and [Mpa(1),Ica(2),Val(4),D-Arg(8)]VP (pA(2) = 7.09 and 7.50, respectively). On the other hand, peptides modified with (2S,4R)-4-(naphthalene-2-ylmethyl)pyrrolidine-2-carboxylic acid, apart from their moderate antioxytocic activity, turned out to be weak antagonists of the pressor response to arginine vasopressin. The results of this study provide useful information about the structure-activity relationship of arginine vasopressin analogues and can help to design compounds with desired biological properties. PMID:23205571

Kwiatkowska, Anna; Lewandowska, Monika; Borovi?ková, Lenka; Slaninová, Ji?ina; Lammek, Bernard; Prahl, Adam



Salmonella enterica MTAN at 1.36 ? resolution. Structure-based design of new transition state analogues  

PubMed Central

SUMMARY Accumulation of 5?-methylthioadenosine (MTA) and S-adenosylhomocysteine (SAH) in bacteria disrupts the S-adenosylmethionine pool to alter biological methylations, synthesis of polyamines and production of quorum sensing molecules. Bacterial metabolism of MTA and SAH depends on MTA/SAH nucleosidase (MTAN), an enzyme not present in humans, and a target for quorum sensing since MTAN activity is essential for synthesis of autoinducer-2 molecules. Crystals of Salmonella enterica MTAN with product and transition state analogues of MTA and SAH explain the pM binding affinity and reveal ‘water-wire’ channel for the catalytic nucleophile. The crystal structure shows an extension of the binding pocket filled with polyethylene glycol. We exploited that discovery by the design and synthesis of new modifications of the currently existing transition state analogues to fill this site. This site was previously unknown in MTANs and reveals powerful inhibitors with solvent access. Novel inhibitors with dissociation constants of 5 to 15 pM are characterized.

Haapalainen, Antti M.; Thomas, Keisha; Tyler, Peter C.; Evans, Gary B.; Almo, Steven C.; Schramm, Vern L.



Structure-activity relationships of neoechinulin A analogues with cytoprotection against peroxynitrite-induced PC12 cell death.  


Neoechinulin A, an alkaloid from Eurotium rubrum Hiji025, protected neuronal PC12 cells against cell death induced by peroxynitrite derived from SIN-1 (3-(4-morpholinyl)sydnonimine hydrochloride). In this study, we investigated the structure-activity relationships of neoechinulin A and a set of its analogues by using assays to measure anti-nitration and antioxidant activities and cytoprotection against SIN-1-induced PC12 cell death. The presence of the diketopiperazine ring was essential for both the antioxidant and anti-nitration activities of neoechinulin A derivatives. Nevertheless, a derivative lacking the diketopiperazine ring could still protect PC12 cells against SIN-1 cytotoxicity. An acyclic analogue completely lost the cytoprotective effect while retaining its antioxidant/anti-nitration activities. Pre-incubation of the cells with neoechinulin A for at least 12 hours was essential for the cells to gain SIN-1 resistance. These results suggest that neoechinulin A endows the cells with cytoprotection through a biological effect different from the apparent antioxidant/anti-nitration activities. PMID:17965477

Kimoto, Kuniaki; Aoki, Toshiaki; Shibata, Yasushi; Kamisuki, Shinji; Sugawara, Fumio; Kuramochi, Kouji; Nakazaki, Atsuo; Kobayashi, Susumu; Kuroiwa, Kenji; Watanabe, Nobuo; Arai, Takao



Structure-based design, synthesis and preliminary anti-inflammatory activity of bolinaquinone analogues.  


As a part of our drug discovery efforts we developed a series of simplified derivatives of bolinaquinone (BLQ), a hydroxyquinone marine metabolite, showing potent anti-inflammatory activity. Thirteen new hydroxyquinone derivatives closely related to BLQ were synthesized and tested on mouse macrophage-like RAW 264.7 cell line in order to investigate their ability to modulate the production of Prostaglandin E2 (PGE2). This optimization process led to the identification of three strictly correlated compounds with comparable and higher inhibitory potency than BLQ on PGE2 production. To evaluate the affinity of BLQ and its analogues for hsPLA2, surface plasmon resonance (SPR) experiments were performed. PMID:21163556

Petronzi, Carmen; Filosa, Rosanna; Peduto, Antonella; Monti, Maria Chiara; Margarucci, Luigi; Massa, Antonio; Ercolino, Simona Francesca; Bizzarro, Valentina; Parente, Luca; Riccio, Raffaele; de Caprariis, Paolo



Structural effects of dinotefuran and analogues in insecticidal and neural activities.  


The insecticidal potencies of dinotefuran and analogues against the adult male American cockroach, Periplaneta americana (L) were measured by injection with or without metabolic inhibitors. The potency of dinotefuran was close to those of clothianidin and imidacloprid under the conditions used. The nerve-excitatory and nerve-blocking activities were measured with central nerve cords of P americana. The nerve-excitatory activity of dinotefuran was lower than that of imidacloprid, but was comparable with that of clothianidin. The nerve-blocking activity of dinotefuran was comparable with that of imidacloprid and slightly higher than that of clothianidin. Quantitative analyses showed that variations in the insecticidal activity were better correlated with variations in the nerve-blocking activity than with those in the nerve-excitatory activity when the contribution of the hydrophobic factor was allowed for. PMID:12146167

Kiriyama, Kazuhisa; Nishimura, Keiichiro



Crystal structure and computational investigation of an analogue of Grubbs' second generation catalyst with a fluorous phosphine.  


A fluorous phosphine analogue of Grubbs' second generation olefin metathesis catalyst, (H(2)IMes)((R(f8)(CH(2))(2))(3)P)(Cl)(2)Ru(=CHPh) (1; H(2)IMes/R(f8) = 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene/(CF(2))(7)CF(3)) is crystallized and the X-ray structure analyzed in detail. The bond lengths and angles about ruthenium are compared to those of two solvates and five derivatives of Grubbs' second generation catalyst. All exhibit distorted square pyramidal geometries in which the alkylidene ligands occupy apical positions, and geometric trends are interpreted with the help of density functional calculations. The perfluoroalkyl groups (1) exhibit helical conformations, as manifested by various torsional relationships, (2) segregate in the lattice, and (3) align in pairs of opposite helical chiralities. PMID:22954330

Tuba, Robert; Brothers, Edward N; Reibenspies, Joseph H; Bazzi, Hassan S; Gladysz, John A



Synthesis of pavoninin-1, a shark repellent substance, and its structural analogues toward mechanistic studies on their membrane perturbation.  


Pavoninin-1 (1), which was isolated from a defense secretion of the sole Pardachirus spp. as an ichthyotoxic and a shark repellent principle, and its structural analogue 2 were synthesized, where glycosylation using an 2-azidoglycosyl sulfoxide (10) afforded the corresponding beta-glycoside exclusively in high yield. Introduction of the alpha,beta-unsaturated ketone system in the ring A of 1 was achieved by phenylselenenylation of dihydropavoninin-1 (3) and subsequent oxidative elimination without protection of the hydroxyl groups in the sugar portion. The mode of action of these glycosides was evaluated for their perturbation on phosphatidylcholine liposomal membrane, using the fluorescent dye leakage method. The results revealed that membrane affinity does not parallel membrane perturbation but rather compensates it, and the spatial arrangement of hydrophobic and hydrophilic regions within a molecule is likely to reflect on the difference in potency of action among them. PMID:9459023

Ohnishi, Y; Tachibana, K



Structural analyses of covalent enzyme-substrate analogue complexes reveal strengths and limitations of de novo enzyme design  

PubMed Central

We report the cocrystal structures of a computationally designed and experimentally optimized retro-aldol enzyme with covalently bound substrate analogs. The structure with covalently bound substrate analog is similar but not identical to the design model, with an RMSD over the active site residues and equivalent substrate atoms of 1.4Å. As in the design model, the binding pocket orients the substrate through hydrophobic interactions with the naphthyl moiety such that the oxygen atoms analogous to the carbinolamine and ?-hydroxyl oxygens are positioned near a network of bound waters. However, there are differences between the design model and the structure: the orientation of the naphthyl group and the conformation of the catalytic lysine are slightly different; the bound water network appears to be more extensive; and the bound substrate analog exhibits more conformational heterogeneity than in typical native enzyme-inhibitor complexes. Alanine scanning of the active site residues shows that both the catalytic lysine and the residues around the binding pocket for the substrate naphthyl group make critical contributions to catalysis. Mutating the set of water-coordinating residues also significantly reduces catalytic activity. The crystal structure of the enzyme with a smaller substrate analogue that lacks the naphthyl rings shows the catalytic lysine to be more flexible than in the naphthyl substrate complex; increased preorganization of the active site would likely improve catalysis. The covalently bound complex structures and mutagenesis data highlight strengths and weaknesses of the de novo enzyme design strategy.

Wang, Ling; Althoff, Eric A.; Bolduc, Jill; Jiang, Lin; Moody, James; Lassila, Jonathan K.; Giger, Lars; Hilvert, Donald; Stoddard, Barry; Baker, David



Crystal Structures of HIV-1 Reverse Transcriptase with Picomolar Inhibitors Reveal Key Interactions for Drug Design  

PubMed Central

X-ray crystal structures at 2.9 Å resolution are reported for complexes of catechol diethers 1 and 2 with HIV-1 reverse transcriptase. The results help elucidate the structural origins of the extreme antiviral activity of the compounds. The possibility of halogen bonding between the inhibitors and Pro95 is addressed. Structural analysis reveals key interactions with conserved residues P95 and W229 of importance for design of inhibitors with high potency and favorable resistance profiles.

Frey, Kathleen M.; Bollini, Mariela; Mislak, Andrea C.; Cisneros, Jose A.; Gallardo-Macias, Ricardo; Jorgensen, William L.; Anderson, Karen S.



Structures and synthesis of framework Rb and Cs uranyl arsenates and their relationships with their phosphate analogues  

NASA Astrophysics Data System (ADS)

Two hydrated uranyl arsenates, Cs 2(UO 2)[(UO 2)(AsO 4)] 4(H 2O) 2 ( CsUAs) and Rb 2(UO 2)[(UO 2)(AsO 4)] 4(H 2O) 4.5 ( RbUAs), were synthesized by hydrothermal methods. Intensity data were collected at room temperature using Mo K? radiation and a CCD-based area detector. The crystal structure of RbUAs was solved by direct methods, whereas the structure model of the phosphate Cs 2(UO 2)[(UO 2)(PO 4)] 4(H 2O) 2 was used for CsUAs; both were refined by full-matrix least-squares techniques on the basis of F2 to agreement indices ( CsUAs, RbUAs) w R2=0.061,0.041, for all data, and R1=0.032,0.021, calculated for 5098, 4991 unique observed reflections (| Fo|>4 ?F), respectively. The compound CsUAs is orthorhombic, space group Cmc2 1, Z=4, a=15.157(2), b=14.079(2), c=13.439(2) Å, V=2867.9(1) Å 3. RbUAs is monoclinic, space group C2/ m, Z=4, a=13.4619(4), b=15.8463(5), c=14.0068(4) Å, ?=92.311(1)°, V=2985.52(2) Å 3. The structures consist of sheets of arsenate tetrahedra and uranyl pentagonal bipyramids, with composition [(UO 2)(AsO 4)] -, that are topologically identical to the uranyl silicate sheets in uranophane-beta. These sheets are connected by a uranyl pentagonal bipyramid in the interlayer that shares corners with two arsenate tetrahedra on each of two adjacent sheets and whose fifth equatorial vertex is an H 2O group, resulting in an open framework with alkali metal cations in the larger cavities of the structures. CsUAs is isostructural with its phosphate analogue, and has two Cs atoms and a H 2O group in its structural cavities. RbUAs is not isostructural with its phosphate analogue, although it has a homeotypic framework. Its structural cavities are occupied by three Rb atoms and four H 2O groups; one Rb position and three of the interstitial H 2O groups are half-occupied. The partial occupancies of these positions probably result from the accommodation of the larger As atoms (relative to P) in the framework and resultant larger cavities.

Locock, Andrew J.; Burns, Peter C.



The Crystal and Electronic Structures of Cd3As2, the Three-Dimensional Electronic Analogue of Graphene.  


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) Å 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

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



Identification of enterodiol as a masker for caffeine bitterness by using a pharmacophore model based on structural analogues of homoeriodictyol.  


Starting from previous structure-activity relationship studies of taste modifiers based on homoeriodictyol, dihydrochalcones, deoxybenzoins, and trans-3-hydroxyflavones as obvious analogues were investigated for their masking effect against caffeine. The most active compounds of the newly investigated taste modifiers were phloretin, the related dihydrochalcones 3-methoxy-2',4,4'-trihydroxydihydrochalcone and 2',4-dihydroxy-3-methoxydihydrochalcone, and the deoxybenzoin 2-(4-hydroxy-3-methoxyphenyl)-1-(4-hydroxyphenyl)ethanone. Starting with the whole set of compounds showing activity >22%, a (Q)SAR pharmacophore model for maskers of caffeine bitterness was calculated to explain the structural requirements. After docking of the pharmacophore into a structural model of the broadly tuned bitter receptor hTAS2R10 and docking of enterolactone and enterodiol as only very weakly related structures, it was possible to predict qualitatively their modulating activity. Enterodiol (25 mg L(-1)) reduced the bitterness of the 500 mg L(-1) caffeine solution by about 30%, whereas enterolactone showed no masking but a slight bitter-enhancing effect. PMID:22670770

Ley, Jakob P; Dessoy, Marco; Paetz, Susanne; Blings, Maria; Hoffmann-Lücke, Petra; Reichelt, Katharina V; Krammer, Gerhard E; Pienkny, Silke; Brandt, Wolfgang; Wessjohann, Ludger




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...


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

PubMed Central

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.

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



Bisphenol A and Its Analogues Activate Human Pregnane X Receptor  

PubMed Central

Background: Bisphenol A (BPA) is a base chemical used extensively in many consumer products. BPA and its analogues are present in environmental and human samples. Many endocrine-disrupting chemicals, including BPA, have been shown to activate the pregnane X receptor (PXR), a nuclear receptor that functions as a master regulator of xenobiotic metabolism. However, the detailed mechanism by which these chemicals activate PXR remains unknown. Objective: We investigated the mechanism by which BPA interacts with and activates PXR and examined selected BPA analogues to determine whether they bind to and activate PXR. Methods: Cell-based reporter assays, in silico ligand–PXR docking studies, and site-directed mutagenesis were combined to study the interaction between BPA and PXR. We also investigated the influence of BPA and its analogues on the regulation of PXR target genes in human LS180 cells. Results: We found that BPA and several of its analogues are potent agonists for human PXR (hPXR) but do not affect mouse PXR activity. We identified key residues within hPXR’s ligand-binding pocket that constitute points of interaction with BPA. We also deduced the structural requirements of BPA analogues that activate hPXR. BPA and its analogues can also induce PXR target gene expression in human LS180 cells. Conclusions: The present study advances our understanding of the mechanism by which BPA interacts with and activates human PXR. Activation of PXR by BPA may explain some of the adverse effects of BPA in humans.

Sui, Yipeng; Ai, Ni; Park, Se-Hyung; Rios-Pilier, Jennifer; Perkins, Jordan T.; Welsh, William J.



Design, conformational studies and analysis of structure-function relationships of PTH (1-11) analogues: the essential role of Val in position 2.  


The N-terminal 1-34 segment of parathyroid hormone (PTH) is fully active in vitro and in vivo and it elicits all the biological responses characteristic of the native intact PTH. Recent studies reported potent helical analogues of the PTH (1-11) with helicity-enhancing substitutions. This work describes the synthesis, biological activity, and conformational studies of analogues obtained from the most active non-natural PTH (1-11) peptide H-Aib-Val-Aib-Glu-Ile-Gln-Leu-Nle-His-Gln-Har-NH2; specifically, the replacement of Val in position 2 with D-Val, L-(?Me)-Val and N-isopropyl-Gly was studied. The synthesized analogues were characterized functionally by in-cell assays and their structures were determined by CD and NMR spectroscopy. To clarify the relationship between the structure and activity, the structural data were used to generate a pharmacophoric model, obtained overlapping all the analogues. This model underlines the fundamental functional role of the side chain of Val2 and, at the same time, reveals that the introduction of conformationally constrained C?-tetrasubstituted ?-amino acids in the peptides increases their helical content, but does not necessarily ensure significant biological activity. PMID:21918876

Caporale, A; Gesiot, L; Sturlese, M; Wittelsberger, A; Mammi, S; Peggion, E



Sphingolipid Analogues Inhibit Development of Malaria Parasites  

PubMed Central

Plasmodium-infected erythrocytes have been shown to employ sphingolipids from both endogenous metabolism as well as existing host pools. Therapeutic agents that limit these supplies have thus emerged as intriguing, mechanistically distinct putative targets for the treatment of malaria infections. In an initial screen of our library of sphingolipid pathway modulators for efficacy against two strains of the predominant human malaria species Plasmodium falciparum and Plasmodium knowlesi, a series of orally available, 1-deoxysphingoid bases were found to possess promising in vitro antimalarial activity. To better understand the structural requirements that are necessary for this observed activity, a second series of modified analogues were prepared and evaluated. Initial pharmacokinetic assessments of key analogues were investigated to evaluate plasma and red blood cell concentrations in vivo.



Highly potent HIV inhibition: engineering a key anti-HIV structure from PSC-RANTES into MIP-1 beta/CCL4.  


The HIV coreceptor CCR5 is a validated target for both the prevention and therapy of HIV infection. PSC-RANTES, an N-terminally modified analogue of one of the natural chemokine ligands of CCR5 (RANTES/CCL5), is a potent inhibitor of HIV entry into target cells. Here, we set out to engineer the anti-HIV activity of PSC-RANTES into another natural CCR5 ligand (MIP-1beta/CCL4), by grafting into it the key N-terminal pharmacophore region from PSC-RANTES. We were able to identify MIP-1beta/CCL4 analogues that retain the receptor binding profile of MIP-1beta/CCL4, but acquire the very high anti-HIV potency and characteristic inhibitory mechanism of PSC-RANTES. Unexpectedly, we discovered that in addition to N-terminal structures from PSC-RANTES, the side chain of Lys33 is also necessary for full anti-HIV potency. PMID:18178567

Gaertner, Hubert; Lebeau, Olivier; Borlat, Irène; Cerini, Fabrice; Dufour, Brigitte; Kuenzi, Gabriel; Melotti, Astrid; Fish, Richard J; Offord, Robin; Springael, Jean-Yves; Parmentier, Marc; Hartley, Oliver



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

ERIC Educational Resources Information Center

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…

Sjoberg, Daniel



Stability and structure of C sub 12 B sub 24 N sub 24 : A hybrid analogue of buckminsterfullerene  

SciTech Connect

The 60-vertex, truncated icosahedral cluster system known as buckminsterfullerene (buckyball, C{sub 60}), has attracted increased attention following recent reports of its laboratory-scale synthesis. Various efforts to add heteroatoms (especially nucleophiles) to the periphery of C{sub 60} frameworks have been successful, and possible structures for hydrogenated species have been discussed. Since for any fullerene structure there are exactly 12 pentagons, it should be possible to substitute all but 12 carbons of C{sub 60} with alternating boron and nitrogen atoms. The resulting cluster would have the molecular formula C{sub 12}B{sub 24}N{sub 24}, with six C-C, 12 C-B, 12 C-N, and 60 B-N nearest-neighbor interactions. Detailed quantum calculations for a range of BN-substituted buckyball analogues are in progress. However, to estimate the stability of C{sub 12}B{sub 24}N{sub 24}, the authors have carried out a simple Hueckel calculation of the type used by Haymet to predict the stability of C{sub 60} itself.

Bowser, J.R.; Jelski, D.A. (State Univ. of New York, Fredonia (United States)); George, T.F. (Washington State Univ., Pullman (United States))



Remarkable isolation, structural characterisation and electrochemistry of unexpected scrambling analogues of 5-ferrocenyl-10,20-diphenylporphyrin.  


Selective condensation of 5-ferrocenyldipyrromethane, 1, and dipyrromethane, 2, with benzaldehyde, 3, led to 5-ferrocenyl-10,20-diphenylporphyrin, 5. During the condensation, an unusually large amount of scrambling was observed which led to the isolation of two further ferrocenylated porphyrin analogues 6 and 7. The structure of 6 was confirmed by a single-crystal X-ray study. A mechanism is proposed for this atypical scrambling which is likely to involve acid-catalysed reversion of the dipyrromethane synthesis. (1)H NMR further elucidated the structures of each complex and showed the existence of atropisomerism. An electrochemical study (cyclic voltammetry, Osteryoung square wave and linear sweep voltammetry) showed that there exists a linear relationship between the sum of the group electronegativities of meso substituents of the obtained porphyrins and the formal reduction potentials of the two observed ring-centred reduction processes, the meso substituent ferrocenyl-based oxidation process and the first ring-centred oxidation wave. These four relationships could be mathematically quantified. Due to the strong electron-withdrawing properties of the oxidised ferrocenium group, the second ring centred oxidation wave fell outside the potential window of dichloromethane as solvent. PMID:17700824

Auger, Aurélien; Muller, Alfred J; Swarts, Jannie C



Structural diversity of lamellar zeolite Nu-6(1)-postsynthesis of delaminated analogues.  


Nu-6(1) zeolite, the lamellar precursor of NSI topology, was firstly synthesized with 4'4-bipyridine as the structure-directing agent (SDA) and then subjected to HCl-EtOH treatment for the purpose of structural modification. Interlayer deconstruction and reconstruction took place alternately in this acid treatment. An intermediate named ECNU-4 was separated at the initial stage of this continuous treatment process, which exhibited a special X-ray diffraction pattern without obvious reflection peaks at low angles. The zeolitic structure in the intralayer sheets was supposed to be well preserved in ECNU-4, whereas the interlayer structure became extremely disordered. The ECNU-4 intermediate showed structural diversity. It was converted into the reconstructed and interlayer expanded zeolite IEZ-NSI without an external silicon source by prolonging the HCl-EtOH treatment to 24 h. Moreover, with a partially delaminated structure, ECNU-4 was easily interlayer swollen at room temperature with cetyltrimethyl ammonium bromide in the presence of tetrapropyl ammonium hydroxide. The swollen material was further sonicated to yield a more deeply delaminated zeolite, Del-Nu-6. ECNU-4 and Del-Nu-6 differed in delamination degree, structural disordering and textural properties, especially surface area. PMID:24658572

Xu, Hao; Jia, Lili; Wu, Haihong; Yang, Boting; Wu, Peng



[Leishmania donovani: structural insignt in the recognition of C-methylated analogues of spermidine as natural polyamine].  


The ability of alpha-, beta-, gamma- and omega-methylated spermidine analogues to restore the growth of L. donovani promastigotes that were depleted of putrescine and spermidine was investigated. Only beta-methylated spermidine, like natural spermidine was capable of restoring the growth of L. donovani, while the remaining three analogues turned out to be inactive. Considering that alpha-methylated spermidine is a functionally active spermidine surrogate both in vivo and in vitro, this analogue can be considered as an antidote in the host-parasite system, especially in cases where inhibitors of polyamine biosynthesis are used for the therapy of leishmaniasis. PMID:21954600

Mandal, S; Khomutov, M A; Simonian, A P; Kochetkov, S N; Madhubala, R



Aspartame and Its Analogues  

NASA Astrophysics Data System (ADS)

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.

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



Structure of the p300 histone acetyltransferase bound to acetyl-coenzyme A and its analogues.  


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 enzyme's 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

Maksimoska, Jasna; Segura-Peña, Dario; Cole, Philip A; Marmorstein, Ronen



Sparsely substituted chlorins as core constructs in chlorophyll analogue chemistry. III. Spectral and structural properties  

PubMed Central

The availability of stable chlorins bearing few or no substituents has enabled a variety of fundamental studies. The studies described herein report absorption spectra of diverse chlorins, comparative NMR features of chlorins bearing 0–3 meso-aryl substituents, and X-ray structures of the fully unsubstituted chlorin and the oxochlorin.

Taniguchi, Masahiko; Ptaszek, Marcin; McDowell, Brian E.; Boyle, Paul D.; Lindsey, Jonathan S.



Bioturbation structures of polychaetes in modern shallow marine environments and their analogues to Chondrites group traces  

Microsoft Academic Search

The present interdisciplinary study comprising actuopalaeontology, marine biology and marine chemistry reveals particular polychaete species as trace-makers of distinct branched burrow systems in modern intertidal and shallow subtidal deposits. In this way, the study concerns one of the most enigmatic trace fossils in earth history, the cosmopolitan ichnogenus Chondrites. Bioturbate structures of this type are frequently found and described in

Günther Hertweck; Achim Wehrmann; Gerd Liebezeit



Structural Analysis of Silanediols as Transition-State-Analogue Inhibitors of the Benchmark Metalloprotease Thermolysin † , ‡  

Microsoft Academic Search

Dialkylsilanediols have been found to be an effective functional group for the design of active- site-directed protease inhibitors, including aspartic (HIV protease) and metallo (ACE and thermolysin) proteases. The use of silanediols is predicated on its resemblance to the hydrated carbonyl transition-state structure of amide hydrolysis. This concept has been tested by replacing the presumed tetrahedral carbon of a thermolysin

Douglas H. Juers; Jaeseung Kim; Brian W. Matthews; Scott Mc N. Sieburth



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

PubMed Central

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-3? (GSK-3?), 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.

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, Jurg; Hamann, Mark T.



Structure-In Vitro Activity Relationships of Pentamidine Analogues and Dication-Substituted Bis-Benzimidazoles as New Antifungal Agents  

PubMed Central

Twenty analogues of pentamidine, 7 primary metabolites of pentamidine, and 30 dicationic substituted bis-benzimidazoles were screened for their inhibitory and fungicidal activities against Candida albicans and Cryptococcus neoformans. A majority of the compounds had MICs at which 80% of the strains were inhibited (MIC80s) comparable to those of amphotericin B and fluconazole. Unlike fluconazole, many of these compounds were found to have potent fungicidal activity. The most potent compound against C. albicans had an MIC80 of ?0.09 ?g/ml, and the most potent compound against C. neoformans had an MIC80 of 0.19 ?g/ml. Selected compounds were also found to be active against Aspergillus fumigatus, Fusarium solani, Candida species other than C. albicans, and fluconazole-resistant strains of C. albicans and C. neoformans. It is clear from the data presented here that further studies on the structure-activity relationships, mechanisms of action and toxicities, and in vivo efficacies of these compounds are warranted to determine their clinical potential.

Del Poeta, Maurizio; Schell, Wiley A.; Dykstra, Christine C.; Jones, Susan; Tidwell, Richard R.; Czarny, Agnieszka; Bajic, Miroslav; Bajic, Marina; Kumar, Arvind; Boykin, David; Perfect, John R.



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

SciTech Connect

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.

Kim, Hyunjung [University of Tennessee, Knoxville (UTK); Guiochon, Georges A [ORNL



Determination of 1-aminocyclopropane-1-carboxylic acid and its structural analogue by liquid chromatography and ion spray tandem mass spectrometry.  


Liquid chromatography coupled to ion spray tandem mass spectrometry was developed as a method for the simultaneous analysis of the amino acid 1-aminocyclopropane-1-carboxylic acid (ACC) and its structural analogue, cyclopropane-1,1-dicarboxylic acid (CDA). ACC and CDA fragmentation as well as optimization of MS parameters were investigated in positive ion mode. In selective reaction monitoring mode the protonated molecule [M+H]+ was selected as parent ion for both ACC and CDA, while the immonium ion from ACC and the [M+H-H2O]+ ion from CDA were selected, respectively, as product ions. In spite of the high selectivity of MS/MS among the 20 protein amino acids potentially present with ACC and CDA in the plant material analyzed, Glu and Thr can interfere with the signal of ACC. As a result, their chromatographic separation is necessary. This was achieved in less than 4 min by ion-pair reversed-phase chromatography with nonafluoropentanoic acid as ion-pair reagent. A linear response within a concentration range of 1-5 mg l(-1) was observed for this LC method and the detection limit was found to be 20 pmol for ACC and 150 pmol for CDA (using a 20-microl loop). This methodology was successfully applied to the detection of ACC in apple tissue. PMID:11093668

Petritis, K; Dourtoglou, V; Elfakir, C; Dreux, M



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


1. The aim of this study was to find taurinergic compounds that do not interact with brain GABA ergic systems. 2. Washed synaptic membranes (SM) from whole rabbit brain were able to bind [(3)H]muscimol. Saturation experiments of the binding of [(3)H]GABA to GABA(B) receptors showed that SM possess two binding components; twice Triton X-100-treated SM contained 0.048 mmol endogenous taurine/kg protein and bound [(3)H]taurine in a saturable manner (K(d)=249.0+/-6.3 nM and B(max)=3.4+/-1.0 pmol mg(-1) prot). 3. 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 [(3)H]taurine binding (K(i)=0.13, 0.13, 13.5 and 4.0 micro M, respectively). These analogues did not interact with GABA(A) and GABA(B) receptors and did not affect taurine- and GABA-uptake systems and GABA-transaminase activity. 4. 3-Aminopropanesulfonic acid (OMO), beta-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 [(3)H]muscimol binding to GABA(A) receptors with different affinities (K(i)=0.013, 7.9, 24.6, 47.5, 52.0, 91.0, 47.5, 118.1 and 166.3 micro M, respectively). Taurine, 2-aminoethylphosphonic acid, DMT, TMT and OMO inhibited the binding of [(3)H]GABA to GABA(B) receptors with K(i)'s in the micro M range (0.8, 3.5, 4.4, 11.3 and 5.0, respectively). GES inhibited taurine uptake (IC(50)=3.72 micro M) and PSA GABA transaminase activity (IC(50)=103.0 micro M). 5. In conclusion, AEA, TAG, ISE and CAHS fulfill the criteria for taurinergic agents. PMID:12684273

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



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

PubMed Central

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 ?M, 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), ?-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 ?M, respectively). Taurine, 2-aminoethylphosphonic acid, DMT, TMT and OMO inhibited the binding of [3H]GABA to GABAB receptors with Ki's in the ?M range (0.8, 3.5, 4.4, 11.3 and 5.0, respectively). GES inhibited taurine uptake (IC50=3.72 ?M) and PSA GABA transaminase activity (IC50=103.0 ?M). In conclusion, AEA, TAG, ISE and CAHS fulfill the criteria for taurinergic agents.

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



Itraconazole Side Chain Analogues: Structure-Activity Relationship Studies for Inhibition of Endothelial Cell Proliferation, Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Glycosylation, and Hedgehog Signaling  

PubMed Central

Itraconazole is an antifungal drug that was recently found to possess potent antiangiogenic activity and anti-hedgehog (Hh) pathway activity. To search for analogues of itraconazole with greater potency and to understand the structure–activity relationship in both antiangiogenic and Hh targeting activity, 25 itraconazole side chain analogues were synthesized and assayed for inhibition of endothelial cell proliferation and Gli1 transcription in a medulloblastoma (MB) culture. Through this analysis, we have identified analogues with increased potency for inhibiting endothelial cell proliferation and the Hh pathway, as well as VEGFR2 glycosylation that was recently found to be inhibited by itraconazole. An SAR analysis of these activities revealed that potent activity of the analogues against VEGFR2 glycosylation was generally driven by side chains of at least four carbons in composition with branching at the ? or ? position. SAR trends for targeting the Hh pathway were divergent from those related to HUVEC proliferation or VEGFR2 glycosylation. These results also suggest that modification of the sec-butyl side chain can lead to enhancement of the biological activity of itraconazole.

Shi, Wei; Nacev, Benjamin A.; Aftab, Blake T.; Head, Sarah; Rudin, Charles M.; Liu, Jun O.



The influence of cooling on the advance of lava flows: insights from analogue experiments on the feedbacks between flow dynamics and thermal structure  

NASA Astrophysics Data System (ADS)

During an effusive volcanic eruption, the crisis management is mainly based on the prediction of lava flows advance and its velocity. The spreading of a lava flow, seen as a gravity current, depends on its "effective rheology" and the eruptive mass flux. These two parameters are not known a priori during an eruption and a key question is how to evaluate them in near real-time (rather than afterwards.) There is no generic macroscopic model for the rheology of an advancing lava flow, and analogue modelling is a precious tool to empirically estimate the rheology of a complex flow. We investigate through laboratory experiments the simultaneous spreading and cooling of horizontal currents fed at constant rate from a point source. The materials used are silicone oil (isoviscous), and poly-ethylene glycol (PEG) wax injected in liquid state and solidiying during its advance. In the isoviscous case, the temperature field is a passive tracer of the flow dynamics, whereas in the PEG experiments there is a feedback between the cooling of the flow and its effective rheology. We focus on the evolution of the current area and of the surface thermal structure, imaged with an infrared camera, to assess how the thermal structure can be related to the flow rate. The flow advance is continuous in the viscous case, and follows the predictions of Huppert (1982); in that case the surface temperature become steady after a transient time and the radiated heat flux is shown to be proportional to the input rate. For the PEG experiments, the spreading occurs through an alternation of stagnation and overflow phases, with a mean spreading rate decreasing as the experiment goes on. As in the case of lava flows, these experiments can exhibit a compound flow field, solid levees, thermal erosion, liquid overflows and channelization. A key observation is that the effective rheology of the solifying PEG material depends on the input flow rate, with high input rates yielding a rheology closer to the one of an isoviscous fluid. The radiated heat flux evolves by stages, and includes two contributions : the one from "active" flowing part of the flow, and the one from non-moving cooling regions. The "active" thermal signal of the liquid PEG becomes steady as in the isoviscous case. Experimental results show that flow modelling, used to predict lava flow advance or to build hazard maps, should consider the variation of lava rheology as a function of the effusion rate.The experiments show also that dense time series of radiance signals, with high temporal and spectral resolution, are necessary to discriminate active and inactive lava fields, and to interpret the remote-sensed thermal signal in terms of dynamics of lava flows.

Garel, F.; Kaminski, E.; Tait, S.; Limare, A.



Analysis of wave propagation in stratified structures using circuit analogues, with application to electromagnetic absorbers  

NASA Astrophysics Data System (ADS)

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 elements. It is seen that electric material properties act as shunt elements, and magnetic material properties act as series elements. When the sheets have periodic patterns, they can be represented with resonant circuits. When designing, for instance, an absorber for electromagnetic waves, the circuit models can be used as a starting point to derive a basic, stable design, which can later be optimized using full wave simulations if necessary.

Sjöberg, Daniel



Structure-inhibitory activity relationships of pyrrolnitrin analogues on its biosynthesis  

Microsoft Academic Search

Pyrrolnitrin is a bacterial metabolite, served as a natural lead of agricultural fungicides. In a previous study, fenpiclonil\\u000a was proven to inhibit the oxidative transformation of aminopyrrolnitrin to pyrrolnitrin, catalyzed by aminopyrrolnitrin oxidase\\u000a (PrnD). This monooxygenase has an interesting catalytic activity of selective oxidation of aromatic amines, rather than aliphatic\\u000a amines. However, its structural details are not well understood. In

Young Soo Keum; Yong-Zhe Zhu; Jeong-Han Kim



Locked nucleoside analogues expand the potential of DNAzymes to cleave structured RNA targets  

PubMed Central

Background DNAzymes cleave at predetermined sequences within RNA. A prerequisite for cleavage is that the DNAzyme can gain access to its target, and thus the DNAzyme must be capable of unfolding higher-order structures that are present in the RNA substrate. However, in many cases the RNA target sequence is hidden in a region that is too tightly structured to be accessed under physiological conditions by DNAzymes. Results We investigated how incorporation of LNA (locked nucleic acid) monomers into DNAzymes improves their ability to gain access and cleave at highly-structured RNA targets. The binding arms of DNAzymes were varied in length and were substituted with up to three LNA and ?-L-LNA monomers (forming LNAzymes). For one DNAzyme, the overall cleavage reaction proceeded fifty times faster after incorporation of two ?-L-LNA monomers per binding arm (kobs increased from 0.014 min-1 to 0.78 min-1). Conclusion The data demonstrate how hydrolytic performance can be enhanced by design of LNAzymes, and indicate that there are optimal lengths for the binding arms and for the number of modified LNA monomers.

Vester, Birte; Hansen, Lykke H; Bo Lundberg, Lars; Babu, B Ravindra; S?rensen, Mads D; Wengel, Jesper; Douthwaite, Stephen



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


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

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



Boron-nitrogen analogues of the fullerenes: electronic and structural properties  

Microsoft Academic Search

On the basis of a systematic density functional tight-binding study of boron-nitrogen polyhedra (BN)x composed entirely of four- and six-membered rings, it is predicted that octahedron-like structures B12N12, B16N16 and B28N28 are “magic” (i.e. anomalously stable) clusters. The infrared spectrum of B12N12 is predicted. The similarities and differences between these “inorganic fullerenes” and the carbon-based equivalents are outlined. Ahigh stability

G. Seifert; P. W. Fowler; D. Mitchell; D. Porezag; Th. Frauenheim



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

SciTech Connect

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.

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



Synthesis and X-ray structures of new cycloalka[ e]pyrano[2,3- b]pyridine derivatives: novel tacrine analogues  

Microsoft Academic Search

A new series of tacrine (9-amino-1,2,3,4-tetrahydroacridine) analogues consisting of a cycloalka[e]pyrano[2,3-b]pyridine linked to a quinolyl ring has been synthesized. These compounds were prepared from the appropriately substituted pyran derivative via a Friedländer reaction with selected cycloalkanones in high yields. Single crystal X-ray structures are reported for four compounds.

H. Hayour; A. Bouraiou; S. Bouacida; F. Berrée; B. Carboni; T. Roisnel; A. Belfaitah



Crystal structures of HIV-1 gp120 envelope glycoprotein in complex with NBD analogues that target the CD4-binding site.  


Efforts to develop therapeutic agents that inhibit HIV-1 entry have led to the identification of several small molecule leads. One of the most promising is the NBD series, which binds within a conserved gp120 cavity and possesses para-halogen substituted aromatic rings, a central oxalamide linker, and a tetramethylpiperidine moiety. In this study, we characterized structurally the interactions of four NBD analogues containing meta-fluoro substitution on the aromatic ring and various heterocyclic ring replacements of the tetramethylpiperidine group. The addition of a meta-fluorine to the aromatic ring improved surface complementarity and did not alter the position of the analogue relative to gp120. By contrast, heterocyclic ring replacements of the tetramethylpiperidine moiety exhibited diverse positioning and interactions with the vestibule of the gp120 cavity. Overall, the biological profile of NBD-congeners was modulated by ligand interactions with the gp120-cavity vestibule. Herein, six co-crystal structures of NBD-analogues with gp120 provide a structural framework for continued small molecule-entry inhibitor optimization. PMID:24489681

Kwon, Young Do; LaLonde, Judith M; Yang, Yongping; Elban, Mark A; Sugawara, Akihiro; Courter, Joel R; Jones, David M; Smith, Amos B; Debnath, Asim K; Kwong, Peter D



Synthesis and molecular structure of a zinc complex of the vitamin K3 analogue phthiocol  

NASA Astrophysics Data System (ADS)

The complex [Zn(phthiocol)2(H2O)2]; 1, where phthiocol is 2-hydroxy-3-methyl-1,4-naphthoquinone, has been synthesized and characterized by elemental analysis, FT-IR, 1H NMR, UV–vis spectroscopy, thermogravimetric (TG) analysis, electrochemical and single crystal X-ray diffraction studies. The ?CO stretch shifts to lower frequencies upon complexation of phthiocol to Zn2+. 1H NMR spectra show an upfield shift of the benzenoid ring protons in 1. There is a bathochromic shift of the LMCT band in the UV–vis spectra of 1. Single crystal X-ray structure of 1 show distorted octahedral geometry around Zn2+. Two phthiocol ligands are in plane with the metal, while water molecules are trans to this plane. Coordination of deprotonated phthiocol ligands is 'trans, trans' to Zn2+. Intra as well as intermolecular interactions are observed in 1. Molecules of 1 show three dimensional network through CH⋯O and OH⋯O interactions. Additional anodic peaks are observed in cyclic voltammogram of phthiocol ligand due to oxidation of reduced species formed during reduction. One-electron reduction of 1 is shown to be reversible and DFT studies define this redox event as ligand-centered.

Kathawate, Laxmi; Sproules, Stephen; Pawar, Omkar; Markad, Ganesh; Haram, Santosh; Puranik, Vedavati; Salunke-Gawali, Sunita



Cymantrene radical cation family: spectral and structural characterization of the half-sandwich analogues of ferrocenium ion.  


The anodic one-electron oxidation of three members of the half-sandwich family of piano-stool compounds MnCp (gamma)(CO) 3, where Cp (gamma) is a generic cyclopentadienyl ligand, has been studied in a CH 2Cl 2/[NBu 4][TFAB] electrolyte (TFAB = [B(C6F5) 4] (-)). The long-sought 17 e (-) radical cation of the parent complex MnCp(CO) 3 (cymantrene, 1, E 1/2 = 0.92 V vs ferrocene) has been shown to be persistent in solutions that use weakly coordinating anions in place of more nucleophilic traditional electrolyte anions. Spectroscopically characterized for the first time, 1 (+) was shown to absorb in the visible (530 nm), near-IR (2066 nm), and IR (2118, 1934 cm (-1)) regions. It was ESR-active at low temperatures (g parallel = 2.213, g perpendicular = 2.079, A parallel (Mn) = 79.2 G, A perpendicular (Mn) = 50 G) and NMR active at room temperature (delta = 22.4 vs TMS). The radical cations of the Cp-functionalized analogues, Mn(eta (5)-C5H 4NH2)(CO) 3, 2, E 1/2 = 0.62 V, and MnCp*(CO) 3 (Cp*= eta (5)-C 5Me 5, 3), E 1/2 = 0.64 V, were generated electrochemically as well by the chemical oxidant [ReCp(CO) 3] (+). The structures of 2 (+) and 3 (+) were determined by X-ray crystallographic studies of their TFAB salts. Compared to the structures of the corresponding neutral compounds, the cations showed elongated Mn-C(O) bonds and shortened C-O bonds, displaying the effect of diminished metal-to-CO backbonding. The bond-length changes in the Mn(CO) 3 moiety were much larger in 3 (+) (avg changes, Mn-C(O) = + 0.142 A, C-O = -0.063 A) than in 2 (+) (avg changes, Mn-C(O) = + 0.006 A, C-O = -0.003 A). Although there were only minor changes in the metal-to-center ring distances upon oxidation of either 2 or 3, there was decidedly less bending of the C(N) atom out of the cyclopentadienyl plane in 2 (+) compared to 2. The optical, vibrational, and magnetic resonance spectra of radicals 2 (+) and 3 (+) were also observed. The spectral data argue for the SOMOs of the 17-electron species being largely located on the Mn(CO) 3 moiety, having 40-50% Mn d-orbital character, with the ground states of the radicals, most likely (2)A'', lying close in energy (within about 6000 cm (-1)) to excited states that are responsible for their rapid electronic relaxations. The cymantrenyl moiety is proposed as an anodic redox tag (or label) having physical and chemical properties that are significantly different from those of its ferrocenyl analogue. PMID:18597460

Laws, Derek R; Chong, Daesung; Nash, Karen; Rheingold, Arnold L; Geiger, William E



Key technological issues in LMFBR high-temperature structural design - the US perspective  

SciTech Connect

The purpose of this paper is: (1) to review the key technological issues in LMFBR high-temperature structural design, particularly as they relate to cost reduction; and (2) to provide an overview of activities sponsored by the US Department of Energy to resolve the issues and to establish stable, standardized, and defensible structural design methods and criteria. Specific areas of discussion include: weldments, structural validation tests, simplified design analysis procedures, design procedures for piping, validation of the methodology for notch-like geometries, improved life assessment procedures, thermal striping, extension of the methodology to new materials, and ASME high-temperature Code reform needs. The perceived problems and needs in each area are discussed, and the current status of related US activities is given.

Corum, J.M.



Cation radii induced structural variation in fluorescent alkaline earth networks constructed from tautomers of a nucleobase analogue.  


Nucleobase tautomers and their metal complexes have attracted considerable attention due to their fascinating architectures along with wide applications. In this paper, 4,6-dihydroxypyrimidine (H(2)DHP), an analogue of uracil and thymine, was employed to react with the vital elements of alkaline earth metals in an aqueous solution and lead to the formation of four novel complexes, [Mg(HDHP)(2) (H(2)O)(4)] (1), [Ca(HDHP)(2)(H(2)O)(3)](n)·nH(2)O (2), [Sr(HDHP)(2)(H(2)O)(3)](n)·nH(2)O (3), and [Ba(HDHP)(2)(H(2)O)(2)](n)·nH(2)O (4), which have been characterized by elemental analysis, IR, TG, UV-Vis, PL, powder and single-crystal X-ray diffraction and progressively evolve from zero-dimensional (0D) mononuclear, one-dimensional (1D) zig-zag double chain, two-dimensional (2D) double layer, to a three-dimensional (3D) porous network along with the increase of cation radii. This tendency in dimensionality follows salient crystal engineering principles and can be explained by considering factors such as hard-soft acid-base principles and cation radii. The deprotonated H(2)DHP ligand exhibits four new coordination modes, namely, O-monodentate (complex 1), N,O-chelating (complexes 2 and 3), O,O-bridging (complexes 2 and 3), and ?(1)O:?(2)O-bridging mode (complex 4). Interestingly, the structural investigation indicates that the HDHP(-) monoanion shows three unusual types of tautomers, which are essential for the diagnosis of disease and investigation of medicine. Furthermore, the four complexes exhibit strong blue emission compared to free H(2)DHP ligand at room temperature and may be potential candidates for blue fluorescent biological materials used in organisms. PMID:22635055

Deng, Zhao-Peng; Kang, Wei; Zhu, Zhi-Biao; Huo, Li-Hua; Zhao, Hui; Gao, Shan



Pulmonary surfactant: emerging protein analogues.  


Surfactant preparations, which are effective in the treatment of respiratory distress syndrome (RDS), contain phospholipids and small amounts of the 2 hydrophobic surfactant proteins SP-B and SP-C. At present, surfactant preparations are obtained from animal lungs. However, since information concerning the structure of SP-B and SP-C is now available, it appears possible to design analogues that can replace the native proteins and so formulate a synthetic peptide/lipid surfactant. This would circumvent problems associated with current purification procedures and also facilitate the production of quantities sufficient for evaluation of surfactant therapy in other respiratory diseases. SP-C analogues which effectively accelerate the spreading of surfactant lipids and exhibit physiological activity in animal models of RDS have been developed. However, the in vivo activity of surfactant preparations based on SP-C analogues are inferior to those of surfactant preparations derived from natural sources. This may be caused by lack of covalently linked palmitoyl groups in the SP-C analogues tested and/or that SP-B is required for full activity. The larger size of SP-B compared to SP-C makes the design of SP-B analogues more demanding. Surfactant preparations containing single peptides that may resemble SP-B have shown promising results in vitro and in vivo. Identification of further SP-B analogues as well as suitable combinations of SP-B and SP-C analogues appear to be important topics for future studies. PMID:18031116

Johansson, J; Gustafsson, M; Palmblad, M; Zaltash, S; Robertson, B; Curstedt, T



Structural and magnetic properties of nanoparticles of prussian blue analogue Ni3[Cr(CN)6]2.nH2O  

NASA Astrophysics Data System (ADS)

Nanoparticles of Prussian blue analogues, Ni3[Cr(CN)6]2.nH2O, have been synthesized using co-precipitation method and their structural and magnetic properties are investigated using X-ray diffraction (XRD), infra red spectroscopy (IR) and dc magnetization measurements. XRD results show that the Ni3[Cr(CN)6]2.nH2O sample formed nanocrystalline in nature with particle size of ~15 nm. The characteristic peaks, observed in the IR spectrum, confirm the formation of Prussian blue analogues with CN ligands. The magnetization measurement provides an evidence of soft ferromagnetic nature of the compound with Curie temperature (TC), maximum magnetization and coercive field of ~28K, ~4.2 ?B/f.u. and ~22 Oe, respectively.

Bhatt, Pramod; Bhatt, Ranu; Yusuf, S. M.



Structural basis for binding of cyclic 2-oxoglutarate analogues to factor-inhibiting hypoxia-inducible factor.  


Aromatic analogues of the 2-oxoglutarate co-substrate of the hypoxia-inducible factor hydroxylases are shown to bind at the active site iron: Pyridine-2,4-dicarboxylate binds as anticipated with a single molecule chelating the iron in a bidentate manner. The binding mode of a hydroxamic acid analogue, at least in the crystalline state, is unusual because two molecules of the inhibitor are observed at the active site and partial displacement of the iron binding aspartyl residue was observed. PMID:20822901

Conejo-Garcia, Ana; McDonough, Michael A; Loenarz, Christoph; McNeill, Luke A; Hewitson, Kirsty S; Ge, Wei; Liénard, Benoît M; Schofield, Christopher J; Clifton, Ian J



Cytotoxic iron chelators: characterization of the structure, solution chemistry and redox activity of ligands and iron complexes of the di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) analogues.  


Di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) and a range of its analogues comprise a series of monobasic acids that are capable of binding iron (Fe) as tridentate ( N, N, O) ligands. Recently, we have shown that these chelators are highly cytotoxic, but show selective activity against cancer cells. Particularly interesting was the fact that cytotoxicity of theHPKIH analogues is maintained even after complexation with Fe. To understand the potent anti-tumor activity of these compounds, we have fully characterized their chemical properties. This included examination of the solution chemistry and X-ray crystal structures of both the ligands and Fe complexes from this class and the ability of these complexes to mediate redox reactions. Potentiometric titrations demonstrated that all chelators are present predominantly in their charge-neutral form at physiological pH (7.4), allowing access across biological membranes. Keto-enol tautomerism of the ligands was identified, with the tautomers exhibiting distinctly different protonation constants. Interestingly, the chelators form low-spin (diamagnetic) divalent Fe complexes in solution. The chelators form distorted octahedral complexes with Fe(II), with two tridentate ligands arranged in a meridional fashion. Electrochemistry of the Fe complexes in both aqueous and non-aqueous solutions revealed that the complexes are oxidized to their ferric form at relatively high potentials, but this oxidation is coupled to a rapid reaction with water to form a hydrated (carbinolamine) derivative, leading to irreversible electrochemistry. The Fe complexes of theHPKIH analogues caused marked DNA degradation in the presence of hydrogen peroxide. This observation confirms that Fe complexes from theHPKIH series mediate Fenton chemistry and do not repel DNA. Collectively, studies on the solution chemistry and structure of theseHPKIH analogues indicate that they can bind cellular Fe and enhance its redox activity, resulting in oxidative damage to vital biomolecules. PMID:14564555

Bernhardt, Paul V; Caldwell, Lorraine M; Chaston, Timothy B; Chin, Piao; Richardson, Des R



Key Golgi Factors for Structural and Functional Maturation of Bunyamwera Virus  

PubMed Central

Several complex enveloped viruses assemble in the membranes of the secretory pathway, such as the Golgi apparatus. Among them, bunyaviruses form immature viral particles that change their structure in a trans-Golgi-dependent manner. To identify key Golgi factors for viral structural maturation, we have purified and characterized the three viral forms assembled in infected cells, two intracellular intermediates and the extracellular mature virion. The first viral form is a pleomorphic structure with fully endo-?-N-acetylglucosaminidase H (Endo-H)-sensitive, nonsialylated glycoproteins. The second viral intermediate is a structure with hexagonal and pentagonal contours and partially Endo-H-resistant glycoproteins. Sialic acid is incorporated into the small glycoprotein of this second viral form. Growing the virus in glycosylation-deficient cells confirmed that acquisition of Endo-H resistance but not sialylation is critical for the trans-Golgi-dependent structural maturation and release of mature viruses. Conformational changes in viral glycoproteins triggered by changes in sugar composition would then induce the assembly of a compact viral particle of angular contours. These structures would be competent for the second maturation step, taking place during exit from cells, that originates fully infectious virions.

Novoa, Reyes R.; Calderita, Gloria; Cabezas, Pilar; Elliott, Richard M.; Risco, Cristina



Structural and sensory characterization of key pungent and tingling compounds from black pepper (Piper nigrum L.).  


To gain a more comprehensive knowledge on whether, besides the well-known piperine, other compounds are responsible for the pungent and tingling oral impression imparted by black pepper, an ethanol extract prepared from black pepper (Piper nigrum L.) was screened for its key sensory-active nonvolatiles by application of taste dilution analysis (TDA). Purification of the compounds perceived with the highest sensory impact, followed by LC-MS and 1D/2D NMR experiments as well as synthesis, led to the structure determination of 25 key pungent and tingling phytochemicals, among which the eight amides 1-(octadeca-2E,4E,13Z-trienyl)piperidine, 1-(octadeca-2E,4E,13Z-trienyl)pyrrolidine, (2E,4E,13Z)-N-isobutyl-octadeca-2,4,13-trienamide, 1-(octadeca-2E,4E,12Z-trienoyl)-pyrrolidine, 1-(eicosa-2E,4E,15Z-trienyl)piperidine, 1-(eicosa-2E,4E,15Z-trienyl)pyrrolidine, (2E,4E,15Z)-N-isobutyl-eicosa-2,4,15-trienamide, and 1-(eicosa-2E,4E,14Z-trienoyl)-pyrrolidine were not yet reported in literature. Sensory studies by means of a modified half-tongue test revealed recognition thresholds ranging from 3.0 to 1150.2 nmol/cm² for pungency and from 520.6 to 2162.1 nmol/cm² for the tingling orosensation depending on their chemical structure. PMID:22352449

Dawid, Corinna; Henze, Andrea; Frank, Oliver; Glabasnia, Anneke; Rupp, Mathias; Büning, Kirsten; Orlikowski, Diana; Bader, Matthias; Hofmann, Thomas



New selective inhibitors of steroid 11beta-hydroxylation in the adrenal cortex. Synthesis and structure-activity relationship of potent etomidate analogues.  


Derivatives of etomidate were evaluated as inhibitors of adrenal steroid 11beta-hydroxylations. Stereoselective coupling by Mitsunobu produced chirally pure analogues to study the effect of configuration, modification of the ester, and substitution in the phenyl ring, with the aim to probe specific sites for introducing a radionuclide. Iodophenyl metomidate (IMTO) labeled with iodine-131 served as radioligand for structure-affinity relationship studies. We have characterized the kinetic parameters of specific (131)I-IMTO binding on rat adrenal membranes and used the displacement of (131)I-IMTO binding to evaluate functionalized MTO analogues. Our results indicated that (1) ( R)-configuration is essential for high affinity, (2) highest potency resides in the ethyl, 2-propyl, and 2-fluoroethyl esters, and (3) substitution of the phenyl ring is well tolerated. The clinically used inhibitors metyrapone and ketoconazole inhibited (131)I-IMTO binding with low affinity. Incubation of selected analogues with human adrenocortical NCI-h295 cells demonstrated a high correlation with the inhibitory effect on cortisol secretion. PMID:18348518

Zolle, Ilse M; Berger, Michael L; Hammerschmidt, Friedrich; Hahner, Stefanie; Schirbel, Andreas; Peric-Simov, Biljana



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

SciTech Connect

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.

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.



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

PubMed Central

?-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]KIIIA7–14 and Ac-cyclo9/13[Lys9,Asp13]KIIIA7–14, displayed µM 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.

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



Evaluating minimalist mimics by exploring key orientations on secondary structures (EKOS).  


Peptide mimics that display amino acid side-chains on semi-rigid scaffolds (not peptide polyamides) can be referred to as minimalist mimics. Accessible conformations of these scaffolds may overlay with secondary structures giving, for example, "minimalist helical mimics". It is difficult for researchers who want to apply minimalist mimics to decide which one to use because there is no widely accepted protocol for calibrating how closely these compounds mimic secondary structures. Moreover, it is also difficult for potential practitioners to evaluate which ideal minimalist helical mimics are preferred for a particular set of side-chains. For instance, what mimic presents i, i + 4, i + 7 side-chains in orientations that best resemble an ideal ?-helix, and is a different mimic required for a i, i + 3, i + 7 helical combination? This article describes a protocol for fitting each member of an array of accessible scaffold conformations on secondary structures. The protocol involves: (i) use quenched molecular dynamics (QMD) to generate an ensemble consisting of hundreds of accessible, low energy conformers of the mimics; (ii) representation of each of these as a set of C? and C? coordinates corresponding to three amino acid side-chains displayed by the scaffolds; (iii) similar representation of each combination of three side-chains in each ideal secondary structure as a set of C? and C? coordinates corresponding to three amino acid side-chains displayed by the scaffolds; and, (iv) overlay C? and C? coordinates of all the conformers on all the sets of side-chain "triads" in the ideal secondary structures and express the goodness of fit in terms of root mean squared deviation (RMSD, Å) for each overlay. We refer to this process as Exploring Key Orientations on Secondary structures (EKOS). Application of this procedure reveals the relative bias of a scaffold to overlay on different secondary structures, the "side-chain correspondences" (e.g. i, i + 4, i + 7 or i, i + 3, i + 4) of those overlays, and the energy of this state relative to the minimum located. This protocol was tested on some of the most widely cited minimalist ?-helical mimics (1-8 in the text). The data obtained indicates several of these compounds preferentially exist in conformations that resemble other secondary structures as well as ?-helices, and many of the ?-helical conformations have unexpected side-chain correspondences. These observations imply the featured minimalist mimics have more scope for disrupting PPI interfaces than previously anticipated. Finally, the same simulation method was used to match preferred conformations of minimalist mimics with actual protein/peptide structures at interfaces providing quantitative comparisons of predicted fits of the test mimics at protein-protein interaction sites. PMID:24121516

Xin, Dongyue; Ko, Eunhwa; Perez, Lisa M; Ioerger, Thomas R; Burgess, Kevin



The cardiolipin analogues of Archaea  

Microsoft Academic Search

The present article reviews studies of the structure and functional roles of the cardiolipin analogues of extremely halophilic prokaryotes belonging to the Archaea domain. Analogies and differences between the archaeal bisphosphatidylglycerol and the mitochondrial cardiolipin are presented. Furthermore the structure of archaeal glycophospholipid dimers is illustrated together with the available information on their function. The studies on the function of

Angela Corcelli



Synthesis and evaluation of pyrazolo[3,4- b]pyridines and its structural analogues as TNF-? and IL6 inhibitors  

Microsoft Academic Search

In the present article, we have synthesized three different series of pyrazolo[3,4-b]pyridines and their structural analogues using novel synthetic strategy involving one-pot condensation of 5,6-dihydro-4H-pyran-3-carbaldehyde\\/2-formyl-3,4,6-tri-O-methyl-d-glucal\\/chromone-3-carbaldehyde with heteroaromatic amines. All synthesized compounds were evaluated for their anti-inflammatory activity against TNF-? and IL-6. Out of 28 compounds screened, 40, 51, 52 and 56 exhibited promising activity against IL-6 with 60–65% inhibition at

Sandip B. Bharate; Tushar R. Mahajan; Yogesh R. Gole; Mahesh Nambiar; T. T. Matan; Asha Kulkarni-Almeida; Sarala Balachandran; H. Junjappa; Arun Balakrishnan; Ram A. Vishwakarma



The cardiolipin analogues of Archaea.  


The present article reviews studies of the structure and functional roles of the cardiolipin analogues of extremely halophilic prokaryotes belonging to the Archaea domain. Analogies and differences between the archaeal bisphosphatidylglycerol and the mitochondrial cardiolipin are presented. Furthermore the structure of archaeal glycophospholipid dimers is illustrated together with the available information on their function. The studies on the function of cardiolipin analogues in archaebacteria point out the tight interaction established by these phospholipids with membrane proteins and their role as bioactive lipids in the adaptation of microorganisms to osmotic stress. PMID:19464258

Corcelli, Angela



Synthesis and modifications of phosphinic dipeptide analogues.  


Pseudopeptides containing the phosphinate moiety (-P(O)(OH)CH(2)-) have been studied extensively, mainly as transition state analogue inhibitors of metalloproteases. The key synthetic aspect of their chemistry is construction of phosphinic dipeptide derivatives bearing appropriate side-chain substituents. Typically, this synthesis involves a multistep preparation of two individual building blocks, which are combined in the final step. As this methodology does not allow simple variation of the side-chain structure, many efforts have been dedicated to the development of alternative approaches. Recent achievements in this field are summarized in this review. Improved methods for the formation of the phosphinic peptide backbone, including stereoselective and multicomponent reactions, are presented. Parallel modifications leading to the structurally diversified substituents are also described. Finally, selected examples of the biomedical applications of the title compounds are given. PMID:23154272

Mucha, Artur



Glutamate provides a key structural contact between reticulon-4 (Nogo-66) and phosphocholine.  


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, the association with lipid and the 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. This article is part of a special issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova. PMID:24863057

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



Antitrypanosomal and Antileishmanial Activities of Flavonoids and Their Analogues: In Vitro, In Vivo, Structure-Activity Relationship, and Quantitative Structure-Activity Relationship Studies  

PubMed Central

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 ?g/ml) and catechol (IC50, 0.8 ?g/ml). The activity against T. cruzi was moderate, and only chrysin dimethylether and 3-hydroxydaidzein had IC50s less than 5.0 ?g/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 ?g/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.

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



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


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

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



Key structures of bacterial peptidoglycan and lipopolysaccharide triggering the innate immune system of higher animals: Chemical synthesis and functional studies  

PubMed Central

Chemistry-based investigation is reviewed which led to identification of the active entities responsible for the immunostimulating potencies of peptidoglycan and lipopolysaccharide. Though these glycoconjugates which ubiquitously occur in wide range of bacteria as the essential components of their cell envelopes have long been known to enhance the immunological responses of higher animals, neither the precise chemical structures required nor the mechanism of their action remained to be elucidated until early 1970s. Chemical synthesis of partial structures of peptidoglycan proved N-acetylmuramyl-L-alanyl-D-isoglutamine to be the minimum structure responsible for the activity and led to later identification of its receptor protein Nod2 present in animal cells. Another active partial structure of peptidoglycan, ?-D-glutamyl-meso-diaminopimelic acid, and its receptor Nod1 were also identified as well. With regard to lipopolysaccharide, its glycolipid part named lipid A was purified and the structure studied. Chemically synthesized lipid A according to the newly elucidated structure exhibited full activity described for lipopolysaccharide known as endotoxin. Synthetic homogeneous lipid A and its structural analogues and labeled derivatives enabled precise studies of their interaction with receptor proteins and the mechanism of their action. Chemical synthesis of homogeneous partial structures of peptidoglycan and lipopolysaccharide gave unequivocal evidences for the concept that definite small molecular parts of these complex macromolecular bacterial glycoconjugates are specifically recognized by their respective receptors and trigger our defense system now widely recognized as innate immunity.

Kusumoto, Shoichi; Fukase, Koichi; Shiba, Tetsuo



The 2.1 A structure of Torpedo californica creatine kinase complexed with the ADP-Mg(2+)-NO(3)(-)-creatine transition-state analogue complex.  


Creatine kinase (CK) catalyzes the reversible conversion of creatine and ATP to phosphocreatine and ADP, thereby helping maintain energy homeostasis in the cell. Here we report the first X-ray structure of CK bound to a transition-state analogue complex (CK-TSAC). Cocrystallization of the enzyme from Torpedo californica (TcCK) with ADP-Mg(2+), nitrate, and creatine yielded a homodimer, one monomer of which was liganded to a TSAC complex while the second monomer was bound to ADP-Mg(2+) alone. The structures of both monomers were determined to 2.1 A resolution. The creatine is located with the guanidino nitrogen cis to the methyl group positioned to perform in-line attack at the gamma-phosphate of ATP-Mg(2+), while the ADP-Mg(2+) is in a conformation similar to that found in the TSAC-bound structure of the homologue arginine kinase (AK). Three ligands to Mg(2+) are contributed by ADP and nitrate and three by ordered water molecules. The most striking difference between the substrate-bound and TSAC-bound structures is the movement of two loops, comprising residues 60-70 and residues 323-332. In the TSAC-bound structure, both loops move into the active site, resulting in the positioning of two hydrophobic residues (one from each loop), Ile69 and Val325, near the methyl group of creatine. This apparently provides a specificity pocket for optimal creatine binding as this interaction is missing in the AK structure. In addition, the active site of the transition-state analogue complex is completely occluded from solvent, unlike the ADP-Mg(2+)-bound monomer and the unliganded structures reported previously. PMID:12437342

Lahiri, Sushmita D; Wang, Pan-Fen; Babbitt, Patricia C; McLeish, Michael J; Kenyon, George L; Allen, Karen N



Cel48A from Thermobifida fusca: structure and site directed mutagenesis of key residues.  


Lignocellulosic biomass is a potential source of sustainable transportation fuels, but efficient enzymatic saccharification of cellulose is a key challenge in its utilization. Cellulases from the glycoside hydrolase (GH) family 48 constitute an important component of bacterial biomass degrading systems and structures of three enzymes from this family have been previously published. We report a new crystal structure of TfCel48A, a reducing end directed exocellulase from Thermobifida fusca, which shows that this enzyme shares important structural features with the other members of the GH48 family. The active site tunnel entrance of the known GH48 exocellulases is enriched in aromatic residues, which are known to interact well with anhydroglucose units of cellulose. We carried out site-directed mutagenesis studies of these aromatic residues (Y97, F195, Y213, and W313) along with two non-aromatic residues (N212 and S311) also located around the tunnel entrance and a W315 residue inside the active site tunnel. Only the aromatic residues located around the tunnel entrance appear to be important for the ability of TfCel48A to access individual cellulose chains on bacterial cellulose (BC), a crystalline substrate. Both Trp residues were found to be important for the processivity of TfCel48A on BC and phosphoric acid swollen cellulose (PASC), but only W313 appears to play a role in the ability of the enzyme to access individual cellulose chains in BC. When acting on BC, reduced processivity was found to correlate with reduced enzyme activity. The reverse, however, is true when PASC is the substrate. Presumably, higher density of available cellulose chain ends and the amorphous nature of PASC explain the increased initial activity of mutants with lower processivity. PMID:24264519

Kostylev, Maxim; Alahuhta, Markus; Chen, Mo; Brunecky, Roman; Himmel, Michael E; Lunin, Vladimir V; Brady, John; Wilson, David B



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

NASA Astrophysics Data System (ADS)

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.

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



Biological activity in Technosols as a key factor of their structure  

NASA Astrophysics Data System (ADS)

The studies of the dynamics of organic matters within soils, show that their structural stability depends on the biological activity bound to the degradation of organic products. We wondered what it was for Technosols there. We then tried to specify the contribution of this biological activity to the structure of three contrasted technosols : - Technosol 1: a material originated from a former steel industry containing steel and coke residues, which was deposited two years ago in lysimetric plots - Technosol 2: a constructed soil (30 months) resulting from the combination of paper-mill sludge, thermally treated soil material excavated from a former coking plant site, and green-waste compost - Technosol 3: 30 years old technosol developed on flotation ponds of a former steel mill with strong metallic pollution, on which grows a forest ecosystem If these 3 technosols presented initially a similar organic carbon content (around 70, the origin of organic matters was different A follow-up of the structural stability of these 3 systems, based on techniques of granulometric soil fractionation and morphological/analytical characterization at ultrastructural scale (TEM/EDX), was realized. Results showed the specific contribution of organic matters to the formation of stable organo-mineral associations, in particular those belonging to (0-50 ?m) fraction. They mainly involved organic matter from vegetal origin coming from the spontaneous colonization of these 3 sites, but also from microbial origin corresponding to rhizospheric bacteria producing exopolymers. Organic matters from the compost and cellulosic fibers from the paper-mill sludge also contributed to the formation of organo-mineral associations all the more that compost was also a source of microorganisms. Organic matters were also associated to pollutant metallic elements (Pb, Zn, Mn) initially brought by the materials, then highlighting their possible transfer and questioning about their (bio)availability. HAP also contributed to the aggregation of technogenic constituents in Technosol 1. The biological activity generated by the presence of exogenous organic matter is thus in short (0-2 years) and mean (30 years) terms, a key factor of the structuration and by there of the pedogenesis of Technosols.

Watteau, Françoise; Villemin, Geneviève; Bouchard, Adeline; Monserié, Marie-France; Séré, Geoffroy; Schwartz, Christophe; Morel, Jean-Louis



Antizyme induction by polyamine analogues as a factor of cell growth inhibition.  


The polyamines spermidine and spermine and their diamine precursor putrescine are essential for mammalian cell growth and viability, and strategies are sought for reducing polyamine levels in order to inhibit cancer growth. Several structural analogues of the polyamines have been found to decrease natural polyamine levels and inhibit cell growth, probably by stimulating normal feedback mechanisms. In the present study, a large selection of spermine analogues has been tested for their effectiveness in inducing the production of antizyme, a key protein in feedback inhibition of putrescine synthesis and cellular polyamine uptake. Bisethylnorspermine, bisethylhomospermine, 1,19-bis-(ethylamino)-5,10,15-triazanonadecane, longer oligoamine constructs and many conformationally constrained analogues of these compounds were found to stimulate antizyme synthesis to different levels in rat liver HTC cells, with some producing far more antizyme than the natural polyamine spermine. Uptake of the tested compounds was found to be dependent on, and limited by, the polyamine transport system, for which all these have approximately equal affinity. These analogues differed in their ability to inhibit HTC cell growth during 3 days of exposure, and this ability correlated with their antizyme-inducing potential. This is the first direct evidence that antizyme is induced by several polyamine analogues. Selection of analogues with this potential may be an effective strategy for maximizing polyamine deprivation and growth inhibition. PMID:11972449

Mitchell, John L A; Leyser, Aviva; Holtorff, Michelle S; Bates, Jill S; Frydman, Benjamin; Valasinas, Aldonia L; Reddy, Venodhar K; Marton, Laurence J



Antizyme induction by polyamine analogues as a factor of cell growth inhibition.  

PubMed Central

The polyamines spermidine and spermine and their diamine precursor putrescine are essential for mammalian cell growth and viability, and strategies are sought for reducing polyamine levels in order to inhibit cancer growth. Several structural analogues of the polyamines have been found to decrease natural polyamine levels and inhibit cell growth, probably by stimulating normal feedback mechanisms. In the present study, a large selection of spermine analogues has been tested for their effectiveness in inducing the production of antizyme, a key protein in feedback inhibition of putrescine synthesis and cellular polyamine uptake. Bisethylnorspermine, bisethylhomospermine, 1,19-bis-(ethylamino)-5,10,15-triazanonadecane, longer oligoamine constructs and many conformationally constrained analogues of these compounds were found to stimulate antizyme synthesis to different levels in rat liver HTC cells, with some producing far more antizyme than the natural polyamine spermine. Uptake of the tested compounds was found to be dependent on, and limited by, the polyamine transport system, for which all these have approximately equal affinity. These analogues differed in their ability to inhibit HTC cell growth during 3 days of exposure, and this ability correlated with their antizyme-inducing potential. This is the first direct evidence that antizyme is induced by several polyamine analogues. Selection of analogues with this potential may be an effective strategy for maximizing polyamine deprivation and growth inhibition.

Mitchell, John L A; Leyser, Aviva; Holtorff, Michelle S; Bates, Jill S; Frydman, Benjamin; Valasinas, Aldonia L; Reddy, Venodhar K; Marton, Laurence J



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)

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.).

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.



Synthesis and Evaluation of ?-Thymidine Analogues as Novel Antimalarials  

PubMed Central

Plasmodium falciparum thymidylate kinase (PfTMPK) is a key enzyme in pyrimidine nucleotide biosynthesis. 3-Trifluoromethyl-4-chloro-phenyl-urea-?-thymidine has been reported as an inhibitor of Mycobacterium tuberculosis TMPK (MtTMPK). Starting from this point, we designed, synthesized and evaluated a number of thymidine analogues as antimalarials. Both 5?-urea-?- and ?-thymidine derivatives were moderate inhibitors of PfTMPK and furthermore showed moderate inhibition of parasite growth. The structure of several enzyme–inhibitor complexes provides a basis for improved inhibitor design. However, we found that certain 5?-urea-?-thymidine analogues had antimalarial activity where inhibition of PfTMPK is not the major mode of action. Optimization of this series resulted in a compound with potent antimalarial activity (EC50 = 28 nM; CC50 = 29 ?M).



Synthesis and Structure of an Open-Cage Thiafullerene C69S: Reactivity Differences of an Open-Cage C70 Tetraketone Relative to Its C60 Analogue.  


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

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



Structures and physical properties of oligomeric and polymeric metal complexes based on bis(pyridyl)-substituted TTF ligands and an inorganic analogue.  


The bis(pyridyl)-substituted TTF derivative, 2,6(7)-bis(4-pyridyl)-1,4,5,8-tetrathiafulvalene (TTF(py)(2)), and an inorganic analogue, [Ni(4-pedt)(2)] (4-pedt = 1-(pyridin-4-yl)ethylene-1,2-dithiolate), were used as bridging ligands to construct two multinuclear complexes {Co(II)(2)(Tp(Ph2))(2)(OAc)(2)[TTF(py)(2)]} (1, Tp(Ph2) = hydridotri(3,5-diphenylpyrazol-1-yl)borate) and {Co(II)(2)(Tp(Ph2))(2)(OAc)(2)[Ni(4-pedt)(2)]} (2), and two 1D zigzag chain complexes, {[M(II)(tta)(2)][TTF(py)(2)]}(n) (M = Cu for 3, and Mn for 4; tta = thenoyltrifluoroacetonate). X-Ray structural studies indicate that complexes 1 and 2 are very similar as a result of the isolobal analogy between TTF(py)(2) and [Ni(4-pedt)(2)], whereas complexes 3 and 4 are isostructural. The absorption spectra, electrochemical and magnetic properties for these new complexes have been studied. The results show that the interactions between the paramagnetic ions are weak owing to the large separation of the bridging ligands of TTFs and the inorganic analogue. PMID:21152487

Wang, Ru; Kang, Ling-Chen; Xiong, Jing; Dou, Xiao-Wei; Chen, Xiao-Yu; Zuo, Jing-Lin; You, Xiao-Zeng



Platinum(IV) analogues of AMD473 (cis-[PtCl2(NH3)(2-picoline)]): preparative, structural, and electrochemical studies.  


The preparation and oxidation of the anticancer drug AMD473, cis-[PtCl2(NH3)(2-pic)] (2-pic = 2-methylpyridine), has been investigated. cis-[PtCl2(NH3)(2-pic)] is readily oxidized with peroxide to give the trans-dihydroxoplatinum(IV) complex cis,trans,cis-[PtCl2(OH)2(NH3)(2-pic)]. The crystal structure of this complex reveals that it is highly strained as a result of a steric clash between the methyl group of the 2-picoline ligand and an axial hydroxo ligand, with the Pt-N-C angle adjacent to this clash opened up to an unprecedented 138.6(6) degrees . Attempts at converting the dihydroxoplatinum(IV) complex to dichloro and diacetato analogues were unsuccessful with reaction with HCl leading to loss and protonation of the 2-picoline ligand to form the salt (2-picH)[PtCl5(NH3)] and the platinum(II) complex cis-[PtCl2(NH3)(2-pic)], both confirmed by crystallography. Electrochemical studies revealed that cis,trans,cis-[PtCl2(OH)2(NH3)(2-pic)] is reduced more readily (-714 mV vs Ag/AgCl) than its pyridine analogue cis,trans,cis-[PtCl2(OH)2(NH3)(pyridine)] (-770 mV vs Ag/AgCl) consistent with the steric clash in the former complex destabilizing the platinum(IV) oxidation state. PMID:16878941

Battle, Andrew R; Choi, Robin; Hibbs, David E; Hambley, Trevor W



Synthesis of the reported structure of piperazirum using a nitro-Mannich reaction as the key stereochemical determining step  

PubMed Central

Summary Piperazirum, isolated from Arum palaestinum Boiss, was originally assigned as r-3,c-5-diisobutyl-c-6-isopropylpiperazin-2-one. The reported structure was synthesised diastereoselectively using a key nitro-Mannich reaction to set up the C5/C6 relative stereochemistry. The structure was unambiguously assigned by single crystal X-ray diffraction but the spectroscopic data did not match those reported for the natural product. The structure of the natural product must therefore be revised.

Kalogirou, Andreas S; Porter, Michael J; Tizzard, Graham J



Synthesis and structure-activity relationship of berberine analogues in LDLR up-regulation and AMPK activation.  


Currently there is no approved medicine for the treatment of metabolic syndrome. A series of new derivatives of berberine (BBR) or pseudoberberine (1) was synthesized and evaluated for their activity on AMP-activated protein kinase (AMPK) activation and up-regulatory low-density-lipoprotein receptor (LDLR) gene expression, respectively. In addition, the four major metabolites of BBR in vivo were also examined for their activity on AMPK in order to further understand the chemical mechanisms responsible for its glucose-lowering efficacy. Among those BBR analogues, compound 1 exhibited the potential effect on AMPK activation and LDLR up-regulation as compared with BBR. The results suggested that compound 1 might be a multiple-target agent for the treatment of metabolic syndrome, and thus was selected as a promising drug candidate for further development. PMID:23058107

Wang, Yan-Xiang; Kong, Wei-Jia; Li, Ying-Hong; Tang, Sheng; Li, Zheng; Li, Yang-Biao; Shan, Yong-Qiang; Bi, Chong-Wen; Jiang, Jian-Dong; Song, Dan-Qing



Synthesis, structure-activity relationships and biological evaluation of barbigerone analogues as anti-proliferative and anti-angiogenesis agents.  


A series of barbigerone analogues (7a-7w, 13a-13x) were designed, synthesized and biologically evaluated for their anti-proliferative and anti-angiogenic activities. Among these compounds, compound 13a exhibited the most potent inhibitory effect on the proliferation of HUVECs, HepG2, A375, U251, B16, and HCT116 cells (IC50=3.80, 0.28, 1.58, 3.50, 1.09 and 0.68?M, respectively). Compound 13a inhibited the angiogenesis in zebrafish embryo assay in a concentration-dependent manner. Furthermore, 13a also effectively inhibited the migration and capillary like tube formation of human umbilical vein endothelial cell in vitro. These results support the further investigation of this class of compounds as potential anti-proliferative and anti-angiogenesis agents. PMID:24863745

Wang, Guangcheng; Wang, Fang; Cao, Dong; Liu, Yibin; Zhang, Ronghong; Ye, Haoyu; Li, Xiuxia; He, Lin; Yang, Zhuang; Ma, Liang; Peng, Aihua; Xiang, Mingli; Wei, Yuquan; Chen, Lijuan



Similar coronary vascular effects in the rat perfused heart of platelet-activating factor structural analogues with agonist and antagonist properties.  

PubMed Central

1. Selective blockade of platelet-activating factor (PAF) receptor subtypes by PAF receptor antagonists has been demonstrated. However, selective activation of PAF receptor subtypes by PAF receptor agonists has not been reported. 2. When structural analogues of PAF that have been shown to possess either agonist or antagonist effects were administered by a bolus injection in the rat perfused heart, they all showed agonist effects. Lower amounts produced vasodilation while higher amounts produced vasodilation followed by vasoconstriction. These coronary vascular effects were typical of that observed with PAF. Lyso-PAF did not show the same typical pattern of coronary vascular effect, confirming that the detergent effect of PAF structural analogues did not play a role in the coronary vascular effects. Other PAF antagonists, CV-6209 and WEB 2170, also did not produce the PAF-like response in the rat perfused heart. 3. The coronary vascular effects of hexanolamine-PAF (H-PAF, putative antagonist) and ethanolamine-PAF (E-PAF, agonist) were further studied. Pretreatment with FR-900452 (a PAF receptor antagonist) or MK-886 (a leukotriene synthesis inhibitor) significantly reduced the vasodilator and vasoconstrictor effects of H-PAF and E-PAF. 4. Pretreatment of rat perfused hearts with low concentrations of H-PAF and E-PAF blocked the response to PAF administration in a dose- and time-dependent manner. However, the pretreatment with either H-PAF or E-PAF did not result in a coronary vascular effect expected of a PAF receptor agonist. These results were compatible with H-PAF and E-PAF behaving as PAF receptor antagonists. 5. In summary, our results demonstrate that several PAF structural analogues possess agonist action in the rat perfused heart. Like the coronary vascular effects of PAF, the effects of H-PAF and E-PAF were blocked by a PAF antagonist (FR-900452) and a leukotriene synthesis inhibitor (MK-886). This suggests that both H-PAF and E-PAF mediate their effect through activation of PAF receptors with a subsequent release of leukotrienes that produced vasodilatation and vasoconstriction. Furthermore, pretreatment of perfused hearts with these compounds blocked the response to PAF in these hearts. Thus these compounds can also behave like a PAF receptor antagonist. This latter action may be due to a gradual receptor inactivation or desensitization by the pretreatment of H-PAF and E-PAF through a PAF receptor agonist effect rather than being a PAF receptor antagonist.

Man, R. Y.; Kinnaird, A. A.



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

SciTech Connect

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.

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



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

Low molecular mass purine nucleoside phosphorylases (PNPs, E.C. 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).

Chojnowski, Grzegorz [Department of Biophysics, Institute of Experimental Physics, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw (Poland) [Department of Biophysics, Institute of Experimental Physics, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw (Poland); International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw (Poland); Breer, Katarzyna; Narczyk, Marta; Wielgus-Kutrowska, Beata [Department of Biophysics, Institute of Experimental Physics, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw (Poland)] [Department of Biophysics, Institute of Experimental Physics, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw (Poland); Czapinska, Honorata [International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw (Poland)] [International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw (Poland); Hashimoto, Mariko; Hikishima, Sadao; Yokomatsu, Tsutomu [School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392 (Japan)] [School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392 (Japan); Bochtler, Matthias [International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw (Poland) [International Institute of Molecular and Cell Biology, Trojdena 4, 02-109 Warsaw (Poland); Schools of Chemistry and Biosciences, Park Place, CF10 3AT Cardiff (United Kingdom); Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstr. 108, 01309 Dresden (Germany); Girstun, Agnieszka; Staron, Krzysztof [Department of Molecular Biology, Institute of Biochemistry, University of Warsaw, Miecznikowa 1, 02-096 Warsaw (Poland)] [Department of Molecular Biology, Institute of Biochemistry, University of Warsaw, Miecznikowa 1, 02-096 Warsaw (Poland); Bzowska, Agnieszka, E-mail: [Department of Biophysics, Institute of Experimental Physics, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw (Poland)] [Department of Biophysics, Institute of Experimental Physics, University of Warsaw, Zwirki i Wigury 93, 02-089 Warsaw (Poland)



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

PubMed Central

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.

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



Structure reassignment and synthesis of Jenamidines A1/A2, synthesis of (+)-NP25302, and formal synthesis of SB-311009 analogues.  


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

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



[IR spectroscopic research on the impact of chemical analogues of autoregulatory d1 factors of microorganisms on structural changes in DNA].  


Using IR spectroscopy, we investigated the impact of chemical analogues of autoregulatory d1 factors of microorganisms (methylresorcinol, hexylresorcinol, and tyrosol) on the conformational changes in DNA in films upon altering (decreasing) the relative humidity. We analyzed the appearance/disappearance of characteristic absorption bands of A and B DNA forms and determined D1080/D1224, the ratio between the band intensities of symmetrical and asymmetrical oscillations in their phosphate groups. The data obtained suggest the slowing down of the B-->A structural transition in DNA in the presence of methylresorcinol and its speeding up in the presence of tyrosol. We discuss the mechanisms of this phenomenon in relation to the chemical composition of d1 factors and their biological function. PMID:17633405

Davydova, O K; Deriabin, D G; El'-Registan, G I



Evaluating the role of syn-thrusting sedimentation and interaction with frictional detachment in the structural evolution of the SW Tarim basin, NW China: Insights from analogue modeling  

NASA Astrophysics Data System (ADS)

The structural evolution of the fold-and-thrust belt in SW Tarim Basin, NW China is poorly understood as the region is covered by thick Pliocene-Quaternary conglomerate, which significantly decreases the quality of seismic images. We here improve the understanding of the thrust belt evolution with an investigation using analogue modeling on the deformation mechanism based on a case of real geological section, in which we focus on the impact of syn-thrusting sedimentation on the structural style and evolution. The results show that syn-thrusting sedimentation significantly increases the distance and rate of foreland propagation, resulting in a much broader fold-and-thrust belt. The modeling results also suggest that the fold-and-thrust belt exhibits different structural patterns under different syn-thrusting sedimentary conditions. In the case of thick syn-thrusting sediments, a frictional detachment layer of mudstone acts as décollement and the fold-and-thrust belt develops a duplex pattern in the hinterland. In the case of thin syn-thrusting deposits, the belt develops a pop-up structure with backthrusts in the foreland region which cut through the detachment layer. The striking similarity between the model with thick syn-thrusting sediments and the real geologic section implies that the overlying thick Pliocene-Quaternary sediments play a major role in shaping the structure pattern in the fold-and-thrust belt of SW Tarim Basin.

Wang, Chun-yang; Chen, Han-lin; Cheng, Xiao-gan; Li, Kang



Heterocyclic chalcone analogues as potential anticancer agents.  


Chalcones, aromatic ketones and enones acting as the precursor for flavonoids such as Quercetin, are known for their anticancer effects. Although, parent chalcones consist of two aromatic rings joined by a three-carbon ?,?-unsaturated carbonyl system, various synthetic compounds possessing heterocyclic rings like pyrazole, indole etc. are well known and proved to be effective anticancer agents. In addition to their use as anticancer agents in cancer cell lines, heterocyclic analogues are reported to be effective even against resistant cell lines. In this connection, we hereby highlight the potential of various heterocyclic chalcone analogues as anticancer agents with a brief summary about therapeutic potential of chalcones, mechanism of anticancer action of various chalcone analogues, and current and future prospects related to the chalcones-derived anticancer research. Furthermore, some key points regarding chalcone analogues have been reviewed by analyzing their medicinal properties. PMID:22721390

Sharma, Vikas; Kumar, Vipin; Kumar, Pradeep



A tandem regression-outlier analysis of a ligand cellular system for key structural modifications around ligand binding  

PubMed Central

Background A tandem technique of hard equipment is often used for the chemical analysis of a single cell to first isolate and then detect the wanted identities. The first part is the separation of wanted chemicals from the bulk of a cell; the second part is the actual detection of the important identities. To identify the key structural modifications around ligand binding, the present study aims to develop a counterpart of tandem technique for cheminformatics. A statistical regression and its outliers act as a computational technique for separation. Results A PPAR? (peroxisome proliferator-activated receptor gamma) agonist cellular system was subjected to such an investigation. Results show that this tandem regression-outlier analysis, or the prioritization of the context equations tagged with features of the outliers, is an effective regression technique of cheminformatics to detect key structural modifications, as well as their tendency of impact to ligand binding. Conclusions The key structural modifications around ligand binding are effectively extracted or characterized out of cellular reactions. This is because molecular binding is the paramount factor in such ligand cellular system and key structural modifications around ligand binding are expected to create outliers. Therefore, such outliers can be captured by this tandem regression-outlier analysis.



Synthesis, antigenicity against human sera and structure-activity relationships of carbohydrate moieties from Toxocara larvae and their analogues.  


Stereocontrolled syntheses of biotin-labeled oligosaccharide portions containing the Gal?1-3GalNAc core of the TES-glycoprotein antigen obtained from larvae of the parasite Toxocara and their analogues have been accomplished. Trisaccharides Fuc2Me?1-2Gal4Me?1-3GalNAc?1-OR (A), Fuc?1-2Gal4Me?1-3GalNAc?1-OR (B), Fuc2Me?1-2Gal?1-3GalNAc?1-OR (C), Fuc?1-2Gal?1-3GalNAc?1-OR (D) and a disaccharide Fuc2Me?1-2Gal4Me?1-OR (E) (R = biotinylated probe) were synthesized by block synthesis using 5-(methoxycarbonyl)pentyl-2,3,4,6-tetra-O-acetyl-?-D-galactopyranosyl-(1-->3)-2-azide-4-O-benzyl-2-deoxy-?-D-galactopyranoside as a common glycosyl acceptor. We examined the antigenicity of these five oligosaccharides by enzyme linked immunosorbent assay (ELISA). Our results demonstrate that the O-methyl groups in these oligosaccharides are important for their antigenicity and the biotinylated oligosaccharides A, B, C and E have high serodiagnostic potential to detect infections caused by Toxocara larvae. PMID:22847142

Koizumi, Akihiko; Yamano, Kimiaki; Tsuchiya, Takashi; Schweizer, Frank; Kiuchi, Fumiyuki; Hada, Noriyasu



Diacetylenic lipid microstructures: Structural characterization by X-ray diffraction and comparison with the saturated phosphatidylcholine analogue  

SciTech Connect

Thermotropic and lyotropic mesomorphism in the polymerizable lecithin 1,2-ditricosa-10,12-diynoyl-sn-glycero-3-phosphocholine and its saturated analogue, 1,2-ditricosanoyl-sn-glycero-3-phosphocholine, has been investigated by wide- and low-angle X-ray diffraction of both powder and oriented samples and by differential scanning calorimetry. The diffraction results indicate that at low temperatures fully hydrated tubules and sheets have an identical lamellar repeat size and crystalline-like packing of the acyl chains. Chain packing in the lamellar crystalline phase is hydration independent. A model for the polymerizable lecithin with (1) fully extended all-trans methylene segments, (2) a long-axis tilt of 32{degree}, and (3) minimal chain interdigitation seems most reasonable on energetic grounds, is consistent with the diffraction data (to 3.93-{angstrom} resolution), and is likely to support facile polymerization. Above the chain melting' transition the lamellar repeat of the polymerizable lipid increases to 74 {angstrom}. The data suggest that although a high degree of conformational order is a pertinent feature of tubules, this character alone is not sufficient to account for tubule formation. The conformation of the corresponding saturated phosphatidylcholine appears to be similar to that of other saturated phosphatidylcholines in the lamellar gel phase. Furthermore, above the main transition temperature, the dry, saturated lipid shows evidence of a P{sub {delta}} phase (112C), whereas, the diacetylenic lipid appears to exhibit a centered rectangular phase, R{sub {alpha}} (55C).

Caffrey, M.; Hogan, J. (Ohio State Univ., Columbus (United States)); Rudolph, A.S. (Naval Research Lab., Washington, DC (United States))



Synthesis and in vitro antitumor activity of novel ring D analogues of the marine pyridoacridine ascididemin: structure-activity relationship.  


Marine compounds with pyridoacridine skeletons are known to exhibit interesting antitumor activities. Ascididemin has already been reported as displaying significant antitumor activities in vitro and has also been found to have a relatively high global toxicity in vivo. We synthesized a series of 16 analogues (among which 11 compounds were different from previously described ones) with the aim of developing new anticancer agents with significantly improved efficacy/tolerability ratios. These compounds were obtained either by total synthesis from 5,8-quinolinedione and substituted 2-aminoacetophenones or by the direct substitution of ascididemin. The different compounds and ascididemin used as the control compound were tested at six different concentrations on 12 different human cancer cell lines of various histopathological types (glioblastomas and breast, colon, lung, prostate, and bladder cancers). The IC(50) value (i.e., the drug concentration inhibiting the mean growth value of the 12 cell lines by 50%) of these compounds ranged over five log concentrations, i.e., between 10 000 and 0.1 nM. For several new chemical entities, the antitumor activity (determined in vitro) and tolerability (determined in vivo) were superior to those of the parent alkaloids, i.e., ascididemin and 2-bromoleptoclinidone. PMID:12166949

Delfourne, Evelyne; Darro, Francis; Portefaix, Philippe; Galaup, Chantal; Bayssade, Sylvie; Bouteillé, Anne; Le Corre, Laurent; Bastide, Jean; Collignon, Françoise; Lesur, Brigitte; Frydman, Armand; Kiss, Robert



Preferred 3D-structure of peptides rich in a severely conformationally restricted cyclopropane analogue of phenylalanine.  


Terminally blocked, homo-peptide amides of (R,R)-1-amino-2,3-diphenylcyclopropane-1-carboxylic acid (c3diPhe), a chiral member of the family of Calpha-tetrasubstituted alpha-amino acids, from the dimer to the tetramer, and diastereomeric co-oligopeptides of (R,R)- or (S,S)-c3diPhe with (S)-alanine residues to the trimer level were prepared in solution and fully characterized. The synthetic effort was extended to terminally protected co-oligopeptide esters to the hexamer, where c3diPhe residues are combined with achiral alpha-aminoisobutyric acid residues. The preferred conformations of the peptides were assessed in solution by FT-IR absorption, NMR, and CD techniques, and for seven oligomers in the crystal state (by X-ray diffraction) as well. This study clearly indicates that c3diPhe, a sterically demanding cyclopropane analogue of phenylalanine, tends to fold peptides into beta-turn and 3(10)-helix conformations. However, when c3diPhe is in combination with other chiral residues, the conformation preferred by the resulting peptides is also dictated by the chiral sequence of the amino acid building blocks. The (S,S)-enantiomer of this alpha-amino acid, unusually lacking asymmetry in the main chain, strongly favors the left-handedness of the turn/helical peptides formed. PMID:16281320

Crisma, Marco; De Borggraeve, Wim M; Peggion, Cristina; Formaggio, Fernando; Royo, Soledad; Jiménez, Ana I; Cativiela, Carlos; Toniolo, Claudio



How does conformational flexibility influence key structural features involved in activation of anaplastic lymphoma kinase?  


Anaplastic Lymphoma Kinase (ALK) plays a major role in developing tumor processes and therefore has emerged as a validated therapeutic target. Applying atomistic molecular dynamics simulations on the wild type enzyme and the nine most frequently occurring and clinically important activation mutants we revealed important conformational effects on key interactions responsible for the activation of the enzyme. PMID:24675991

Karabencheva, Tatyana G; Lee, Christian C; Black, Gary W; Donev, Rossen; Christov, Christo Z



Key structural forest connectors can be identified by combining landscape spatial pattern and network analyses  

Microsoft Academic Search

Conservation and enhancement of ecological connectivity is widely recognized as one of the key objectives of forest landscape management. However, practical difficulties still exist due to the lack of pragmatic and operational methodologies that can be efficiently applied for these purposes within the scope of a forest management plan. Here we present the novel integration of two recent approaches for

Santiago Saura; Peter Vogt; Javier Velázquez; Ana Hernando; Rosario Tejera



NMR structure determination of a synthetic analogue of bacillomycin Lc reveals the strategic role of L-Asn1 in the natural iturinic antibiotics  

NASA Astrophysics Data System (ADS)

Iturins are a group of antifungal produced by Bacillus subtilis. All are cyclic lipopeptides with seven ?-amino acids of configuration LDDLLDL and one ?-amino fatty acid. The bacillomycin L is a member of this family and its NMR structure was previously resolved using the sequence Asp-Tyr-Asn-Ser-Gln-Ser-Thr. In this work, we carefully examined the NMR spectra of this compound and detected an error in the sequence. In fact, Asp1 and Gln5 need to be changed into Asn1 and Glu5, which therefore makes it identical to bacillomycin Lc. As a consequence, it now appears that all iturinic peptides with antibiotic activity share the common ?-amino fatty acid 8- L-Asn1- D-Tyr2- D-Asn3 sequence. To better understand the conformational influence of the acidic residue L-Asp1, present, for example in the inactive iturin C, the NMR structure of the synthetic analogue SCP [cyclo ( L-Asp1- D-Tyr2- D-Asn3- L-Ser4- L-Gln5- D-Ser6- L-Thr7-?-Ala8)] was determined and compared with bacillomycin Lc recalculated with the corrected sequence. In both cases, the conformers obtained were separated into two families of similar energy which essentially differ in the number and type of turns. A detailed analysis of both cyclopeptide structures is presented here. In addition, CD and FTIR spectra were performed and confirmed the conformational differences observed by NMR between both cyclopeptides.

Volpon, Laurent; Tsan, Pascale; Majer, Zsuzsa; Vass, Elemer; Hollósi, Miklós; Noguéra, Valérie; Lancelin, Jean-Marc; Besson, Françoise



Structural studies of human brain-type creatine kinase complexed with the ADP-Mg2+-NO3- -creatine transition-state analogue complex.  


Creatine kinase is a member of the phosphagen kinase family, which catalyzes the reversible phosphoryl transfer reaction that occurs between ATP and creatine to produce ADP and phosphocreatine. Here, three structural aspects of human-brain-type-creatine-kinase (hBB-CK) were identified by X-ray crystallography: the ligand-free-form at 2.2A; the ADP-Mg2+, nitrate, and creatine complex (transition-state-analogue complex; TSAC); and the ADP-Mg2+-complex at 2.0A. The structures of ligand-bound hBB-CK revealed two different monomeric states in a single homodimer. One monomer is a closed form, either bound to TSAC or the ADP-Mg2+-complex, and the second monomer is an unliganded open form. These structural studies provide a detailed mechanism indicating that the binding of ADP-Mg2+ alone may trigger conformational changes in hBB-CK that were not observed with muscle-type-CK. PMID:18977227

Bong, Seoung Min; Moon, Jin Ho; Nam, Ki Hyun; Lee, Ki Seog; Chi, Young Min; Hwang, Kwang Yeon



Solution structure of an analogue of vasoactive intestinal peptide as determined by two-dimensional NMR and circular dichroism spectroscopies and constrained molecular dynamics  

SciTech Connect

Structures have been determined for a potent analogue (VIP') of vasoactive intestinal peptide (VIP) in methanol/water solutions. In CD studies, both VIP and VIP' were helical in methanol/water, with the percentage of {alpha}-helix increasing with percentage methanol. The pH had little effect on the structure. Complete {sup 1}H NMR assignments were made for VIP' in 25% methanol at pH 4 and 6 and in 50% methanol at pH 6, using two-dimensional COSY, NOESY, and relay-COSY experiments. There were no widespread changes in chemical shifts between the samples at pH 4 and 6; however, widespread changes were observed between the samples in 25% and 50% methanol. Complete sets of NOEs were obtained for VIP' in 25% methanol, pH 4, and in 50% methanol, pH 6. These NOEs were converted into distance constraints and applied in molecular dynamics and energy minimization calculations using the program CHARMM. A set of low-energy structures was obtained for VIP' in each solvent system. In 25% methanol, VIP' has two helical segments at residues 9-17 and 23-28. The remainder of the structure is not well determined. In 50% methanol, residues 8-26 form a regular, well-defined {alpha}-helix and residues 5-8 form a type III {beta}-turn. The remaining residues are not ordered. These structural assessments agree with the CD data. In the lowest energy structure in 50% methanol, the side chains of Asp{sup 3}, Phe{sup 6}, Thr{sup 7}, and Tyr{sup 10} are clustered together--these residues are conserved throughout the family of peptide hormones homologous to VIP.

Fry, D.C.; Madison, V.S.; Bolin, D.R.; Greeley, D.N.; Toome, V.; Wegrzynski, B.B. (Hoffmann-La Roche Inc., Nutley, NJ (USA))



Enzymatic transition states: thermodynamics, dynamics and analogue design  

Microsoft Academic Search

Kinetic isotope effects and computational chemistry have defined the transition state structures for several members of the N-ribosyltransferase family. Transition state analogues designed to mimic their cognate transition state structures are among the most powerful enzyme inhibitors. In complexes of N-ribosyltransferases with their transition state analogues, the dynamic nature of the transition state is converted to an ordered, thermodynamic structure

Vern L. Schramm



Synthesis of a new chiral source, (1R,2S)-1-Phenylphospholane-2-carboxylic acid, via a key intermediate alpha-phenylphospholanyllithium borane complex: configurational stability and X-ray crystal structure of an alpha-monophosphinoalkyllithium borane complex.  


A synthetic route to enantiomerically pure (1R,2S)-1-phenylphospholane-2-carboxylic acid (1), which is a phosphorus analogue of proline, has been established. A key step is the deprotonation-carboxylation of the 1-phenylphospholane borane complex 3 by using sBuLi/1,2-dipiperidinoethane (DPE). Configurational stability of the key intermediate, the amine-coordinated alpha-phosphinoalkyllithium borane complex 4, was investigated by employing lithiodestannylation-carboxylation of both diastereomers of the 1-phenyl-2-trimethylstannylphospholane borane complex 7 in the presence of several kinds of amines, and as a result, 4 was found to be configurationally labile even at -100 degrees C. The key intermediate, the DPE-coordinated trans-1-phenyl-2-phospholanyllithium borane complex 9, was isolated, and the structure was identified by X-ray crystal structure analysis. This is the first X-ray crystal structure determined for an alpha-monophosphinoalkyllithium borane complex. Remarkably, the alkyllithium complex is monomeric and tricoordinate at the lithium center with a slightly pyramidalized environment, and the existence of a Li--C bond (2.170 A) has been confirmed. Moreover, (1)H-(7)Li HOESY and (6)Li NMR analyses suggested the structure of 9 in solution as well as the existence of an equilibrium between 9, its cis isomer, and the ion pair 8 at room temperature, which was extremely biased towards 9 at -100 degrees C. Finally, 1 was used as a chiral ligand in a palladium-catalyzed allylic substitution, and the desired product was obtained in high yield with good enantioselectivity. PMID:15551317

Sun, Xiang-Min; Manabe, Kei; Lam, William W-L; Shiraishi, Nobuyuki; Kobayashi, Jun; Shiro, Motoo; Utsumi, Hiroaki; Kobayashi, Shu



Synthesis and antitumour activity of ?-hydroxyisovalerylshikonin analogues  

Microsoft Academic Search

A series of novel ?-hydroxyisovalerylshikonin analogues bearing oxygen-containing substituents at the side-chain hydroxyl of shikonin were designed and synthesized. The cytotoxicities of these compounds were evaluated in vitro against multi-drug resistant (MDR) cell lines DU-145 and HeLa. Most compounds exhibited significant inhibitory activity on both cell lines. The structure–activity relationship showed the analogues with ether substituents displayed the most potent antitumour

Zhen Rao; Xin Liu; Wen Zhou; Jing Yi; Shao-Shun Li



The IRAM key project: small-scale structure of pre-star forming regions. Combined mass spectra and scaling laws  

Microsoft Academic Search

One objective of the IRAM key project small-scale structure of pre-star forming regions is to determine the continuation of the mass spectra for molecular cloud fragments and other scaling laws from large scales down to smallest scales accessible with single-dish telescopes. In this Letter we present first results of the combination of the small scale data from this project and

A. Heithausen; F. Bensch; J. Stutzki; E. Falgarone; J. F. Panis



Inhibition of Siderophore Biosynthesis in Mycobacterium tuberculosis with Nucleoside Bisubstrate Analogues: Structure-Activity Relationships of the Nucleobase Domain of 5?-O-[N-(Salicyl)sulfamoyl]adenosine  

PubMed Central

5?-O-[N-(salicyl)sulfamoyl]adenosine (Sal-AMS) is a prototype for a new class of antitubercular agents that inhibit the aryl acid adenylating enzyme (AAAE) known as MbtA involved in biosynthesis of the mycobactins. Herein, we report the structure-based design, synthesis, biochemical, and biological evaluation of a comprehensive and systematic series of analogues, exploring the structure–activity relationship of the purine nucleobase domain of Sal-AMS. Significantly, 2-phenyl-Sal-AMS derivative 26 exhibited exceptionally potent antitubercular activity with an MIC99 under iron-deficient conditions of 0.049 µM while the N-6-cyclopropyl-Sal-AMS 16 led to improved potency and to a 64-enhancement in activity under iron-deficient conditions relative to iron-replete conditions, a phenotype concordant with the designed mechanism of action. The most potent MbtA inhibitors disclosed here display in vitro antitubercular activity superior to most current first line TB drugs, and these compounds are also expected to be useful against a wide range of pathogens that require aryl-capped siderphores for virulence.

Neres, Joao; Labello, Nicholas P.; Somu, Ravindranadh V.; Boshoff, Helena I.; Wilson, Daniel J.; Vannada, Jagadeshwar; Chen, Liqiang; Barry, Clifton E.; Bennett, Eric M.; Aldrich, Courtney C.



Key Labeling Technologies to Tackle Sizeable Problems in RNA Structural Biology  

PubMed Central

The ability to adopt complex three-dimensional (3D) structures that can rapidly interconvert between multiple functional states (folding and dynamics) is vital for the proper functioning of RNAs. Consequently, RNA structure and dynamics necessarily determine their biological function. In the post-genomic era, it is clear that RNAs comprise a larger proportion (>50%) of the transcribed genome compared to proteins (?2%). Yet the determination of the 3D structures of RNAs lags considerably behind those of proteins and to date there are even fewer investigations of dynamics in RNAs compared to proteins. Site specific incorporation of various structural and dynamic probes into nucleic acids would likely transform RNA structural biology. Therefore, various methods for introducing probes for structural, functional, and biotechnological applications are critically assessed here. These probes include stable isotopes such as 2H, 13C, 15N, and 19F. Incorporation of these probes using improved RNA ligation strategies promises to change the landscape of structural biology of supramacromolecules probed by biophysical tools such as nuclear magnetic resonance (NMR) spectroscopy, X-ray crystallography and Raman spectroscopy. Finally, some of the structural and dynamic problems that can be addressed using these technological advances are outlined.

Dayie, Kwaku T.



Natural product juglone targets three key enzymes from Helicobacter pylori: inhibition assay with crystal structure characterization  

Microsoft Academic Search

Aim:To investigate the inhibition features of the natural product juglone (5-hydroxy-1,4-naphthoquinone) against the three key enzymes from Helicobacter pylori (cystathionine ?-synthase [HpCGS], malonyl-CoA:acyl carrier protein transacylase [HpFabD], and ?-hydroxyacyl-ACP dehydratase [HpFabZ]).Methods:An enzyme inhibition assay against HpCGS was carried out by using a continuous coupled spectrophotometric assay approach. The inhibition assay of HpFabD was performed based on the ?-ketoglutarate dehydrogenase-coupled system,

Yun-hua Kong; Liang Zhang; Zheng-yi Yang; Cong Han; Li-hong Hu; Hua-liang Jiang; Xu Shen



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

NASA Astrophysics Data System (ADS)

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.

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



Aza analogues of nucleic acid bases: experimental determination and computational prediction of the crystal structure of anhydrous 5-azauracil  

NASA Astrophysics Data System (ADS)

The crystal and molecular structure of 5-azauracil, C 3H 3O 2N 3, Mr=113.07 Da, was determined from X-ray diffraction data. The material crystallizes in the orthorhombic space group Pbca with eight molecules of 5-azauracil in a cell of dimensions a=6.5135(3), b=13.5217(4), c=6.5824(4) Å, crystal density Dc=1.779 g cm -3. The structure was determined using direct methods and refined by full-matrix least-squares to a conventional R index of 0.0337 for 763 observed reflections and 86 parameters. Two strong hydrogen bonds, N1H1…O4 and N3H3…N5, and several weaker intermolecular interactions produce a crinkled sheet structure. This crystal structure was independently predicted by a search for minima in the lattice energy, as calculated using an ab initio optimised molecular structure and a distributed multipole model for the electrostatic interactions. Indeed, the global minimum in the search corresponded to the same Pbca space group, with rms errors in the cell lengths of 3.7%. There is a larger energy gap separating the observed hydrogen bonding motif structure from alternative structures, with different hydrogen bonds and connectivity, for 5-azauracil than for 6-azauracil and uracil.

Potter, Brian S.; Palmer, Rex A.; Withnall, Robert; Chowdhry, Babur Z.; Price, Sarah L.



Correlation Between Archean Rocks From Fhe Kola Superdeep Borehole and Their Surface Analogues: On The Data of Structural-petrological and Petrophysical Studies  

NASA Astrophysics Data System (ADS)

The results of complex structural-petrological and petrophysical studies on core sam- ples from the Kola Superdeep borehole (SG-3) and their surface analogous are evi- dence in favour of choosing Mustantunturi site for correlation between Archean rocks of Kola series from the depths of 8-10 km and from the surface. The samples of the both groups show similarity in the mode of occurrence, mineral composition, tex- ture character and formation conditions. Using the data of the SG-3 investigations it was found that the degree of rock anisotropy has been increasing with depth, but such variations were not linear, being controlled by a combination of different fac- tors. It also depended on initial composition, intensities of plastic deformations syn- chronous with Early-Proterozoic zonal progressive metamorphism. Later overprinted fragile strains and regressive processes led to its decrease. Data on the northern flank of the Pechenga structure and its setting are in conflict with these observations, but generally, anisotropy of longitudinal waves at the surface is lower than that at the depth. This conclusion is verified by Avp determinations on reference gneiss and am- phibolite samples and their surface analogues. The investigations illuminate the con- tinuously debated issue of the anomalously high rock porosity and the anomalously low elastic wave velocities at the deep levels of the ancient continental crust cut by SG-3. The results of petrophysical and experimental study on the reference core sam- ples and their surface analogues show that the gneisses and amphibolites at the depths of 8-11 are characterized by normal values of density (2,71-2,74 and 3,05-3,06 g/cm3, respectively) typical for such rocks and by velocities of longitudinal (5,57-5,83 and 6,29-6,50 km/s) and shear (2,72-3,18 and 3,31-3,45 km/s) elastic waves. With lifting to the surface from the depth more than 7 km core undergo decompression and that leads to softening and loosening of rock material. As a result, the value of rock poros- ity may comprise 0,5- 0,8 %. The results of our petrophysical study give reason to believe that in situ porosity of the Archean gneisses and amphibolites is 0,5 % and permeability values are from 10-20 to 10-18 m2. This study was supported by the RFBR (projects nos. 01-05-64294, 01-05-64295).

Lobanov, K.; Kazansky, V.


Blackbody Infrared Radiative Dissociation of Bradykinin and Its Analogues: Energetics, Dynamics, and Evidence for Salt-Bridge Structures in the Gas Phase  

PubMed Central

Blackbody infrared radiative dissociation (BIRD) spectra of singly and doubly protonated bradykinin and its analogues are measured in a Fourier-transform mass spectrometer. Rate constants for dissociation are measured as a function of temperature with reaction delays up to 600 s. From these data, Arrhenius activation parameters in the zero-pressure limit are obtained. The activation parameters and dissociation products for the singly protonated ions are highly sensitive to small changes in ion structure. The Arrhenius activation energy (Ea) and pre-exponential (or frequency factor, A) of the singly protonated ions investigated here range from 0.6 to 1.4 eV and 105 to 1012 s?1, respectively. For bradykinin and its analogues differing by modification of the residues between the two arginine groups on either end of the molecule, the singly and doubly protonated ions have average activation energies of 1.2 and 0.8 eV, respectively, and average A values of 108 and 1012 s?1, respectively, i.e., the presence of a second charge reduces the activation energy by 0.4 eV and decreases the A value by a factor of 104. This demonstrates that the presence of a second charge can dramatically influence the dissociation dynamics of these ions. The doubly protonated methyl ester of bradykinin has an Ea of 0.82 eV, comparable to the value of 0.84 eV for bradykinin itself. However, this value is 0.21 ± 0.08 eV greater than that of singly protonated methyl ester of bradykinin, indicating that the Coulomb repulsion is not the most significant factor in the activation energy of this ion. Both singly and doubly protonated Lys-bradykinin ions have higher activation energies than the corresponding bradykinin ions indicating that the addition of a basic residue stabilizes these ions with respect to dissociation. Methylation of the carboxylic acid group of the C-terminus reduces the Ea of bradykinin from 1.3 to 0.6 eV and the A factor from 1012 to 105 s?1. This modification also dramatically changes the dissociation products. Similar results are observed for [Ala6]-bradykinin and its methyl ester. These results, in combination with others presented here, provide experimental evidence that the most stable form of singly protonated bradykinin is a salt-bridge structure.

Schnier, Paul D.; Price, William D.; Jockusch, Rebecca A.



Oligomeric integrity--the structural key to thermal stability in bacterial alcohol dehydrogenases.  

PubMed Central

Principles of protein thermostability have been studied by comparing structures of thermostable proteins with mesophilic counterparts that have a high degree of sequence identity. Two tetrameric NADP(H)-dependent alcohol dehydrogenases, one from Clostridium beijerinckii (CBADH) and the other from Thermoanaerobacter brockii (TBADH), having exceptionally high (75%) sequence identity, differ by 30 degrees in their melting temperatures. The crystal structures of CBADH and TBADH in their holo-enzyme form have been determined at a resolution of 2.05 and 2.5 A, respectively. Comparison of these two very similar structures (RMS difference in Calpha = 0.8 A) revealed several features that can account for the higher thermal stability of TBADH. These include additional ion pairs, "charged-neutral" hydrogen bonds, and prolines as well as improved stability of alpha-helices and tighter molecular packing. However, a deeper structural insight, based on the location of stabilizing elements, suggests that enhanced thermal stability of TBADH is due mainly to the strategic placement of structural determinants at positions that strengthen the interface between its subunits. This is also supported by mutational analysis of structural elements at critical locations. Thus, it is the reinforcement of the quaternary structure that is most likely to be a primary factor in preserving enzymatic activity of this oligomeric bacterial ADH at elevated temperatures.

Korkhin, Y.; Kalb (Gilboa), A. J.; Peretz, M.; Bogin, O.; Burstein, Y.; Frolow, F.



GA topology optimization using random keys for tree encoding of structures  

Microsoft Academic Search

Topology optimization consists in finding the spatial distribution of a given total volume of material for the resulting structure\\u000a to have some optimal property, for instance, maximization of structural stiffness or maximization of the fundamental eigenfrequency.\\u000a In this paper a Genetic Algorithm (GA) employing a representation method based on trees is developed to generate initial feasible\\u000a individuals that remain feasible

J. F. Aguilar Madeira; H. L. Pina; H. C. Rodrigues



Efficient synthesis of mibefradil analogues: an insight into in vitro stability.  


This article describes the synthesis and biological evaluation of a chemical library of mibefradil analogues to investigate the effect of structural modification on in vitro stability. The construction of the dihydrobenzopyran structure in mibefradil derivatives 2 was achieved through two efficient approaches based on a diastereoselective intermolecular Reformatsky reaction and an intramolecular carbonyl-ene cyclization. In particular, the second strategy through the intramolecular carbonyl-ene reaction led to the formation of a key intermediate 3 in a short and highly stereoselective way, which has allowed for practical and convenient preparation of analogues 2. Using this protocol, we could obtain 22 new mibefradil analogues 2, which were biologically tested for in vitro efficacies against T-type calcium channels and metabolic stabilities. Among the synthesized compounds, we found that analogue 2aa containing a dihydrobenzopyran ring and a secondary amine linker showed high % remaining activities of the tested CYP enzymes retaining the excellent T-type calcium channel blocking activity. These findings indicated that the structural modification of 1 was effective for improving in vitro stability, i.e., reducing CYP inhibition and metabolic degradation. PMID:24964394

Lee, Ji Eun; Kwon, Tae Hui; Gu, Su Jin; Lee, Duck-Hyung; Kim, B Moon; Lee, Jae Yeol; Lee, Jae Kyun; Seo, Seon Hee; Pae, Ae Nim; Keum, Gyochang; Cho, Yong Seo; Min, Sun-Joon



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

PubMed Central

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.

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.



Why do the heavy-atom analogues of acetylene E2H2 (E = Si-Pb) exhibit unusual structures?  


DFT calculations at BP86/QZ4P have been carried out for different structures of E(2)H(2) (E = C, Si, Ge, Sn, Pb) with the goal to explain the unusual equilibrium geometries of the heavier group 14 homologues where E = Si-Pb. The global energy minima of the latter molecules have a nonplanar doubly bridged structure A followed by the singly bridged planar form B, the vinylidene-type structure C, and the trans-bent isomer D1. The energetically high-lying trans-bent structure D2 possessing an electron sextet at E and the linear form HEEH, which are not minima on the PES, have also been studied. The unusual structures of E(2)H(2) (E = Si-Pb) are explained with the interactions between the EH moieties in the (X(2)Pi) electronic ground state which differ from C(2)H(2), which is bound through interactions between CH in the a(4)Sigma(-) excited state. Bonding between two (X(2)Pi) fragments of the heavier EH hydrides is favored over the bonding in the a(4)Sigma(-) excited state because the X(2)Pi --> a(4)Sigma(-) excitation energy of EH (E = Si-Pb) is significantly higher than for CH. The doubly bridged structure A of E(2)H(2) has three bonding orbital contributions: one sigma bond and two E-H donor-acceptor bonds. The singly bridged isomer B also has three bonding orbital contributions: one pi bond, one E-H donor-acceptor bond, and one lone-pair donor-acceptor bond. The trans-bent form D1 has one pi bond and two lone-pair donor-acceptor bonds, while D2 has only one sigma bond. The strength of the stabilizing orbital contributions has been estimated with an energy decomposition analysis, which also gives the bonding contributions of the quasi-classical electrostatic interactions. PMID:15853336

Lein, Matthias; Krapp, Andreas; Frenking, Gernot



Comparison of the structure of key variants of microcystin to vasopressin.  


Microcystins (MCs) are cyclic heptapeptide compounds [where X(2) (position 2) and Z(4) (position 4) are variable l-aminoacids] produced by cyanobacteria and responsible for severe liver damage in animals ingesting acute doses of the toxic compounds. Certain variants of microcystins are more toxic than others, the differences being commonly ascribed to the hydrophobic nature of the variant. Microcystin-LR (MCLR) [X = l-leucine (L); Z = l-arginine (R); R1 = R2 = CH(3)] is the most toxic of all the microcystins investigated to date. This study investigates the similarity of the structures of MCLR and selected MC variants to the liver specific hormone vasopressin. Structures were compiled in HyperChem(®) (professional version 5.1). Initial comparisons of the MCLR and vasopressin indicated comparable volumes, surface areas and masses. Further studies using RMS overlays show that the microcystin derivative MCLR(Dha(7)) is comparably similar to vasopressin in terms of tertiary structure. PMID:21783489

Gehringer, Michelle M; Milne, Pieter; Lucietto, Franco; Downing, Tim G



Chemical Synthesis, Crystal Structure and Enzymatic Evaluation of a Dinucleotide Spore Photoproduct Analogue Containing a Formacetal Linker  

PubMed Central

Spore photoproduct (SP) is the exclusive DNA photodamage product found in bacterial endospores. Its photoformation and repair by a metal-loenzyme spore photoproduct lyase (SPL) composes the unique SP biochemistry. Despite the fact that the SP was discovered almost 50 years ago, its crystal structure is still unknown and the lack of structural information greatly hinders the study of SP biochemistry. Employing a formacetal linker and organic synthesis, we successfully prepared a dinucleotide SP isostere 5R-CH2SP, which contains a neutral CH2 moiety between the two thymine residues instead of a phosphate. The neutral linker dramatically facilitates the crystallization process, allowing us to obtain the crystal structure for this intriguing thymine dimer half a century after its discovery. Further ROESY spectroscopic, DFT computational, and enzymatic studies of this 5R-CH2SP compound prove that it possesses similar properties with the 5R-SP species, suggesting that the revealed structure truly reflects that of SP generated in Nature.

Lin, Gengjie; Chen, Chun-Hsing; Pink, Maren; Pu, Jingzhi; Li, Lei



The crystal structures at 80 K and IR spectra of the complex of 4-methylpyridine with pentachlorophenol and its deuterated analogue  

NASA Astrophysics Data System (ADS)

The crystal structures of the complex of 4-methylpyridine with pentachlorophenol (MP?PCP) and its deuterated analogue (MP?PCP- d) were determined at 80 K by X-ray diffraction. The MP?PCP complex crystallizes in the space group P 1¯ with a = 7.267(7), b = 8.966(9), c = 13.110(14) Å, ? = 99.70(8), ? = 118.16(9), ? = 103.38(8)° and Z = 2 and the MP?PCP- d complex in the monoclinic Cc space group with a = 3.826(2), b = 27.54(2), c = 13.209(12) Å, ? = 101.38(9)° and Z = 4. The O…H…N bridge bond distance of 2.515(4) Å is significantly shorter than that determined at room temperature (2.552(4) Å) and the O?D…N bond length of 2.628(6) Å is only slightly shorter than at room temperature (2.638(3) Å). The temperature dependence of the IR spectra confirms the symmetrization of the OHN hydrogen bond.

Malarski, Z.; Majerz, I.; Lis, T.



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

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-?B 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.

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



Structure-activity studies in E. coli strains on ochratoxin A (OTA) and its analogues implicate a genotoxic free radical and a cytotoxic thiol derivative as reactive metabolites.  


Ochratoxin A (OTA), its major metabolite in rodents, ochratoxin alpha, and seven structurally related substances were assayed for SOS DNA repair inducing activity in Escherichia coli strain PQ37. At concentrations of 0.1-4 mM, OTA, chloroxine, 5-chloro-8-quinolinol, 4-chloro-meta-cresol and chloroxylenol induced SOS DNA repair in the absence of an exogenous metabolic activation system. Ochratoxin B, ochratoxin alpha, 5-chlorosalicylic acid and citrinin were inactive, but all except ochratoxin alpha were cytotoxic. Thus, the presence of chlorine at C-5 appears to be one determinant of genotoxicity in these substances. Amino oxyacetic acid, an inhibitor of the cysteine conjugate beta-lyase, decreased the cytotoxicity of OTA but did not alter its genotoxic activity, suggesting the formation of a cytotoxic thiol-containing derivative. The mechanisms by which OTA and some of its active analogues induce SOS DNA repair activity was further investigated in E. coli PQ37 and in three derived strains (PQ300, OG100 and OG400), containing deletions within the oxy R regulon. The response in strain PQ37 was measured in the absence and presence of Trolox C, a water-soluble form of vitamin E. Trolox C completely quenched the genotoxicity of OTA, and the effect was similar in the mutant and wild-type strains. These results implicate an OTA-derived free radical rather than reduced oxygen species as genotoxic intermediate(s) in bacteria. PMID:7513790

Malaveille, C; Brun, G; Bartsch, H



Thermodynamic functions and intra-particle mass transfer kinetics of structural analogues of a template on molecularly imprinted polymers in liquid chromatography.  


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. PMID:16298188

Kim, Hyunjung; Guiochon, Georges



Synthesis and structure-activity relationships of a new class of selective EP3 receptor agonist, 13,14-didehydro-16-phenoxy analogues of prostaglandin E1.  


A series of 13,14-didehydro-16-phenoxy analogues of prostaglandin E1 was synthesized and their agonistic activity on EP receptor subtypes was evaluated. 13,14-Didehydro-16-phenoxy-1-decarboxy analogues, 7e and 7f, display highly selective activity on the EP3 receptor subtype, thus, their utility as a selective anti-ulcer agent can be expected. PMID:10722158

Shimazaki, Y; Kameo, K; Tanami, T; Tanaka, H; Ono, N; Kiuchi, Y; Okamoto, S; Sato, F; Ichikawa, A



Mutation of a conserved residue enhances the sensitivity of analogue-sensitised kinases to generate a novel approach to the study of mitosis in fission yeast.  


The chemical genetic strategy in which mutational enlargement of the ATP-binding site sensitises of a protein kinase to bulky ATP analogues has proved to be an elegant tool for the generation of conditional analogue-sensitive kinase alleles in a variety of model organisms. Here, we describe a novel substitution mutation in the kinase domain that can enhance the sensitivity of analogue-sensitive kinases. Substitution of a methionine residue to phenylalanine in the +2 position after HRDLKxxN motif of the subdomain VIb within the kinase domain markedly increased the sensitivities of the analogue-sensitive kinases to ATP analogues in three out of five S. pombe kinases (i.e. Plo1, Orb5 and Wee1) that harbor this conserved methionine residue. Kinome alignment established that a methionine residue is found at this site in 5-9% of kinases in key model organisms, suggesting that a broader application of this structural modification may enhance ATP analogue sensitivity of analogue-sensitive kinases in future studies. We also show that the enhanced sensitivity of the wee1.as8 allele in a cdc25.22 background can be exploited to generate highly synchronised mitotic and S phase progression at 36°C. Proof-of-principle experiments show how this novel synchronisation technique will prove of great use in the interrogation of the mitotic or S-phase functions through temperature sensitivity mutation of molecules of interest in fission yeast. PMID:23986474

Tay, Ye-Dee; Patel, Avinash; Kaemena, Daniel F; Hagan, Iain M



Deciphering key features in protein structures with the new ENDscript server.  


ENDscript 2 is a friendly Web server for extracting and rendering a comprehensive analysis of primary to quaternary protein structure information in an automated way. This major upgrade has been fully re-engineered to enhance speed, accuracy and usability with interactive 3D visualization. It takes advantage of the new version 3 of ESPript, our well-known sequence alignment renderer, improved to handle a large number of data with reduced computation time. From a single PDB entry or file, ENDscript produces high quality figures displaying multiple sequence alignment of proteins homologous to the query, colored according to residue conservation. Furthermore, the experimental secondary structure elements and a detailed set of relevant biophysical and structural data are depicted. All this information and more are now mapped on interactive 3D PyMOL representations. Thanks to its adaptive and rigorous algorithm, beginner to expert users can modify settings to fine-tune ENDscript to their needs. ENDscript has also been upgraded as an open platform for the visualization of multiple biochemical and structural data coming from external biotool Web servers, with both 2D and 3D representations. ENDscript 2 and ESPript 3 are freely available at and, respectively. PMID:24753421

Robert, Xavier; Gouet, Patrice



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

ERIC Educational Resources Information Center

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…

Hosford, Helga


Functionalization of the A ring of pyridoacridine as a route toward greater structural diversity. Synthesis of an octacyclic analogue of eilatin  

Microsoft Academic Search

In an effort to increase the structural diversity of pyrido[4,3,2-kl]acridines, compounds containing amino substituents on the A ring were synthesized. The key-reactions involve regioselective electrophilic aromatic substitutions. The methodology was applied to the synthesis of the extended angular octacycle 8, which conjugates the physicochemical and spectroscopic properties of the pyridoacridine skeleton with the ability of [1,10]phenanthroline ring for metal complexation.

Laurent Bouffier; Rodica Dinica; Julien Debray; Pascal Dumy; Martine Demeunynck



Smad3 deficiency alters key structural elements of the extracellular matrix and mechanotransduction of wound closure  

PubMed Central

The loss of TGF? or its downstream mediator, Smad3, key players in tissue repair, accelerates closure of incisional wounds in mice. In contrast, we now report that excisional ear wounds in mice lacking Smad3 enlarge compared with wild-type controls resulting from changes in extracellular matrix molecules, which alter the mechanotransduction properties of these wounds. Specifically, levels of elastin and glycosoaminoglycans are increased, collagen fibers are more compactly organized, and matrix modulators like integrins, TGF?1, and matrix metalloproteinases (MMPs) are altered both basally and after wounding in Smad3 knockout mice. Mechanical testing of dorsal skin correlates these changes in matrix composition with functional parameters, specifically an increased elastic modulus, suggesting an imbalance of tissue forces. We propose that the altered mechanical elastic properties translate into a persistent retractile force that is opposed by decreased wound contractile forces contributing to the enlarging ear wound in Smad3 knockout mice. These studies highlight a previously undescribed role for Smad3 in the mechanotransduction of matrix unsupported ear wound closure.

Arany, Praveen R.; Flanders, Kathleen C.; Kobayashi, Tetsu; Kuo, Catherine K.; Stuelten, Christina; Desai, Kartiki V.; Tuan, Rocky; Rennard, Stephen I.; Roberts, Anita B.



The HOBYS Key Program: When Herschel links high-mass star formation to cloud structure  

NASA Astrophysics Data System (ADS)

With its unprecedented spatial resolution and high sensitivity in the far-infrared to submillimetre regime, {Herschel} is revolutionizing our understanding of star formation. The HOBYS key program is an {Herschel} mapping survey dedicated to the formation of OB-type stars (Motte, Zavagno, Bontemps et al. 2010; see {}. HOBYS aims at 1) discovering and characterizing the progenitors of high-mass stars, 2) making the link between the latters and their filamentary background, and 3) assessing the importance of triggering. Among the HOBYS highlights is the discovery of ``mini-starburst ridges" defined as high-density dominating filaments supersonically contracting and efficiently forming clusters of high-mass stars. Their existence is predicted by dynamical models of cloud formation such as converging flows and is favoring a (high-mass) star formation scenario involving gas flows and global infall. The present star formation rate measured within these ridges is high enough for these 1-10 pc^2 regions to be considered as miniature and instantaneous models of extragalactic starbursts.

Motte, F.; Bontemps, S.; Hennemann, M.; Nguyen Luong, Q.; Schneider, N.; Didelon, P.; Zavagno, A.



Molecular structure of the nucleoside analogue inosine using DFT methods: Conformational analysis, crystal simulations and possible behaviour  

NASA Astrophysics Data System (ADS)

Five tautomers of the nucleoside inosine were determined and optimized at the MP2 and B3LYP levels of theory. Several correlations were identified. A comprehensive conformational analysis was carried out on the most stable tautomer N1, and the whole conformational parameters (?, ?, ?, ?, ?, ?', P, ?max) were studied as well as the NBO Natural atomic charges. The calculations were carried out with full relaxation of all geometrical parameters. The search located at least 69 stable structures, 3 of which are within a 1 kcal/mol electronic energy range of the global minimum, and 4 conformers are within a 1 kcal/mol Gibbs energy range. A lower reactivity in inosine than in the natural nucleoside guanosine appears in the N1 and N3 nitrogen atoms. The solid state was simulated through a pentamer form and the structural parameters were compared with the X-ray crystal data available. Several general conclusions were emphasized.

Alvarez-Ros, M. C.; Alcolea Palafox, M.



Structural Insights into Maize Viviparous14, a Key Enzyme in the Biosynthesis of the Phytohormone Abscisic Acid W  

SciTech Connect

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.

Messing, S.; Gabelli, S; Echeverria, I; Vogel, J; Guan, J; Tan, B; Klee, H; McCarty, D; Amzela, M



The Structural Requirements of Histone Deacetylase Inhibitors: Suberoylanilide Hydroxamic Acid Analogues Modified at the C3 Position Display Isoform Selectivity  

PubMed Central

The FDA-approved drug suberoylanilide hydroxamic acid (SAHA, Vorinostat) was modified to improve its selectivity for a single histone deaetylase (HDAC) isoform. We show that attaching an ethyl group at the C3 position transforms SAHA from non-selective to an HDAC6-selective inhibitor. Theses results indicate that small structural changes in SAHA can significantly influence selectivity, which will lead future anti-cancer design efforts targeting HDAC proteins.

Choi, Sun Ea; Weerasinghe, Sujith V. W.; Pflum, Mary Kay H.



Prognostic factors in prostate cancer. Key elements in structured histopathology reporting of radical prostatectomy specimens.  


Prostate cancer is the most common visceral cancer and the second most common cause of cancer death in males. The number of radical prostatectomies performed each year is increasing and accurate data from the histopathological examination of these specimens aid clinicians in stratifying patients for surveillance and adjuvant therapies. This review focuses on the histopathological prognostic factors which should be routinely recorded in pathology reports and complements the Royal College of Pathologists of Australasia Structured Reporting Protocol for Prostate Cancer (Radical Prostatectomy). Such structured pathology reports have been shown to significantly enhance the completeness and quality of data provided to clinicians. The review also discusses the International Society for Urological Pathology Consensus Conference recommendations which were published recently. PMID:21716159

Kench, James G; Clouston, David R; Delprado, Warick; Eade, Thomas; Ellis, David; Horvath, Lisa G; Samaratunga, Hemamali; Stahl, Jurgen; Stapleton, Alan M F; Egevad, Lars; Srigley, John R; Delahunt, Brett



Crystal structure of LeuA from Mycobacterium tuberculosis, a key enzyme in leucine biosynthesis  

PubMed Central

The leucine biosynthetic pathway is essential for the growth of Mycobacterium tuberculosis and is a potential target for the design of new anti-tuberculosis drugs. The crystal structure of ?-isopropylmalate synthase, which catalyzes the first committed step in this pathway, has been determined by multiwavelength anomalous dispersion methods and refined at 2.0-Å resolution in complex with its substrate ?-ketoisovalerate. The structure reveals a tightly associated, domain-swapped dimer in which each monomer comprises an (?/?)8 TIM barrel catalytic domain, a helical linker domain, and a regulatory domain of novel fold. Mutational and crystallographic data indicate the latter as the site for leucine feedback inhibition of activity. Domain swapping enables the linker domain of one monomer to sit over the catalytic domain of the other, inserting residues into the active site that may be important in catalysis. The ?-ketoisovalerate substrate binds to an active site zinc ion, adjacent to a cavity that can accommodate acetyl-CoA. Sequence and structural similarities point to a catalytic mechanism similar to that of malate synthase and an evolutionary relationship with an aldolase that catalyzes the reverse reaction on a similar substrate.

Koon, Nayden; Squire, Christopher J.; Baker, Edward N.



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

NASA Astrophysics Data System (ADS)

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.

François, Thomas; Burov, Evgueni



The current structure of key actors involved in research on land and soil degradation  

NASA Astrophysics Data System (ADS)

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.

Escadafal, Richard; Barbero, Celia; Exbrayat, Williams; Marques, Maria Jose; Ruiz, Manuel; El Haddadi, Anass; Akhtar-Schuster, Mariam



Fluoroartemisinin: trifluoromethyl analogues of artemether and artesunate.  


The synthesis of a series of C-10 trifluoromethyl ethers of artemisinin has been achieved from key bromide 8, itself carried out in two steps from artemisinin. The substitution of 8 with methanol, ethanol, or succinic acid allowed the access of C-10 CF(3) analogues of beta-artemether, beta-arteether, or artesunate, respectively, in good yields (up to 89%). The presence of the CF(3) group at C-10 of artemisinin clearly increased the chemical stability under simulated stomach acid conditions. For example, the CF(3) analogue of arteether was found to be around 45 times more stable than arteether itself. The influence of the CF(3) moiety on biological activity was also highlighted. CF(3) analogues of artemether and arteether exhibited a high in vivo antimalarial activity on mice infected with Plasmodium berghei NK173, with a complete clearance of the parasitemia during the entire observation period (25 days). PMID:15115411

Magueur, Guillaume; Crousse, Benoit; Charneau, Sébastien; Grellier, Philippe; Bégué, Jean-Pierre; Bonnet-Delpon, Danièle



Analogues of FAUC 73 revealing new insights into the structural requirements of nonaromatic dopamine D3 receptor agonists.  


Employing the nonaromatic D3 agonist FAUC 73 as a lead compound, the dopaminergic enynes 1a,b and the diene 2 (FAUC 206) were synthesized via palladium-catalyzed cross-coupling. FAUC 206 showed remarkable D3 affinity and enhanced selectivity over D4 when compared to the lead compound. To learn more about the bioactive structure of the diene moiety, computational studies including DFT-based conformational analysis and calculations of the magnetic shielding properties were performed. The electrostatic properties of the pharmacophoric pi-systems were visualized by diagnostic MEP maps. PMID:14697776

Lenz, Carola; Boeckler, Frank; Hübner, Harald; Gmeiner, Peter



Tautomerism of the natural thymidine nucleoside and the antiviral analogue D4T. Structure and influence of an aqueous environment using MP2 and DFT methods.  


A comparative theoretical conformational analysis of the tautomerism of the four most stable conformers of the antiviral analogue D4T (stavudine) and natural thymidine (Thy) nucleosides was carried out, by using the B3LYP and MP2 quantum chemical methods. The calculated structure data and energy values of the tautomers were compared with the T1 keto form and with the results determined for the thymine molecule. For each conformer, only two stable enol forms, T3 and T5, were obtained when considering different positions of hydrogen around the base. Tautomer T3 always appears more stable than T5, and more stable in the natural nucleoside Thy than in thymine or in D4T.The effect of water on the tautomers was estimated by using an explicit number of up to five water molecules to surround the nucleoside, and also by Tomasi's polarized continuum model (PCM). A total of about 200 clusters were optimised and the geometrical parameters and energies discussed. The water net differs in the three tautomers of D4T and Thy. Depending on the nature of the tautomers, cyclic, distributed water molecules, or clustered structures are formed. The deformation and interaction counterpoise (CP)-corrected energies between the nucleoside and water molecules were determined. The relative stabilities of all tautomers were established. The microhydrated environment stabilizes remarkably the enol forms more than the canonical keto one, although this one continues being the most stable. The changes in the intramolecular H-bondings and in the total atomic charges were discussed. Intramolecular H-bonds being stronger in D4T than in Thy could indicate a higher molecular flexibility for Thy. PMID:20066373

Alcolea Palafox, M; Iza, N



Crystal structure of Bifidobacterium Longum phosphoketolase; key enzyme for glucose metabolism in Bifidobacterium.  


The crystal structure of Bifidobacterium longum phosphoketolase, a thiamine diphosphate (TPP) dependent enzyme, has been determined at 2.2A resolution. The enzyme is a dimer with the active sites located at the interface between the two identical subunits with molecular mass of 92.5 kDa. The bound TPP is almost completely shielded from solvent except for the catalytically important C2-carbon of the thiazolium ring, which can be accessed by a substrate sugar through a narrow funnel-shaped channel. In silico docking studies of B. longum phosphoketolase with its substrate enable us to propose a model for substrate binding. PMID:20674574

Takahashi, Kazutoshi; Tagami, Uno; Shimba, Nobuhisa; Kashiwagi, Tatsuki; Ishikawa, Kohki; Suzuki, Ei-ichiro



Isolation, gene expression and solution structure of a novel moricin analogue, antibacterial peptide from a lepidopteran insect, Spodoptera litura.  


An antibacterial peptide was isolated from a lepidopteran insect, Spodoptera litura. The molecular mass of this peptide was determined to be 4489.55 by matrix assisted laser desorption/ionization-time of flight mass (MALDI-TOF MS) spectrometry. The peptide consists of 42 amino acids and the sequence has 69-98% identity to those of moricin-related peptides, antibacterial peptides from lepidopetran insects. Thus, the peptide was designated S. litura (Sl) moricin. Sl moricin showed a broad antibacterial spectrum against Gram-positive and negative bacteria. Sl moricin gene was inducible by bacterial injection and expressed tissue-specifically in the fat body and hemocytes. Furthermore, the solution structure of Sl moricin was determined by two-dimensional (2D) 1H-nuclear magnetic resonance (NMR) spectroscopy and hybrid distance geometry-simulated annealing calculation. The tertiary structure revealed a long alpha-helix containing eight turns along nearly the full length of the peptide like that of moricin, confirming that Sl moricin is a new moricin-like antibacterial peptide. These results suggest that moricin is present not only in B. mori but also in other lepidopteran insects forming a gene family. PMID:16115804

Oizumi, Yuki; Hemmi, Hikaru; Minami, Masayoshi; Asaoka, Ai; Yamakawa, Minoru



New bitter-masking compounds: hydroxylated benzoic acid amides of aromatic amines as structural analogues of homoeriodictyol.  


Starting from the known bitter-masking flavanones eriodictyol and homoeriodictyol from herba santa some structurally related hydroxybenzoic acid amides of benzylamines were synthesized and evaluated as masking agents toward bitterness of caffeine by sensory methods. The closest structural relatives of homoeriodictyol, the hydroxybenzoic acid vanillylamides 5-9, were the most active and were able to reduce the bitterness of a 500 mg L(-1) caffeine solution by about 30% at a concentration of 100 mg L(-1). 2,4-Dihydroxybenzoic acid vanillylamide 7 showed a clear dose-dependent activity as inhibitor of the bitter taste of caffein between 5 and 500 mg L(-1). Additionally, it was possible to reduce the bitterness of quinine and salicine but not of the bitter peptide N-l-leucyl-l-tryptophan. Combinations of homoeriodictyol and amide 7 showed no synergistic or antagonistic changes in activity. The results for model compound 7 suggested that the hitherto unknown masking mechanism is probably the same for flavanones and the new amides. In the future, the new amides may be alternatives for the expensive flavanones to create flavor solutions to mask bitterness of pharmaceuticals or foodstuffs. PMID:17061836

Ley, Jakob P; Blings, Maria; Paetz, Susanne; Krammer, Gerhard E; Bertram, Heinz-Jürgen



Conserving energy with sulfate around 100 °C--structure and mechanism of key metal enzymes in hyperthermophilic Archaeoglobus fulgidus.  


Sulfate-reducing bacteria and archaea are important players in the biogeochemical sulfur cycle. ATP sulfurylase, adenosine 5'-phosphosulfate reductase and dissimilatory sulfite reductase are the key enzymes in the energy conserving process of SO4(2-) ? H2S reduction. This review summarizes recent advances in our understanding of the activation of sulfate to adenosine 5'-phosphosulfate, the following reductive cleavage to SO3(2-) and AMP, and the final six-electron reduction of SO3(2-) to H2S in the hyperthermophilic archaeon Archaeoglobus fulgidus. Structure based mechanisms will be discussed for these three enzymes which host unique metal centers at their catalytic sites. PMID:23324858

Parey, Kristian; Fritz, Günter; Ermler, Ulrich; Kroneck, Peter M H



Key Performance Outcomes of Patient Safety Curricula: Root Cause Analysis, Failure Mode and Effects Analysis, and Structured Communications Skills  

PubMed Central

As colleges and schools of pharmacy develop core courses related to patient safety, course-level outcomes will need to include both knowledge and performance measures. Three key performance outcomes for patient safety coursework, measured at the course level, are the ability to perform root cause analyses and healthcare failure mode effects analyses, and the ability to generate effective safety communications using structured formats such as the Situation-Background-Assessment-Recommendation (SBAR) situational briefing model. Each of these skills is widely used in patient safety work and competence in their use is essential for a pharmacist's ability to contribute as a member of a patient safety team.



Status and key issues of reduced activation ferritic/martensitic steels as the structural material for a DEMO blanket  

SciTech Connect

The status and key issues of reduced activation ferritic/martensitic (RAFM) steels R&D are reviewed as the primary candidate structural material for fusion energy demonstration reactor blankets. This includes manufacturing technology, the as-fabricated and irradiates material database and joining technologies. The review indicated that the manufacturing technology, joining technology and database accumulation including irradiation data are ready for initial design activity, and also identifies various issues that remain to be solved for engineering design activity and qualification of the material for international fusion material irradiation facility (IFMIF) irradiation experiments that will validate the data base.

Tanigawa, Hiroyasu [ORNL; Stoller, Roger E [ORNL; Sokolov, Mikhail A [ORNL; Odette, G.R. [University of California, Santa Barbara; Jitsukawa, Shiro [Japan Atomic Energy Agency (JAEA); Shiba, K. [Japan Atomic Energy Agency (JAEA); Kurtz, Richard [Pacific Northwest National Laboratory (PNNL); Moeslang, A. [Forschungszentrum Karlsruhe, Karlsruhe, Germany; Lindau, R. [Forschungszentrum Karlsruhe, Karlsruhe, Germany



Hantavirus gn and gc envelope glycoproteins: key structural units for virus cell entry and virus assembly.  


In recent years, ultrastructural studies of viral surface spikes from three different genera within the Bunyaviridae family have revealed a remarkable diversity in their spike organization. Despite this structural heterogeneity, in every case the spikes seem to be composed of heterodimers formed by Gn and Gc envelope glycoproteins. In this review, current knowledge of the Gn and Gc structures and their functions in virus cell entry and exit is summarized. During virus cell entry, the role of Gn and Gc in receptor binding has not yet been determined. Nevertheless, biochemical studies suggest that the subsequent virus-membrane fusion activity is accomplished by Gc. Further, a class II fusion protein conformation has been predicted for Gc of hantaviruses, and novel crystallographic data confirmed such a fold for the Rift Valley fever virus (RVFV) Gc protein. During virus cell exit, the assembly of different viral components seems to be established by interaction of Gn and Gc cytoplasmic tails (CT) with internal viral ribonucleocapsids. Moreover, recent findings show that hantavirus glycoproteins accomplish important roles during virus budding since they self-assemble into virus-like particles. Collectively, these novel insights provide essential information for gaining a more detailed understanding of Gn and Gc functions in the early and late steps of the hantavirus infection cycle. PMID:24755564

Cifuentes-Muñoz, Nicolás; Salazar-Quiroz, Natalia; Tischler, Nicole D



Hantavirus Gn and Gc Envelope Glycoproteins: Key Structural Units for Virus Cell Entry and Virus Assembly  

PubMed Central

In recent years, ultrastructural studies of viral surface spikes from three different genera within the Bunyaviridae family have revealed a remarkable diversity in their spike organization. Despite this structural heterogeneity, in every case the spikes seem to be composed of heterodimers formed by Gn and Gc envelope glycoproteins. In this review, current knowledge of the Gn and Gc structures and their functions in virus cell entry and exit is summarized. During virus cell entry, the role of Gn and Gc in receptor binding has not yet been determined. Nevertheless, biochemical studies suggest that the subsequent virus-membrane fusion activity is accomplished by Gc. Further, a class II fusion protein conformation has been predicted for Gc of hantaviruses, and novel crystallographic data confirmed such a fold for the Rift Valley fever virus (RVFV) Gc protein. During virus cell exit, the assembly of different viral components seems to be established by interaction of Gn and Gc cytoplasmic tails (CT) with internal viral ribonucleocapsids. Moreover, recent findings show that hantavirus glycoproteins accomplish important roles during virus budding since they self-assemble into virus-like particles. Collectively, these novel insights provide essential information for gaining a more detailed understanding of Gn and Gc functions in the early and late steps of the hantavirus infection cycle.

Cifuentes-Munoz, Nicolas; Salazar-Quiroz, Natalia; Tischler, Nicole D.



Structural insights into key sites of vulnerability on HIV-1 Env and Influenza HA  

PubMed Central

Summary 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.

Julien, Jean-Philippe; Lee, Peter S.; Wilson, Ian A.



John T. Edsall: his key role in the determination of the structure of proteins.  


A letter, written in 1947 by John Edsall, outlined a declared intent to set up an X-ray crystallographic laboratory devoted to the study of crystalline heavy atom derivatives of proteins in an attempt to learn more about their structure. The fundamental idea, to the recipient (B.W.L.) totally new, revolutionary, and wholly contrary to all learned certainties, led to a correspondence, presented here in excerpt. Detailed plans were made for the laboratory to be built in the Department of Physical Chemistry at the Harvard Medical School. The proteins to be studied were reviewed and debated. The work of the laboratory is briefly described. Lack of success, the fatal consequence of a then unknown feature of the protein first chosen for study, is now only recently understood. The history of the Edsall idea and initiative is explored, from its beginnings to its acceptance and exploitation. John Edsall is here recognized as prime proponent and developer of the fundamental idea behind the most powerful and, for more than three decades, the only successful approach to the determination of protein structure. PMID:12646349

Low, Barbara W



[Dielectric analysis of the rat thyroid gland by modeling the follicle as a key structure].  


To correlate the dielectric behavior of the thyroid gland with its follicle structure, I examined the admittance properties of isolated rat thyroid hemilobes over the frequency range from 100 Hz up to 500 MHz. Rats were divided into three groups: control, thyroxine (T4) administered, and goitrogen (propylthiouracil, PTU) administered. In control glands, observed dielectric dispersions with a permittivity increment (delta epsilon) of 60,000 were of the beta-type having two separate characteristic frequencies (fc1 and fc2) around 12 kHz and 3 MHz. In T4- or PTU-treated thyroid, both delta epsilon and fc1 departed from those of control, resulting in the following sequences: For delta epsilon, T4 < control < PTU, and for fc1, PTU < control < T4. These contrasting results were then correlated with morphological features involved. Histomorphometry revealed apparent differences in follicular size distribution between the three groups of tissue. Based on a model analysis using curve fitting technique, I estimated the electrical conductivity of colloid to be about 2 mS/cm, a value 6-fold smaller than that of blood plasma. Another conclusion worthy of note is that the gross dielectric behavior of the thyroid gland can be interpreted only by taking the follicular structure into account. PMID:1494109

Kozakura, K



X-ray absorption fine-structure spectroscopy studies of Fe sites in natural human neuromelanin and synthetic analogues.  

PubMed Central

X-ray absorption fine-structure spectroscopy is used to study the local environment of the iron site in natural (human) neuromelanin extracted from substantia nigra tissue and in various synthetic neuromelanins. All the materials show Fe centered in a nearest neighbor sixfold (distorted) oxygen octahedron; the Fe-O distances, while slightly different in the natural and synthetic neuromelanin, are both approximately 2.0 A. Appreciable differences arise, however, in the second (and higher) coordination shells. In this case the synthetic melanin has the four planar oxygens bound to carbon rings with Fe-C distances of approximately 2.82 and 4.13 A; the human sample does not show the 2.82 A link but instead indicates a double shell at approximately 3.45 and 3.78 A.

Kropf, A J; Bunker, B A; Eisner, M; Moss, S C; Zecca, L; Stroppolo, A; Crippa, P R



Interpretation of Cometary Dust Size, Structure and Composition From Imagery and Analysis of Stardust Foil Craters and Their Laboratory Analogues.  

NASA Astrophysics Data System (ADS)

Passage of the Stardust spacecraft through the coma of comet Wild 2 in 2004 resulted in capture of numerous particles in the low density silica aerogel collection medium, and many impacts onto exposed aluminum foil strips. The abundant craters on the aluminum Al1100 can be interpreted in terms of impacting particle size, density and mass, with some information concerning particle shape, internal structure and chemical composition. The tightly constrained impact velocity (6.1 km s-1 and trajectory (perpendicular to the collection surface) for dust impinging on Stardust provide conditions that can be duplicated in impact simulations by light gas guns using flight-spare aerogel and foil as targets. We can have much greater confidence in the direct comparison of the experiments with Stardust's impact features than is possible for craters formed by hypervelocity impact in low Earth orbit, where individual particle velocities and trajectories are unknown but certainly vary widely, and include much higher speeds. For Stardust foils, we have performed an extensive suite of calibration experiments to determine the crater top-lip diameter dependence on impacting particle dimensions, the role of particle density in creation of recognizable crater shapes, and the modification of particle composition during the impact process for a wide range of minerals that might be found in cometary dust. During the preliminary evaluation phase of Stardust we have used scanning electron microscopy on the aluminum foils to measure the diameters of large numbers of craters for particle size determination, have created three dimensional digital models of crater shapes and depth profiles for density estimation, and have acquired dozens of energy dispersive X-ray maps of crater impact residues, and thousands of analytical spectra to infer particle composition and, in some cases, mineralogy. In this paper we will reveal results for a suite of Stardust craters spanning a size range from sub-micron to sub-millimeter, and will discuss their implications for understanding the size, structure, and composition of Wild 2 dust.

Kearsley, A.; Burchell, M.; Graham, G.; Wozniakiewicz, P.; Bridges, J.; Borg, J.; Horz, F.



Regioselective Domino Metathesis of Unsymmetrical 7-Oxanorbornenes with Electron-Rich Vinyl Acetate toward Biologically Active Glutamate Analogues  

PubMed Central

In this article a regioselective domino metathesis reaction of unsymmetrical 7-oxanorbornenes, readily available by a tandem Ugi/Diels–Alder reaction as a key step, promoted by the Hoveyda–Grubbs second-generation catalyst in the presence of electron-rich vinyl acetate as a cross metathesis (CM) substrate is reported. The mechanism for the unusually high regioselectivity observed in the CM reaction was investigated, and a reaction course where a Fischer-type carbene [“Ru”= CH(OAc)] generates a steric interaction is proposed. The metathesis products were further converted to four artificial glutamate analogues whose structures were inspired by naturally derived excitatory glutamate analogues, dysiherbaine and neodysiherbaine. Interestingly, one of the synthetic analogues (28a) induced a cataleptic state in mice. Further electrophysiological studies suggest that 28a might inhibit excitatory synaptic transmission by a yet unknown indirect pathway.

Oikawa, Masato; Ikoma, Minoru; Sasaki, Makoto; Gill, Martin B.; Swanson, Geoffrey T.; Shimamoto, Keiko; Sakai, Ryuichi



Study of Kaempferol Glycoside as an Insulin Mimic Reveals Glycon To Be the Key Active Structure  

PubMed Central

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.



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

PubMed Central

Moenomycin A (MmA) belongs to a family of natural products that inhibit peptidoglycan biosynthesis by binding to the peptidoglycan glycosyltransferases (PGTs), 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 analogs designed to probe the importance of the phosphoglycerate. These analogs 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 analogs based on moenomycin scaffolds.

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



Key structural features of ligands for activation of human pregnane X receptor.  


The ligand-binding domain of human pregnane X receptor (hPXR) is highly hydrophobic and flexible, allowing promiscuity in accepting structurally diverse ligands. However, little information is available regarding the critical substituents of compounds involved in the activation of hPXR. The aim of this study was to determine the structure-activity relationships for hPXR-mediated transactivation by barbiturates, hydantoins, and macrolide antibiotics. Most of the barbiturates studied (mephobarbital, pentobarbital, phenobarbital, etc.) activated hPXR. However, barbital, which has a low hydrophobic moiety at the 5-position, and primidone, which has no carbonyl moiety at the 2-position, did not activate hPXR. Therefore, a hydrophobic moiety at the 5-position and a hydrogen-bond acceptor being sufficiently separated from the phenyl-ring are responsible for activation of hPXR by barbiturates. In the case of hydantoins, only mephenytoin and ethotoin, which have an alkylchain at the R1-position, strongly activated hPXR at 300 microM. Phenytoin and 5-(4-methylphenyl)-5-phenylhydantoin, which contain a phenyl or methylphenyl group at both R2- and R3-positions, also activated hPXR, whereas 5-(4-hydroxyphenyl)-5-phenylhydantoin did not activate the receptor. These results suggest that the presence of an alkyl-chain at the R1-position and the presence of bulky and hydrophobic moieties at both R2- and R3-positions are important factors for activation of hPXR by hydantoins. In the case of macrolide antibiotics, troleandomycin, but not oleandomycin, showed significant activation of hPXR. Therefore, triacetate esterification of oleandomycin might increase the hydrophobicity and enhance the activation of hPXR. These findings suggest that hydrophobicity of the ligand and adequate distance between the hydrogen-bond acceptor and the hydrophobic group are important for hPXR activation. PMID:15039302

Kobayashi, Kaoru; Yamagami, Saeko; Higuchi, Tomoaki; Hosokawa, Masakiyo; Chiba, Kan



Structural and functional conservation of key domains in InsP[subscript 3] and ryanodine receptors  

SciTech Connect

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.

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. (UCD); (Toronto); (Cambridge)



Thermophysical Fluid Dynamics: the Key to the Structures of Fluid Objects  

NASA Astrophysics Data System (ADS)

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.

Houben, H.



Structural determination of a key exopolysaccharide in mixed culture aerobic sludge granules using NMR spectroscopy.  


Nuclear magnetic resonance (NMR) techniques were used to elucidate the structure of an exopolysaccharide material previously revealed to be important in formation of aerobic granules. The 1D NMR spectral data acquired showed that this gel-forming polysaccharide was a major component of granular EPS, while 1D and 2D NMR spectra showed it consisted of eight sugar residues. These were assigned as ?-galactose, ?-rhamnose, 2-acetoamido-2-deoxy-?-galactopyranuronic acid, ?-mannose, ?-galactose, ?-glucuronate, ?-glucosamine, and N-acetyl ?-galactosamine. With the exception of 2-acetoamido-2-deoxy-?-galactopyranuronic acid, a highly unusual sugar, their presence was confirmed with high-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD). Carbon and proton shifts were assigned for each sugar. Heteronuclear multiple bond correlation (HMBC) and nuclear Overhauser enhancement spectroscopy (NOESY) were used to identify linkage sites between individual sugar residues. This gel-forming exopolysaccharide appeared to be a highly complex single heteropolysaccharide with a repeat sequence of ?-galactose, ?-mannose, ?-glucosamine, N-acetyl-?-galactosamine, and 2-acetoamido-2-deoxy-?-galactopyranuronic acid. It has a disaccharide branch of ?-galactose and ?-glucuronic acid attached to 2-acetoamido-2-deoxy-?-galactopyranuronic acid and an ?-rhamnose branch attached to ?-galactose. PMID:21033741

Seviour, Thomas; Lambert, Lynette K; Pijuan, Maite; Yuan, Zhiguo



Block of voltage-operated sodium channels by 2,6-dimethylphenol, a structural analogue of lidocaine's aromatic tail  

PubMed Central

The structural features that determine the state-dependent interaction of local anaesthetics with voltage-operated sodium channels are still a matter of debate. We have studied the blockade of sodium channels by 2,6-dimethylphenol, a phenol derivative which resembles the aromatic tail of lidocaine, etidocaine, and bupivacaine. The effects of 2,6-dimethylphenol were studied on heterologously (HEK 293) expressed rat neuronal (rat brain IIA) and human skeletal muscle (hSkM1) sodium channels using whole-cell voltage-clamp experiments. 2,6-Dimethylphenol was effective in blocking whole-cell sodium inward currents. Its potency was comparable to the potency of lidocaine previously obtained with similar protocols by others. The IC50 at ?70 mV holding potential was 150 and 187 ?M for the skeletal muscle and the neuronal isoform, respectively. In both isoforms, the blocking potency increased with the fraction of inactivated channels at depolarized holding potentials. However, the block achieved at ?70 mV with respect to ?150 mV holding potential was significantly higher only in the skeletal muscle isoform. The estimated dissociation constant Kd from the inactivated state was 25 ?M and 28 ?M in the skeletal muscle and the neuronal isoform, respectively. The kinetics of drug equilibration between resting and inactivated channel states were about 10 fold faster compared with lidocaine. Our results show that the blockade induced by 2,6-dimethylphenol retains voltage-dependency, a typical feature of lidocaine-like local anaesthetics. This is consistent with the hypothesis that the ‘aromatic tail' determines the state-dependent interaction of local anaesthetics with the sodium channel.

Haeseler, Gertrud; Bufler, Johannes; Merken, Sarah; Dengler, Reinhard; Aronson, Jeffrey; Leuwer, Martin



Synthesis and SAR studies of 3-phenoxypropyl piperidine analogues as ORL1 (NOP) receptor agonists.  


A series of 3-phenoxypropyl piperidine analogues have been discovered as novel ORL1 receptor agonists. Structure-activity relationships have been explored around the 3-phenoxypropyl region with several potent and selective analogues identified. PMID:15664818

Palin, Ronald; Barn, David R; Clark, John K; Cottney, Jean E; Cowley, Phillip M; Crockatt, Marc; Evans, Louise; Feilden, Helen; Goodwin, Richard R; Griekspoor, Frank; Grove, Simon J A; Houghton, Andrea K; Jones, Philip S; Morphy, Richard J; Smith, Alasdair R C; Sundaram, Hardy; Vrolijk, David; Weston, Mark A; Wishart, Grant; Wren, Paul



Partition coefficients and capacity factors of some nucleoside analogues.  


The AIDS epidemic has brought into focus the development of antiviral agents, of which nucleoside analogues are an important class. The single most important physico-chemical property of a chemotherapeutic agent is its hydrophobicity. This paper reports the hydrophobicity, determined as log partition coefficient (P) by the shake-flask method, of 25 nucleoside analogues. The capacity factors (k') of these analogues were also obtained by reversed-phase liquid chromatography. There is a very strong linear correlation between the log P and the log k' values of all the nucleoside analogues, indicating that hydrophobicity of nucleosides can be determined by liquid chromatography. Examination of the P data indicates that an empirical mathematical relationship exists between the partition coefficient value and the molecular structure of the nucleoside analogues. A table of constants and an equation is proposed to estimate the P of nucleoside analogues. PMID:2376602

Cheung, A P; Kenney, D



Key Role of Hybridization between Actinide 5f and Oxygen 2p Orbitals for Electronic Structure of Actinide Dioxides  

NASA Astrophysics Data System (ADS)

In order to promote our understanding on electronic structure of actinide dioxides, we construct a tight-binding model composed of actinide $5f$ and oxygen $2p$ electrons, which is called $f$-$p$ model. After the diagonalization of the $f$-$p$ model, we compare the eigenenergies in the first Brillouin zone with the results of relativistic band-structure calculations. Here we emphasize a key role of $f$-$p$ hybridization in order to understand the electronic structure of actinide dioxides. In particular, it is found that the position of energy levels of $\\Gamma_7$ and $\\Gamma_8$ states determined from crystalline electric field potentials depends on the $f$-$p$ hybridization. We clarify the condition on the $f$-$p$ hybridization to explain the electronic structure which is consistent with the local crystalline electric field state. We briefly discuss the region of the absolute values of the Slater-Koster integrals for $f$-$p$ hybridization concerning the appearance of octupole ordering in NpO$_2$.

Hasegawa, Yu; Maehira, Takahiro; Hotta, Takashi


Ge3H(n)- anions (n = 0-5) and their neutral analogues: a theoretical investigation on the structure, stability, and thermochemistry.  


The structure, stability, and thermochemistry of various Ge3H(n)- isomers (n = 0-5) and of their neutral analogues have been investigated at the B3LYP/6-311+G(d), MP2(full)/6-31G(d), and Gaussian-2 (G2) level of theory. For Ge3H(-), both the B3LYP and the G2/MP2 methods predict the cyclic, H-bridged structure 1a- as the global minimum, more stable than another cyclic isomer and an open-chain isomer by ca. 10 and 25 kcal mol(-1), respectively. For Ge3H2(-), the B3LYP and the G2/MP2 methods provide a somewhat different description of the potential energy surface. At the G2/MP2 level of theory, the global minimum is the cyclic, H2Ge-bridged structure 2a-, separated by other three nearly degenerate isomers by ca. 10 kcal mol(-1). On the other hand, at the B3LYP level of theory, the cyclic, H-bridged structure 2e-, not located at the MP2 level of theory, is more stable than 2a- by ca. 1 kcal mol(-1). For Ge3H3(-), both the B3LYP and the G2/MP2 methods predict the cyclic, H3Ge-bridged isomer 3a- as the global minimum, but the energy differences with the other five located isomeric structures predicted by the two methods are quantitatively different. Similar to Ge3H2(-), the B3LYP and the G2/MP2 theoretical levels provide a somewhat different description of the Ge3H4(-) potential energy surface. At the G2/MP2 level of theory, the global minimum is the cyclic structure 4b- of C(2v) symmetry, featuring a Ge2H4 moiety and a Ge-bridged atom, which is more stable than other three located isomers by 3, 9, and 17 kcal mol(-1). On the other hand, at the B3LYP level of theory, the open-chain isomer 4a- of H3Ge-Ge-GeH(-) connectivity is more stable than 4b- by ca. 1 kcal mol(-1) and nearly degenerate with the alternative open-chain isomer H3Ge-GeH-Ge(-). For Ge3H5(-), both the B3LYP and the G2/MP2 methods predict the 2-propenyl-like isomer H3Ge-Ge-GeH2(-) as the global minimum, with energy differences with other four isomeric structures which range from ca. 1-2 to 13-17 kcal mol(-1). At the G2 level of theory and 298.15 K, the electron affinities of Ge3H(n) are computed as 2.17 (n = 0), 2.57 (n = 1), 1.70 (n = 2), 2.41 (n = 3), 2.07/1.80 (n = 4), and 2.71/2.46 eV (n = 5). The two alternative values reported for Ge3H4 and Ge3H5 reflect the alternative conceivable choice for the structure of the involved neutrals and ions. The G2 enthalpies of formation of Ge3H(n) and Ge3H(n)- (n = 0-5) have also been calculated using the atomization procedure. Finally, we have briefly discussed the implications of our calculations for previously performed mass spectrometric experiments on the negative ion chemistry of GeH4. PMID:16869693

Antoniotti, Paola; Borocci, Stefano; Grandinetti, Felice



Functionalization of the A ring of pyridoacridine as a route toward greater structural diversity. Synthesis of an octacyclic analogue of eilatin.  


In an effort to increase the structural diversity of pyrido[4,3,2-kl]acridines, compounds containing amino substituents on the A ring were synthesized. The key-reactions involve regioselective electrophilic aromatic substitutions. The methodology was applied to the synthesis of the extended angular octacycle 8, which conjugates the physicochemical and spectroscopic properties of the pyridoacridine skeleton with the ability of [1,10]phenanthroline ring for metal complexation. The 9-aminopyridoacridine 4 displays significant cytostatic activities against two cancer cell lines, and may be considered as a new lead in the search of active derivatives. PMID:19559608

Bouffier, Laurent; Dinica, Rodica; Debray, Julien; Dumy, Pascal; Demeunynck, Martine



Structure and functioning of Mediterranean lagoon fish assemblages: A key for the identification of water body types  

NASA Astrophysics Data System (ADS)

Knowledge on the structure and functioning variability of transitional water fish assemblages may help in finding out the main descriptors for identifying different water body types for which specific biological reference conditions can be reliably derived. Fish assemblages from 19 Mediterranean lagoons were therefore investigated by evaluating the variability of their structure and functioning, and by relating it to the lagoons' environmental features. Fish assemblage structure was measured by its species richness. Functioning was measured by categorizing fish species into functional categories (or guilds) according to their use of lagoon habitat, feeding and reproduction, and by defining the functional structure of fish assemblages as the relative number of species per guild in each lagoon. Mediterranean lagoons' fish assemblages were found to be more similar to each other in their functional structure than in the taxonomical composition, thus confirming a shared functional role of these environments for biological communities. Lagoon local features, such as the lagoon area, its habitat heterogeneity and average salinity, significantly affected the total species richness and the different use that fish make of the lagoon environment, hence playing a primary role in the assessment of these water body types. Latitude also influenced the variability of fish assemblages in the Mediterranean lagoons investigated, with particular regard to their functioning as feeding and reproductive grounds for fish. These results are compared with previous studies and, although this limited the investigation to structural aspects only, were found to confirm in part the previous results and also added new insights about the key factors affecting the functioning of transitional water systems.

Franco, Anita; Franzoi, Piero; Torricelli, Patrizia



Novel ?-MSH Peptide Analogues with Broad Spectrum Antimicrobial Activity  

PubMed Central

Previous investigations indicate that ?-melanocyte-stimulating hormone (?-MSH) and certain synthetic analogues of it exert antimicrobial effects against bacteria and yeasts. However, these molecules have weak activity in standard microbiology conditions and this hampers a realistic clinical use. The aim in the present study was to identify novel peptides with broad-spectrum antimicrobial activity in growth medium. To this purpose, the Gly10 residue in the [DNal(2?)-7, Phe-12]-MSH(6–13) sequence was replaced with conventional and unconventional amino acids with different degrees of conformational rigidity. Two derivatives in which Gly10 was replaced by the residues Aic and Cha, respectively, had substantial activity against Candida strains, including C. albicans, C. glabrata, and C. krusei and against gram-positive and gram-negative bacteria. Conformational analysis indicated that the helical structure along residues 8–13 is a key factor in antimicrobial activity. Synthetic analogues of ?-MSH can be valuable agents to treat infections in humans. The structural preferences associated with antimicrobial activity identified in this research can help further development of synthetic melanocortins with enhanced biological activity.

Auriemma, Luigia; Limatola, Antonio; Di Maro, Salvatore; Merlino, Francesco; Mangoni, Maria Luisa; Luca, Vincenzo; Di Grazia, Antonio; Gatti, Stefano; Campiglia, Pietro; Gomez-Monterrey, Isabel; Novellino, Ettore; Catania, Anna



Novel ?-MSH peptide analogues with broad spectrum antimicrobial activity.  


Previous investigations indicate that ?-melanocyte-stimulating hormone (?-MSH) and certain synthetic analogues of it exert antimicrobial effects against bacteria and yeasts. However, these molecules have weak activity in standard microbiology conditions and this hampers a realistic clinical use. The aim in the present study was to identify novel peptides with broad-spectrum antimicrobial activity in growth medium. To this purpose, the Gly10 residue in the [DNal(2')-7, Phe-12]-MSH(6-13) sequence was replaced with conventional and unconventional amino acids with different degrees of conformational rigidity. Two derivatives in which Gly10 was replaced by the residues Aic and Cha, respectively, had substantial activity against Candida strains, including C. albicans, C. glabrata, and C. krusei and against gram-positive and gram-negative bacteria. Conformational analysis indicated that the helical structure along residues 8-13 is a key factor in antimicrobial activity. Synthetic analogues of ?-MSH can be valuable agents to treat infections in humans. The structural preferences associated with antimicrobial activity identified in this research can help further development of synthetic melanocortins with enhanced biological activity. PMID:23626703

Grieco, Paolo; Carotenuto, Alfonso; Auriemma, Luigia; Limatola, Antonio; Di Maro, Salvatore; Merlino, Francesco; Mangoni, Maria Luisa; Luca, Vincenzo; Di Grazia, Antonio; Gatti, Stefano; Campiglia, Pietro; Gomez-Monterrey, Isabel; Novellino, Ettore; Catania, Anna



Structure Activity Relationship of (N)-Methanocarba Phosphonate Analogues of 5'-AMP as Cardioprotective Agents Acting Through a Cardiac P2X Receptor  

PubMed Central

P2X receptor activation protects in heart failure models. MRS2339 3, a 2-chloro-AMP derivative containing a (N)-methanocarba (bicyclo[3.1.0]hexane) system, activates this cardioprotective channel. Michaelis–Arbuzov and Wittig reactions provided phosphonate analogues of 3, expected to be stable in vivo due to the C-P bond. After chronic administration via a mini-osmotic pump (Alzet), some analogues significantly increased intact heart contractile function in calsequestrin-overexpressing mice (genetic model of heart failure) compared to vehicle-infused mice (all inactive at the vasodilatory P2Y1 receptor). Two phosphonates, (1’S,2’R,3’S,4’R,5’S)-4’-(6-amino-2-chloropurin-9-yl)-2’,3’-(dihydroxy)-1’-(phosphonomethylene)-bicyclo[3.1.0]hexane 4 and its homologue 9, both 5’-saturated, containing a 2-Cl substitution, improved echocardiography-derived fractional shortening (20.25% and 19.26%, respectively, versus 13.78% in controls), while unsaturated 5’-extended phosphonates, all 2-H analogues, and a CH3-phosphonate were inactive. Thus, chronic administration of nucleotidase-resistant phosphonates conferred a beneficial effect, likely via cardiac P2X receptor activation. Thus, we have greatly expanded the range of carbocyclic nucleotide analogues that represent potential candidates for the treatment of heart failure.

Kumar, T. Santhosh; Zhou, Si-Yuan; Joshi, Bhalchandra V.; Balasubramanian, Ramachandran; Yang, Tiehong; Liang, Bruce T.; Jacobson, Kenneth A.



Key stabilizing elements of protein structure identified through pressure and temperature perturbation of its hydrogen bond network  

NASA Astrophysics Data System (ADS)

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.

Nisius, Lydia; Grzesiek, Stephan



Key experimental information on intermediate-range atomic structures in amorphous Ge2Sb2Te5 phase change material  

NASA Astrophysics Data System (ADS)

Laser-induced crystalline-amorphous phase change of Ge-Sb-Te alloys is the key mechanism enabling the fast and stable writing/erasing processes in rewritable optical storage devices, such as digital versatile disk (DVD) or blu-ray disk. Although the structural information in the amorphous phase is essential for clarifying this fast process, as well as long lasting stabilities of both the phases, experimental works were mostly limited to the short-range order by x ray absorption fine structure. Here we show both the short and intermediate-range atomic structures of amorphous DVD material, Ge2Sb2Te5 (GST), investigated by a combination of anomalous x ray scattering and reverse Monte Carlo modeling. From the obtained atomic configurations of amorphous GST, we have found that the Sb atoms and half of the Ge atoms play roles in the fast phase change process of order-disorder transition, while the remaining Ge atoms act for the proper activation energy of barriers between the amorphous and crystalline phases.

Hosokawa, Shinya; Pilgrim, Wolf-Christian; Höhle, Astrid; Szubrin, Daniel; Boudet, Nathalie; Bérar, Jean-François; Maruyama, Kenji



Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues  

PubMed Central

Summary Aurachins are myxobacterial 3-farnesyl-4(1H)-quinolone derived compounds initially described as respiratory chain inhibitors, more specifically as inhibitors of various cytochrome complexes. They are also known as potent antibiotic compounds. We describe herein the first synthesis of aurachin D through a key Conrad–Limpach reaction. The same strategy was used to reach some ring as opposed to chain analogues, allowing for the description of structure–activity relationships. Biological screening of the analogues showed antiparasitic, cytotoxic, antibacterial and antifungal activities, and depletion of the mitochondrial membrane potential. The strongest activity was found on Plasmodium falciparum with a selectivity index of 345, compared to Vero cells, for the natural product and its geranyl analogue. The loss of mitochondrial membrane potential induced by aurachins in human U-2 OS osteosarcoma cells was studied, showing the best activity for aurachin D and a naphthalene analogue, yet without totally explaining the observed cytotoxic activity of the compounds. Finally, a synthetic entry is given to the complete carboheterocyclic core of aurachin H through the N-oxidation/epoxidation of aurachin D and a shorter chain analogue, followed by subsequent biomimetic cyclization.

Li, Xu-Wen; Herrmann, Jennifer; Zang, Yi; Grellier, Philippe; Prado, Soizic



Structure of the MTIP-MyoA complex, a key component of the malaria parasite invasion motor  

PubMed Central

The causative agents of malaria have developed a sophisticated machinery for entering multiple cell types in the human and insect hosts. In this machinery, a critical interaction occurs between the unusual myosin motor MyoA and the MyoA-tail Interacting Protein (MTIP). Here we present one crystal structure that shows three different conformations of Plasmodium MTIP, one of these in complex with the MyoA-tail, which reveal major conformational changes in the C-terminal domain of MTIP upon binding the MyoA-tail helix, thereby creating several hydrophobic pockets in MTIP that are the recipients of key hydrophobic side chains of MyoA. Because we also show that the MyoA helix is able to block parasite growth, this provides avenues for designing antimalarials.

Bosch, Jurgen; Turley, Stewart; Daly, Thomas M.; Bogh, Stephen M.; Villasmil, Michelle L.; Roach, Claudia; Zhou, Na; Morrisey, Joanne M.; Vaidya, Akhil B.; Bergman, Lawrence W.; Hol, Wim G. J.



Network structure and the role of key players in a translational cancer research network: a study protocol  

PubMed Central

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.

Cunningham, Frances C; Braithwaite, Jeffrey



Photochemical synthesis of nucleoside analogues from cyclobutanones: bicyclic and isonucleosides.  


The preparation of two nucleoside analogues are reported. Both syntheses involve a key photochemical ring-expansion of cyclobutanones to an oxacarbene and its subsequent scavenging by 6-chloropurine. The synthesis of a bicyclic (locked) purine starts from a oxabicycloheptanone with a hydroxymethyl pendant. The preparation of an isonucleoside uses a cyclobutanone with an alpha-substituted 6-chloropurine. Irradiation of the latter produces an isonucleoside and acyclic nucleoside analogues. PMID:20657410

Jaffer, Mileina; Ebead, Abdelaziz; Lee-Ruff, Edward



Novel 3-substituted rimonabant analogues lack ?9-tetrahydrocannabinol-like abuse-related behavioural effects in mice  

PubMed Central

Background and Purpose Previous structure–activity relationship studies with analogues of the CB1 receptor antagonist rimonabant have demonstrated that a subset of these analogues with 3-substituent replacements of rimonabant's pyrazole core displayed cannabimimetic profiles seemingly independent of CB1 receptors. We sought to further evaluate these analogues in several behavioural models sensitive to detecting THC-like abuse liability. Experimental Approach Selected analogues were tested in a battery of tests in mice to replicate previous findings. Cross-generalization tests were conducted in mice trained to discriminate either THC or O-6629 from vehicle. Rimonabant and its analogues were also evaluated in substitution and challenge tests. Finally, development of cross-tolerance between THC and O-6211 in the mouse test battery was assessed. Key Results O-6629 and O-6658 produced dose-dependent acute cannabimimetic activity in mice, but neither substituted for nor antagonized THC's discriminative stimulus. Cross-substitution was observed with O-6658 in mice discriminating O-6629, whereas rimonabant neither substituted for nor attenuated the O-6629 discriminative stimulus. THC and morphine did not generate O-6629-like responding. Cross-tolerance did not develop in mice repeatedly treated with THC when tested with O-6211 in the mouse test battery. Conclusions and Implications While some overlap exists between the pharmacological profiles of THC and these 3-substituent rimonabant analogues, the effects are mediated by distinct neural targets. Notably, these analogues are unlikely to possess marijuana-like abuse liability in humans, but general abuse liability has not yet been determined. Efforts to determine the mechanism(s) of action of this seemingly unique class of compounds are underway.

Walentiny, DM; Vann, RE; Mahadevan, A; Kottani, R; Gujjar, R; Wiley, JL



Antitumor agents 286. Design, synthesis, and structure-activity relationships of 3'R,4'R-disubstituted-2',2'-dimethyldihydropyrano[2,3-f]chromone (DSP) analogues as potent chemosensitizers to overcome multidrug resistance.  


In this study, various 3'R,4'R-disubstituted-2',2'-dimethydihydropyrano[2,3-f]chromone (DSP) derivatives were discovered as potent chemosensitizers in the treatment of multidrug resistant cancer cells. Twenty-four DSP analogues (5-28) were synthesized and evaluated against a multidrug resistant (MDR) cell line (KB-Vin) with and without vincristine (VCR). All DSP analogues exhibited low intrinsic cytotoxicity. However, in combination treatment, most DSPs reversed resistance to VCR and lowered the GI?? value of VCR by 12-349-fold. At a concentration of 1 ?g/mL, three compounds, 11, 14, and 21, fully reversed resistance to VCR in KB-Vin cancer cells, a 2-fold increase compared to verapamil, a first-generation chemosensitizer. Detailed structure-activity relationship (SAR) conclusions were established based on 3' and 4' substitutions. Moreover, a preliminary mechanism study indicated that the chemosensitizing activity of DSP analogues results from inhibition of P-glycoprotein (P-gp) overexpressed in MDR cancer cells. PMID:21082774

Zhou, Ting; Shi, Qian; Bastow, Kenneth F; Lee, Kuo-Hsiung



Structure of the Trehalose-6-phosphate Phosphatase from Brugia malayi Reveals Key Design Principles for Anthelmintic Drugs  

PubMed Central

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.

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.



Structure of the Trehalose-6-phosphate Phosphatase from Brugia malayi Reveals Key Design Principles for Anthelmintic Drugs.  


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

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



Peptoid analogues of anoplin show antibacterial activity.  


We have synthesised nine analogues of the antibacterial peptide anoplin with a peptoid residue at position 5 (H-GLLKXIKTLL-NH(2)). The most active compounds showed MIC-values of 12.5 and 25 microM against E.coli and S.aureus. These MIC-values are comparable with anoplin which showed 23 microM and 11 microM against E. coli and S.aureus. However, the selectivity was reversed. Our results indicate that peptoid analogues of anoplin are promising lead structures for developing new antibacterial agents. PMID:19799550

Meinike, K; Hansen, P R



Orally active prostacyclin analogue for cardiovascular disease.  


Prostacyclin has vasoprotective effects such as vasodilation and antiplatelet aggregatory activity. A relative deficiency of prostacyclin contributes to the pathogenesis of cardiovascular disease including pulmonary artery disease (PAH). Inconvenient intravenous dosing of prostacyclin led to the development of more stable, an orally active analogue: beraprost. It is a chemically stable prostacyclin analogue owing to its cyclo-pentabenzofuranyl structure and produces strong vasodilation and inhibition of platelet aggregation. To date, beraprost has been used in the treatment of PAH and peripheral arterial disease (PAD). Recently, we have shown that beraprost induces neovascularization in ischemic myocardium by enhancement of bone marrow cell mobilization. Interestingly, meta-analysis of clinical studies for PAD has shown that repeated administration of beraprost decreases the number of cardiovascular events. These results suggest that oral administration of beraprost has beneficial effects on cardiovascular disease. Orally active prostacyclin analogues, are promising drugs for the treatment of cardiovascular disease. PMID:20357744

Nagaya, N



Lobelane analogues as novel ligands for the vesicular monoamine transporter-2  

PubMed Central

A series of lobelane analogues has been synthesized and their structure–activity relationships at the vesicular monoamine transporter-2 (VMAT2) have been evaluated. The most potent analogues in this series were the cis-2,6-piperidino analogues, 25b, 27b, 28b, and 30b, with Ki values ranging from 430 to 580 nM.

Zheng, Guangrong; Dwoskin, Linda P.; Deaciuc, Agripina G.; Zhu, Jun; Jones, Marlon D.; Crooks, Peter A.



Identifying transcription factors and microRNAs as key regulators of pathways using Bayesian inference on known pathway structures  

PubMed Central

Background Transcription factors and microRNAs act in concert to regulate gene expression in eukaryotes. Numerous computational methods based on sequence information are available for the prediction of target genes of transcription factors and microRNAs. Although these methods provide a static snapshot of how genes may be regulated, they are not effective for the identification of condition-specific regulators. Results We propose a new method that combines: a) transcription factors and microRNAs that are predicted to target genes in pathways, with b) microarray expression profiles of microRNAs and mRNAs, in conjunction with c) the known structure of molecular pathways. These elements are integrated into a Bayesian network derived from each pathway that, through probability inference, allows for the prediction of the key regulators in the pathway. We demonstrate 1) the steps to discretize the expression data for the computation of conditional probabilities in a Bayesian network, 2) the procedure to construct a Bayesian network using the structure of a known pathway and the transcription factors and microRNAs predicted to target genes in that pathway, and 3) the inference results as potential regulators of three signaling pathways using microarray expression profiles of microRNA and mRNA in estrogen receptor positive and estrogen receptor negative tumors. Conclusions We displayed the ability of our framework to integrate multiple sets of microRNA and mRNA expression data, from two phenotypes, with curated molecular pathway structures by creating Bayesian networks. Moreover, by performing inference on the network using known evidence, e.g., status of differentially expressed genes, or by entering hypotheses to be tested, we obtain a list of potential regulators of the pathways. This, in turn, will help increase our understanding about the regulatory mechanisms relevant to the two phenotypes.



Structure-activity relationships among analogues of pemedolac, cis-1-ethyl-1,3,4,9-tetrahydro-4-(phenylmethyl)pyrano[3,4-b]indo le-1-a cetic acid, a potent analgesic agent.  


The syntheses of analogues of pemedolac (cis-1-ethyl-1,3,4,9-tetrahydro-4-(phenylmethyl)pyrano[3,4-b]indol e-1-acetic acid), a potent analgesic, are described. They were tested for analgesic and antiinflammatory effects in vivo and for inhibition of prostaglandin production in vitro. Analysis of structure-activity relationships shows that analgesic activity in this series is associated with 1S-cis stereochemistry, the presence of a pi-system (allyl or benzyl) at position 4, and a log P value greater than 4.0. PMID:3263504

Mobilio, D; Humber, L G; Katz, A H; Demerson, C A; Hughes, P; Brigance, R; Conway, K; Shah, U; Williams, G; Labbadia, F



Stimulation of inositol 1,4,5-trisphosphate (IP3) receptor subtypes by adenophostin A and its analogues.  


Inositol 1,4,5-trisphosphate receptors (IP3R) are intracellular Ca(2+) channels. Most animal cells express mixtures of the three IP3R subtypes encoded by vertebrate genomes. Adenophostin A (AdA) is the most potent naturally occurring agonist of IP3R and it shares with IP3 the essential features of all IP3R agonists, namely structures equivalent to the 4,5-bisphosphate and 6-hydroxyl of IP3. The two essential phosphate groups contribute to closure of the clam-like IP3-binding core (IBC), and thereby IP3R activation, by binding to each of its sides (the ?- and ?-domains). Regulation of the three subtypes of IP3R by AdA and its analogues has not been examined in cells expressing defined homogenous populations of IP3R. We measured Ca(2+) release evoked by synthetic adenophostin A (AdA) and its analogues in permeabilized DT40 cells devoid of native IP3R and stably expressing single subtypes of mammalian IP3R. The determinants of high-affinity binding of AdA and its analogues were indistinguishable for each IP3R subtype. The results are consistent with a cation-? interaction between the adenine of AdA and a conserved arginine within the IBC ?-domain contributing to closure of the IBC. The two complementary contacts between AdA and the ?-domain (cation-? interaction and 3?-phosphate) allow activation of IP3R by an analogue of AdA (3?-dephospho-AdA) that lacks a phosphate group equivalent to the essential 5-phosphate of IP3. These data provide the first structure-activity analyses of key AdA analogues using homogenous populations of all mammalian IP3R subtypes. They demonstrate that differences in the Ca(2+) signals evoked by AdA analogues are unlikely to be due to selective regulation of IP3R subtypes. PMID:23469136

Saleem, Huma; Tovey, Stephen C; Riley, Andrew M; Potter, Barry V L; Taylor, Colin W



A comparison of the solvation thermodynamics of amino acid analogues in water, 1-octanol and 1-n-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ionic liquids by molecular simulation.  


A computational approach is developed to quantitatively study the solvation thermodynamics of amino acid analogues in ionic liquids via molecular simulation. The solvation thermodynamics of amino acid analogues in ionic liquids is important for an understanding of protein-ionic liquid interactions, shedding insight into the structure and solubility of proteins, and the activity of enzymes in ionic liquids. This information is additionally key to developing novel extraction processes. As a result of the challenge of quantitatively describing the solvation behavior of ionic liquids, a key outcome of the present study is the development of a "hydrophobicity" scale to quantitatively describe the amino acid analogues. The scale allows one to separate the results of both the hydrophobic and hydrophillic analogues, simplifying an understanding of the observed trends. Equipped with the proposed hydrophobicity scale, one needs only perform conventional solvation free energy calculations of the amino acid analogues in the ionic liquids of interest. The necessary simulation tools are available in most open-source simulation software, facilitating the adoption of this approach by the simulation community at large. We have studied the case of varying the cation alkyl-chain length of a 1-n-alkyl-3-methylimidazolium cation paired with the bis(trifluoromethylsulfonyl)imide anion. The findings suggest that a judicious selection of both the cation and anion could potentially lead to a solvent for which the amino acid analogues have an affinity far greater than that for both water and a non-polar reference solvent. PMID:23163380

Paluch, Andrew S; Vitter, Cameron A; Shah, Jindal K; Maginn, Edward J



Predicted structures of precursors B{sub 4}N{sub 6}H{sub 8}, B{sub 4}N{sub 8}H{sub 8}, and B{sub 4}N{sub 8}H{sub 6}, and the B{sub 24}N{sub 36} analogue of C{sub 60}  

SciTech Connect

The authors use mathematical modeling to study the structures of boron nitride hydrides, with emphasis on B{sub 24}N{sub 36}, which is predicted to have a C{sub 60} fullerene (buckyball) structure. The authors coined the term {open_quotes}bonnyball{close_quotes} for the boron nitride analogues of buckyball. Predicted structures of bonnyball and its components are given.

Bardo, R.D.; Stanton, C.T. [Naval Surface Warfare Center, Silver Spring, MD (United States); Jones, W.H. [Univ. of West Florida, Pensacola, FL (United States)



Crystal structures of the LsrR proteins complexed with phospho-AI-2 and two signal-interrupting analogues reveal distinct mechanisms for ligand recognition.  


Quorum sensing (QS) is a cell-to-cell communication system responsible for a variety of bacterial phenotypes including virulence and biofilm formation. QS is mediated by small molecules, autoinducers (AIs), including AI-2 that is secreted by both Gram-positive and -negative microbes. LsrR is a key transcriptional regulator that governs the varied downstream processes by perceiving AI-2 signal, but its activation via autoinducer-binding remains poorly understood. Here, we provide detailed regulatory mechanism of LsrR from the crystal structures in complexes with the native signal (phospho-AI-2, D5P) and two quorum quenching antagonists (ribose-5-phosphate, R5P; phospho-isobutyl-AI-2, D8P). Interestingly, the bound D5P and D8P molecules are not the diketone forms but rather hydrated, and the hydrated moiety forms important H-bonds with the carboxylate of D243. The D5P-binding flipped out F124 of the binding pocket, and resulted in the disruption of the dimeric interface-1 by unfolding the ?7 segment. However, the same movement of F124 by the D8P'-binding did not cause the unfolding of the ?7 segment. Although the LsrR-binding affinity of R5P (Kd, ?1 mM) is much lower than that of D5P and D8P (?2.0 and ?0.5 ?M), the ?-anomeric R5P molecule fits into the binding pocket without any structural perturbation, and thus stabilizes the LsrR tetramer. The binding of D5P, not D8P and R5P, disrupted the tetrameric structure and thus is able to activate LsrR. The detailed structural and mechanistic insights from this study could be useful for facilitating design of new antivirulence and antibiofilm agents based on LsrR. PMID:24047255

Ha, Jung-Hye; Eo, Yumi; Grishaev, Alexander; Guo, Min; Smith, Jacqueline A I; Sintim, Herman O; Kim, Eun-Hee; Cheong, Hae-Kap; Bentley, William E; Ryu, Kyoung-Seok



Boron hydride analogues of the fullerenes  

SciTech Connect

The BH moiety is isoelectronic with C. We have studied the stability of the (BH)[sub 60] analogue of the C[sub 60] fullerene as well as the dual-structure (BH)[sub 32] icosahedron, both of them being putative structures, by performing local-density-functional electronic calculations. To aid in our analysis, we have also studied other homologues of these systems. We find that the latter, i.e., the dual structure, is the more stable although the former is as stable as one of the latter's lower homologues. Boron hydrides, it seems, naturally form the dual structures used in algorithmic optimization of complex fullerene systems. Fully relaxed geometries are reported as well as electron affinities and effective Hubbard [ital U] parameters. These systems form very stable anions and we conclude that a search for BH analogues of the C[sub 60] alkali-metal supeconductors might prove very fruitful.

Quong, A.A. (Sandia Livermore National Laboratory, Livermore, California 94551-0969 (United States)); Pederson, M.R.; Broughton, J.Q. (Naval Research Laboratory, Washington, D.C. 20375 (United States))



Structure of a Key Intermediate of the SMN Complex Reveals Gemin2's Crucial Function in snRNP Assembly  

PubMed Central

Summary Assembly of heptameric Sm protein rings on snRNAs (Sm cores), essential for snRNP function, is mediated by the SMN complex. Specific Sm core assembly depends on Sm proteins and snRNA recognition by SMN/Gemin2- and Gemin5-containing subunits, respectively. The mechanism by which the Sm proteins are gathered and illicit Sm core assembly is prevented is unknown. Here, we describe the 2.5 Å crystal structure of Gemin2 bound to SmD1/D2/F/E/G pentamer and SMN’s Gemin2-binding domain, a key assembly intermediate. Remarkably, through its extended conformation, Gemin2 wraps around the crescent-shaped pentamer, interacting with all five Sm proteins and gripping its bottom- and top-sides and outer perimeter. It further reaches into its RNA-binding pocket, preventing it from binding RNA. Interestingly, SMN-Gemin2 interaction is abrogated by an SMA (spinal muscular atrophy)-causing mutation in an SMN helix that mediates Gemin2 binding. These findings provide mechanistic insights into SMN complex function, linking snRNP biogenesis and SMA pathogenesis.

Zhang, Rundong; So, Byung Ran; Li, Pilong; Yong, Jeongsik; Glisovic, Tina; Wan, Lili; Dreyfuss, Gideon



Sensory-guided decomposition of red currant juice (Ribes rubrum) and structure determination of key astringent compounds.  


Sequential application of solvent extraction, gel permeation chromatography, and RP-HPLC in combination with taste dilution analyses, followed by LC-MS and 1D/2D NMR experiments, led to the discovery and structure determination of 25 key astringent compounds of red currant juice. Besides several flavonol glycosides, in particular, 3-carboxymethyl-indole-1-N-beta-D-glucopyranoside, 3-methylcarboxymethyl-indole-1-N-beta-D-glucopyranoside, and a family of previously not identified compounds, namely, 2-(4-hydroxybenzoyloxymethyl)-4-beta-D-glucopyranosyloxy-2(E)-butenenitrile, 2-(4-hydroxy-3-methoxybenzoyloxymethyl)-4-beta-D-glucopyranosyloxy-2(E)-butenenitrile, (E)-6-[3-hydroxy-4-(O-beta-D-glucopyranosyl)phenyl]-5-hexen-2-one named dehydrorubrumin, and (3E,5E)-6-[3-hydroxy-4-(O-beta-D-glucopyranosyl)phenyl]-3,5-hexadien-2-one named rubrumin, have been identified. Determination of the oral astringency thresholds by means of the half-tongue test revealed that the lowest thresholds of 0.3 and 1.0 nmol/L were found for the nitrogen-containing 3-carboxymethyl-indole-1-N-beta-D-glucopyranoside and 3-methylcarboxymethyl-indole-1-N-beta-D-glucopyranoside, which do not belong to the group of plant polyphenols. PMID:17261016

Schwarz, Bernd; Hofmann, Thomas



Synthesis and biological activity of tetralone abscisic acid analogues.  


Bicyclic analogues of the plant hormone abscisic acid (ABA) were designed to incorporate the structural elements and functional groups of the parent molecule that are required for biological activity. The resulting tetralone analogues were predicted to have enhanced biological activity in plants, in part because oxidized products would not cyclize to forms corresponding to the inactive catabolite phaseic acid. The tetralone analogues were synthesized in seven steps from 1-tetralone and a range of analogues were accessible through a second route starting with 2-methyl-1-naphthol. Tetralone ABA 8 was found to have greater activity than ABA in two bioassays. The absolute configuration of (+)-8 was established by X-ray crystallography of a RAMP hydrazone derivative. The hydroxymethyl compounds 10 and 11, analogues for studying the roles of 8- and 9-hydroxy ABA 3 and 6, were also synthesized and found to be active. PMID:16557330

Nyangulu, James M; Nelson, Ken M; Rose, Patricia A; Gai, Yuanzhu; Loewen, Mary; Lougheed, Brenda; Quail, J Wilson; Cutler, Adrian J; Abrams, Suzanne R



Boron hydride analogues of the fullerenes  

Microsoft Academic Search

The BH moiety is isoelectronic with C. We have studied the stability of the (BH)[sub 60] analogue of the C[sub 60] fullerene as well as the dual-structure (BH)[sub 32] icosahedron, both of them being putative structures, by performing local-density-functional electronic calculations. To aid in our analysis, we have also studied other homologues of these systems. We find that the latter,

Andrew Quong; Mark Pederson; Jeremy Broughton



Boron hydride analogues of the fullerenes  

Microsoft Academic Search

The BH moiety is isoelectronic with C. We have studied the stability of the (BH)60 analogue of the C60 fullerene as well as the dual-structure (BH)32 icosahedron, both of them being putative structures, by performing local-density-functional electronic calculations. To aid in our analysis, we have also studied other homologues of these systems. We find that the latter, i.e., the dual

Andrew A. Quong; Mark R. Pederson; Jeremy Q. Broughton



A Strategy for the Late-Stage Divergent Syntheses of Scyphostatin Analogues  

PubMed Central

This account details the synthesis of two scyphostatin analogues exhibiting a reactive polar epoxycyclohexenone core and various amide side chains outfitted for late-stage chemical derivatization into the desirable lipophilic tails. Our efforts highlight a key ipso-dearomatization process and provide new insights regarding the incompatibility and orthogonal reactivity of scyphostatin’s functional groups. We further showcase the utility of resorcinol derived 2,5-cyclohexadienones as synthetic platforms capable of participating in selective chemical reactivity, and we further demonstrate their potential for rapid elaboration into complex structural motifs.

Cha, Jacob Y.; Burnett, G. Leslie; Huang, Yaodong; Davidson, Jarrod B.; Pettus, Thomas R. R.



Structural Basis for the Secretion of EvpC: A Key Type VI Secretion System Protein from Edwardsiella tarda  

PubMed Central

The recently identified type VI secretion system (T6SS) is implicated in the virulence of many Gram-negative bacteria. Edwardsiella tarda is an important cause of hemorrhagic septicemia in fish and also gastro- and extra-intestinal infections in humans. The E. tarda virulent protein (EVP) gene cluster encodes a conserved T6SS which contains 16 open reading frames. EvpC is one of the three major EVP secreted proteins and shares high sequence similarity with Hcp1, a key T6SS virulence factor from Pseudomonas aeruginosa. EvpC contributes to the virulence of E. tarda by playing an essential role in functional T6SS. Here, we report the crystal structure of EvpC from E. tarda PPD130/91 at a 2.8 Å resolution, along with functional studies of the protein. EvpC has a ?-barrel domain with extended loops. The ?-barrel consists of 11 anti-parallel ?-strands with an ?-helix located on one side. In solution, EvpC exists as a dimer at low concentration and as a hexamer at higher concentration. In the crystal, the symmetry related EvpC molecules form hexameric rings which stack together to form a tube similar to Hcp1. Structure based mutagenesis revealed that N-terminal negatively charged residues, Asp4, Glu15 and Glu26, and C-terminal positively charged residues, Lys161, Lys162 and Lys163, played crucial roles in the secretion of EvpC. Moreover, the localization study indicates the presence of wild type EvpC in cytoplasm, periplasm and secreted fractions, whereas the N-terminal and C-terminal mutants were found mostly in the periplasmic region and was completely absent in the secreted fraction. Results reported here provide insight into the structure, assembly and function of EvpC. Further, these findings can be extended to other EvpC homologs for understanding the mechanism of T6SS and targeting T6SS mediated virulence in Gram-negative pathogens.

Jobichen, Chacko; Zheng, Jun; Joseph, Lissa; Mok, Yu-Keung; Leung, Ka Yin; Sivaraman, J.



Synthesis and in vitro antitumor activity of phenanthrolin-7-one derivatives, analogues of the marine pyridoacridine alkaloids ascididemin and meridine: structure-activity relationship.  


A series of substituted pyrido[4,3,2-de][1,7] or [1,10]-phenanthrolin-7-ones, analogues of the marine pyridoacridines meridine and ascididemin, have been synthesized on the basis of Diels-Alder reactions involving different quinoline-5,8-diones and N,N-aldehyde-dimethylhydrazones. All the compounds were evaluated for in vitro cytotoxic activity against 12 distinct human cancer cell lines. They all exhibit cytotoxic activity with IC(50) values at least of micromolar order. PMID:12877592

Delfourne, Evelyne; Kiss, Robert; Le Corre, Laurent; Dujols, Frederic; Bastide, Jean; Collignon, Françoise; Lesur, Brigitte; Frydman, Armand; Darro, Francis



Key Facts

Key Facts Scientists know that: I-131 breaks down rapidly in the atmosphere and environment Exposure was highest in the first few days after each nuclear test explosion Most exposure occurred through drinking fresh milk People received little exposure


Using Keys  

Microsoft Academic Search

\\u000a As discussed in Chap. 3, keys must remain protected from would be attackers in order to provide security. However, they must\\u000a be accessed by trusted users or devices in order for security computations to be performed. These security computations include\\u000a protocols not only for communicating or establishing temporary keys but also for communicating confidential messages, signatures,\\u000a etc. This chapter will

Catherine H. Gebotys


Structure--activity relationship between the in vivo skin sensitizing potency of analogues of phenyl glycidyl ether and the induction of Nrf2-dependent luciferase activity in the KeratinoSens in vitro assay.  


Because of regulatory constraints and ethical considerations, research on alternatives to animal testing to predict the skin sensitization potential of novel chemicals has become a high priority. Ideally, these alternatives should not only predict the hazard of novel chemicals but also rate the potency of skin sensitizers. Currently, no alternative method gives reliable potency estimations for a wide range of chemicals in differing structural classes. Performing potency estimations within specific structural classes has thus been proposed. Detailed structure-activity studies for the in vivo sensitization capacity of a series of analogues of phenyl glycidyl ether (PGE) were recently published. These studies are part of an investigation regarding the allergenic activity of epoxy-resin monomers. Here we report data on the same chemicals in the KeratinoSens in vitro assay, which is based on a stable transgenic keratinocyte cell line with a luciferase gene under the control of an antioxidant response element. A strong correlation between the EC3 values in the local lymph node assay (LLNA) and both the luciferase-inducing concentrations and the cytotoxicity in the cell-based assay was established for six analogues of PGE. This correlation allowed the potency in the LLNA of two novel structurally closely related derivatives to be predicted by read-across with errors of 1.4- and 2.6-fold. However, the LLNA EC3 values of two structurally different bifunctional monomers were overpredicted on the basis of this data set, indicating that accurate potency estimation by read-across based on in vitro data might be restricted to a relatively narrow applicability domain. PMID:21751775

Delaine, Tamara; Niklasson, Ida B; Emter, Roger; Luthman, Kristina; Karlberg, Ann-Therese; Natsch, Andreas



Design, synthesis, and characterization of novel iron chelators: structure-activity relationships of the 2-benzoylpyridine thiosemicarbazone series and their 3-nitrobenzoyl analogues as potent antitumor agents.  


Previously, we demonstrated that the potent antiproliferative activity of the di-2-pyridylketone thiosemicarbazone (DpT) series of Fe chelators was due to their ability to induce Fe depletion and form redox-active Fe complexes (Richardson, D. R.; et al. J. Med. Chem. 2006, 49, 6510-6521). We now examine the role of aromatic substituents on the antiproliferative and redox activity of novel DpT analogues, namely, the 2-benzoylpyridine thiosemicarbazone (BpT) and 2-(3-nitrobenzoyl)pyridine thiosemicarbazone (NBpT) series. Both series exhibited selective antiproliferative effects, with the majority having greater antineoplastic activity than their DpT homologues. This makes the BpT chelators the most active anticancer agents developed within our laboratory. The BpT series Fe complexes exhibit lower redox potentials than their corresponding DpT and NBpT complexes, highlighting their enhanced redox activity. The increased ability of BpT-Fe complexes to catalyze ascorbate oxidation and benzoate hydroxylation, relative to their DpT and NBpT analogues, suggested that redox cycling plays an important role in their antiproliferative activity. PMID:17602603

Kalinowski, Danuta S; Yu, Yu; Sharpe, Philip C; Islam, Mohammad; Liao, Yi-Tyng; Lovejoy, David B; Kumar, Naresh; Bernhardt, Paul V; Richardson, Des R



Synthesis and acetylcholinesterase inhibitory activity of several pyrimidone analogues of huperzine A  

SciTech Connect

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.

Kozlkowski, A.P.; Campiani, G.; Saxena, A.; Doctor, S.P.



Micron-Scale Polymer Analogues  

NASA Astrophysics Data System (ADS)

Disordered fiber mats made of glass microfibers (GMF) immersed in an index matching fluid were studied using small-angle light scattering (SALS), ultra-small-angle x-ray scattering (USAXS) and optical microscopy. In GMF and several other fibrous materials the structure is stocastically randomized at the time of formation leading to an analogy with the thermal randomization which occurs in nanometer-scale, high polymers. The morphology of these materials in the micron-scale displays strong parallels to that of polymers in the nanometer-scale. Observation of Gaussian and self-avoidance scaling over decades in size can be made in these systems depending on preparation conditions. Structural analogues for the coil radius of gyration, persistence unit and scaling regimes are observed. These are useful features both for macroscopically modeling thermally equilibrated polymeric systems, as well as for understanding the physical properties of such disordered fibers through analogy with theoretical understanding of thermally equilibrated polymeric systems. Mechanical deformation and solvent/surfactant treatments lead to interesting variation in these structures. Comparison of optical micrographs with scattering gives a simple analogy for polymer structure in the solution or melt state.

Beaucage, Gregory; Sukumaran, Sathish; Rane, Shrish



Florida Keys  

NASA Technical Reports Server (NTRS)

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



Universal lock and key  

US Patent & Trademark Office Database

A universal lock and key assembly in which the lock is re-keyable and the key is also changeable. The key has a shank portion having a longitudinally extending tooth slot in its top surface. A plurality of teeth have their bottom ends inserted into the tooth slot in any desired sequence to give a predetermined profile to the teeth of the key. The bottom pin cylinder of the lock has mating bottom pins for each of the respective teeth. These are then arranged in a coordinated sequence in the bottom pin cylinder of the lock. The structure of the system allows an individual to change both the configuration of the key and also the mating structure within the lock so it will be operable.



Monoenomycin: A Simplified Trienomycin A Analogue that Manifests Anticancer Activity  

PubMed Central

Macrocyclic natural products are a powerful class of lead-like chemical entities. Despite commonly violating Lipinski’s “rule of 5”, these compounds often demonstrate superior drug-like physicochemical and pharmacokinetic attributes when compared to their acyclic counterparts. However, the elaborate structural architectures of such molecules require rigorous synthetic investigation that complicates analogue development and their application to drug discovery programs. To circumvent these limitations, a conformation-based approach using limited SAR and molecular modeling was implemented to design simplified analogues of trienomycin A, in which the corresponding analogues could be prepared in a succinct manner to rapidly identify essential structural components necessary for biological activity. Trienomycin A is a member of the ansamycin family of natural products that possesses potent anticancer activity. These studies revealed a novel trienomycin A analogue, monoenomycin, which manifests potent anticancer activity.

Brandt, Gary E. L.; Blagg, Brian S. J.



Binding-induced fluorescence of serotonin transporter ligands: A spectroscopic and structural study of 4-(4-(dimethylamino)phenyl)-1-methylpyridinium (APP(+)) and APP(+) analogues.  


The binding-induced fluorescence of 4-(4-(dimethylamino)-phenyl)-1-methylpyridinium (APP(+)) and two new serotonin transporter (SERT)-binding fluorescent analogues, 1-butyl-4-[4-(1-dimethylamino)phenyl]-pyridinium bromide (BPP(+)) and 1-methyl-4-[4-(1-piperidinyl)phenyl]-pyridinium (PPP(+)), has been investigated. Optical spectroscopy reveals that these probes are highly sensitive to their chemical microenvironment, responding to variations in polarity with changes in transition energies and responding to changes in viscosity or rotational freedom with emission enhancements. Molecular docking calculations reveal that the probes are able to access the nonpolar and conformationally restrictive binding pocket of SERT. As a result, the probes exhibit previously not identified binding-induced turn-on emission that is spectroscopically distinct from dyes that have accumulated intracellularly. Thus, binding and transport dynamics of SERT ligands can be resolved both spatially and spectroscopically. PMID:24460204

Wilson, James N; Ladefoged, Lucy Kate; Babinchak, W Michael; Schiøtt, Birgit



Polyamine analogues modulate gene expression by inhibiting Lysine-Specific Demethylase 1 (LSD1) and altering chromatin structure in human breast cancer cells  

PubMed Central

Aberrant epigenetic repression of gene expression has been implicated in most cancers, including breast cancer. The nuclear amine oxidase, lysine-specific demethylase 1 (LSD1) has the ability to broadly repress gene expression by removing the activating mono- and di-methylation marks at the lysine 4 residue of histone 3 (H3K4me1 & me2). Additionally, LSD1 is highly expressed in estrogen receptor ? negative (ER?) breast cancer cells. Since epigenetic marks are reversible, they make attractive therapeutic targets. Here we examine the effects of polyamine analogue inhibitors of LSD1 on gene expression, with the goal of targeting LSD1 as a therapeutic modality in the treatment of breast cancer. Exposure of the ER-negative human breast cancer cells, MDA-MB-231, to the LSD1 inhibitors, 2d or PG11144, significantly increases global H3K4me1 and H3K4me2, and alters gene expression. Array analysis indicated that 98 (75 up and 23 down) and 477 (237 up and 240 down) genes changed expression by at least 1.5-fold or greater after treatment with 2d and PG11144, respectively. The expression of twelve up-regulated genes by 2d and fourteen up-regulated genes by PG11144 was validated by quantitative RT-PCR. Quantitative chromatin immunoprecipitation (ChIP) analysis demonstrated that up-regulated gene expression by polyamine analogues is associated with increase of the active histone marks H3K4me1, H3K4me2 and H3K9ac, and decrease of the repressive histone marks H3K9me2 and H3K27me3, in the promoter regions of the relevant target genes. These data indicate that the pharmacologic inhibition of LSD1 can effectively alter gene expression and that this therapeutic strategy has potential.

Zhu, Qingsong; Huang, Yi; Marton, Laurence J.; Woster, Patrick M.; Davidson, Nancy E.; Casero, Robert A.



Key Nutrients.  

ERIC Educational Resources Information Center

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…

Federal Extension Service (USDA), Washington, DC.


Novel analogues of the therapeutic complement inhibitor compstatin with significantly improved affinity and potency1  

PubMed Central

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-NH2) displayed a 1,000-fold increase in both potency (IC50=62 nM) and binding affinity for C3b (KD=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.

Qu, Hongchang; Magotti, Paola; Ricklin, Daniel; Wu, Emilia L.; Kourtzelis, Ioannis; Wu, You-Qiang; Kaznessis, Yiannis N.; Lambris, John D.



NASA/ESMD Analogue Mission Plans  

NASA Technical Reports Server (NTRS)

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.

Hoffman, Stephen J.



From Key to Shining Key.  

ERIC Educational Resources Information Center

Develops a "living map" project that introduces the topology and climate of the Florida Keys through the use of creative, dramatic movement. Explains that gifted second and third grade students become parts of the environment on a large, topographical floor map. Describes materials, objectives, and procedures. (DB)

James, Sally



Complexes of an anionic gallium(I) N-heterocyclic carbene analogue with group 14 element(II) fragments: synthetic, structural and theoretical studies.  


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

Green, Shaun P; Jones, Cameron; Lippert, Kai-Alexander; Mills, David P; Stasch, Andreas



Pharmacological properties of thalidomide and its analogues.  


Thalidomide and its immunomodulatory imide drugs (IMiDs) analogues CC-5013 (Revlimid, Lenalidomide) and CC-4047 (Actimid, Pomalidomide) have been used as anti-inflammatory and anticancerous drugs in the recent years. Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor-alpha (TNF-alpha), interleukins (IL) 1-beta, 6, 12, and granulocyte macrophage-colony stimulating factor (GM-CSF). They also costimulate primary human T, NKT and NK lymphocytes inducing their proliferation, cytokine production, and cytotoxic activity. On the other hand, the compounds are anti-angiogenic, anti-proliferative, and pro-apoptotic. Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment. In this review, we explore the current trend of the different structures, the new patents, and the possible new applications in different pathologies. PMID:20307255

De Sanctis, Juan B; Mijares, Michael; Suárez, Alírica; Compagnone, Reinaldo; Garmendia, Jenny; Moreno, Dolores; Salazar-Bookaman, Margarita



Chance Discovery in Credit Risk Management: Estimation of Chain Reaction Bankruptcy Structure by Directed KeyGraph  

Microsoft Academic Search

Credit risk management based on portfolio theory becomes popular in recent Japanese financial industry. But consideration\\u000a and modeling of chain reaction bankruptcy effect in credit portfolio analysis leave much room for improvement. That is mainly\\u000a because method for grasping relations among companies with limited data is underdeveloped. In this article, chance discovery\\u000a method with directed KeyGraph is applied to estimate

Shinichi Goda; Yukio Ohsawa



Ultradeep Pyrosequencing and Molecular Modeling Identify Key Structural Features of Hepatitis B Virus RNase H, a Putative Target for Antiviral Intervention  

PubMed Central

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.

Hayer, Juliette; Rodriguez, Christophe; Germanidis, Georgios; Deleage, Gilbert; Zoulim, Fabien; Pawlotsky, Jean-Michel



Inhibition of ATP Synthase by Chlorinated Adenosine Analogue  

PubMed Central

8-Chloroadenosine (8-Cl-Ado) is a ribonucleoside analogue that is currently in clinical trial for chronic lymphocytic leukemia. Based on the decline in cellular ATP pool following 8-Cl-Ado treatment, we hypothesized that 8-Cl-ADP and 8-Cl-ATP may interfere with ATP synthase, a key enzyme in ATP production. Mitochondrial ATP synthase is composed of two major parts; FO intermembrane base and F1 domain, containing ? and ? subunits. Crystal structures of both ? and ? subunits that bind to the substrate, ADP, are known in tight binding (?dp?dp) and loose binding (?tp?tp) states. Molecular docking demonstrated that 8-Cl-ADP/8-Cl-ATP occupied similar binding modes as ADP/ATP in the tight and loose binding sites of ATP synthase, respectively, suggesting that the chlorinated nucleotide metabolites may be functional substrates and inhibitors of the enzyme. The computational predictions were consistent with our whole cell biochemical results. Oligomycin, an established pharmacological inhibitor of ATP synthase, decreased both ATP and 8-Cl-ATP formation from exogenous substrates, however, did not affect pyrimidine nucleoside analogue triphosphate accumulation. Synthesis of ATP from ADP was inhibited in cells loaded with 8-Cl-ATP. These biochemical studies are in consent with the computational modeling; in the ?tp?tp state 8-Cl-ATP occupies similar binding as ANP, a non-hydrolyzable ATP mimic that is a known inhibitor. Similarly, in the substrate binding site (?dp?dp) 8-Cl-ATP occupies a similar position as ATP mimic ADP-BeF3 ?. Collectively, our current work suggests that 8-Cl-ADP may serve as a substrate and the 8-Cl-ATP may be an inhibitor of ATP synthase.

Chen, Lisa S.; Nowak, Billie J.; Ayres, Mary L.; Krett, Nancy L.; Rosen, Steven T.; Zhang, Shuxing; Gandhi, Varsha



Identifying Key Structural Features and Spatial Relationships in Archean Microbialites Using 2D and 3D Visualization Methods  

NASA Astrophysics Data System (ADS)

Microbialites in the 2521 ± 3 Ma Gamohaan Formation, South Africa, have several different end-member morphologies which show distinct growth structures and spatial relationships. We characterized several growth structures and spatial relationships in two samples (DK20 and 2_06) using a combination of 2D and 3D analytical techniques. There are two main goals in studying complicated microbialites with a combination of 2D and 3D methods. First, one can better understand microbialite growth by identifying important structures and structural relationships. Once structures are identified, the order in which the structures formed and how they are related can be inferred from observations of crosscutting relationships. Second, it is important to use both 2D and 3D methods to correlate 3D observations with those in 2D that are more common in the field. Combining analysis provides significantly more insight into the 3D morphology of microbial structures. In our studies, 2D analysis consisted of describing polished slabs and serial sections created by grinding down the rock 100 microns at a time. 3D analysis was performed on serial sections visualized in 3D using Vrui and 3DVisualizer software developed at KeckCAVES, UCD ( Data were visualized on a laptop and in an immersive cave system. Both samples contain microbial laminae and more vertically orients microbial "walls" called supports. The relationships between these features created voids now filled with herringbone and blocky calcite crystals. DK20, a classic plumose structure, contains two types of support structures. Both are 1st order structures (1st order structures with organic inclusions and 1st without organic inclusions) interpreted as planar features based on 2D analysis. In the 2D analysis the 1st order structures show v branching relationships as well as single cuspate relationships (two 1st order structures with inclusions merging upward), and single tented relationships (three supports merging upward). 2_06. a classic cuspate microbialite, shows five types of structural features in 2D: vertical supports, draped laminae, connecting laminae, condensed mat, and condensed draped laminae, all of which were interpreted planar features in 3D. These features show cuspate relationships, tented relationships, rolled /curled mat, and connecting laminae. For 3D analysis of both samples, data are rendered so that the void-filling calcite was transparent and only the microbial features are visible. Structures identified in sample DK20 during 2D analysis where confirmed as planar features during 3D analysis. 3D analysis revealed two new structures: a mound with very abundant inclusions and a linear feature found between the inclusion-rich mound and 1st order structures. Most of the structures identified in sample 2_06 during 2D analysis were confirmed during 3D analysis. The exception are connecting laminae structures which yet to be identified in three-dimensions due to their complicated structure. The analysis of 2_06 in 3D led to the observation that structures originally identified as planar features in 2D are not planar in 3D, although they are continuous. Thus, using both 2D or 3D analysis of 3D structures provides substantially more insight into the true morphology of the microbialites.

Stevens, E. W.; Sumner, D. Y.



Imidazopyridazines as potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1): Preparation and evaluation of pyrazole linked analogues?  

PubMed Central

The structural diversity and SAR in a series of imidazopyridazine inhibitors of Plasmodium falciparum calcium dependent protein kinase 1 (PfCDPK1) has been explored and extended. The opportunity to further improve key ADME parameters by means of lowering log D was identified, and this was achieved by replacement of a six-membered (hetero)aromatic linker with a pyrazole. A short SAR study has delivered key examples with useful in vitro activity and ADME profiles, good selectivity against a human kinase panel and improved levels of lipophilic ligand efficiency. These new analogues thus provide a credible additional route to further development of the series.

Large, Jonathan M.; Osborne, Simon A.; Smiljanic-Hurley, Ela; Ansell, Keith H.; Jones, Hayley M.; Taylor, Debra L.; Clough, Barbara; Green, Judith L.; Holder, Anthony A.



Stimulation of inositol 1,4,5-trisphosphate (IP3) receptor subtypes by analogues of IP3.  


Most animal cells express mixtures of the three subtypes of inositol 1,4,5-trisphosphate receptor (IP(3)R) encoded by vertebrate genomes. Activation of each subtype by different agonists has not hitherto been examined in cells expressing defined homogenous populations of IP(3)R. Here we measure Ca(2+) release evoked by synthetic analogues of IP(3) using a Ca(2+) indicator within the lumen of the endoplasmic reticulum of permeabilized DT40 cells stably expressing single subtypes of mammalian IP(3)R. Phosphorylation of (1,4,5)IP(3) to (1,3,4,5)IP(4) reduced potency by ~100-fold. Relative to (1,4,5)IP(3), the potencies of IP(3) analogues modified at the 1-position (malachite green (1,4,5)IP(3)), 2-position (2-deoxy(1,4,5)IP(3)) or 3-position (3-deoxy(1,4,5)IP(3), (1,3,4,5)IP(4)) were similar for each IP(3)R subtype. The potency of an analogue, (1,4,6)IP(3), in which the orientations of the 2- and 3-hydroxyl groups were inverted, was also reduced similarly for all three IP(3)R subtypes. Most analogues of IP(3) interact similarly with the three IP(3)R subtypes, but the decrease in potency accompanying removal of the 1-phosphate from (1,4,5)IP(3) was least for IP(3)R3. Addition of a large chromophore (malachite green) to the 1-phosphate of (1,4,5)IP(3) only modestly reduced potency suggesting that similar analogues could be used to measure (1,4,5)IP(3) binding optically. These data provide the first structure-activity analyses of key IP(3) analogues using homogenous populations of each mammalian IP(3)R subtype. They demonstrate broadly similar structure-activity relationships for all mammalian IP(3)R subtypes and establish the potential utility of (1,4,5)IP(3) analogues with chromophores attached to the 1-position. PMID:23372785

Saleem, Huma; Tovey, Stephen C; Rahman, Taufiq; Riley, Andrew M; Potter, Barry V L; Taylor, Colin W



Molecular dynamics simulations reveal insight into key structural elements of aaptamines as sortase inhibitors with free energy calculations  

NASA Astrophysics Data System (ADS)

Aaptamine (AAP), demethylaaptamine (DAP), isoaaptamine (IAP) and demethyloxyaaptamine (OAP) are known as selective inhibitors of sortase A (SrtA). The energy decomposition analysis indicates that the interactions between the hydroxyl at C-9 of IAP and Glu44 and between the methyl group at the N-1 of IAP and Gly131 are responsible for inhibition and higher potency. The binding energy difference of SrtA-inhibitors contributes to the difference of the IC50 values of inhibitors. These results imply that hydroxyl at C-9 and the methyl group at the N-1 of aaptamine play a key role in the stabilization of the binding of SrtA-inhibitors.

Lv, Zhuo; Wang, Hong S.; Niu, Xiao D.



Key Molecular Structure Determination of Photoalignment Materials from the Effects of Linearly Polarized Deep UV Light on Several Polymers  

NASA Astrophysics Data System (ADS)

We studied the photoalignment of nematic liquid crystals by examining polyimide, polyester, polystyrene, polyvinylalcohol (PVA), and polymethylmethacrylate (PMMA) exposed to linearly polarized deep UV (LPDUV) light. Polystyrene aligned the liquid crystal parallel to its LPDUV polarization axis, while polyimide and polyester aligned the liquid crystal perpendicular to the polarization axis. Polyimide and polyester exhibited order parameter peaks for small dosages of LPDUV@. PVA and PMMA did not align the liquid crystal. The presence of a phenyl ring is a key to the decomposition-type photoalignment, whose alignment direction depends on the position of the phenyl ring.

Hasegawa, Masaki



Desferrithiocin Analogues and Nephrotoxicity  

PubMed Central

The syntheses of a series of 4?-O-alkylated (S)-4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid and 5?-O-alkylated (S)-4,5-dihydro-2-(2,5-dihydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid ligands are described. Their partition between octanol and water, logPapp, is determined, along with their iron-clearing efficiency (ICE) in both non-iron-overloaded, bile duct-cannulated rodents and in iron-overloaded primates. The ligand-promoted biliary ferrokinetics in rats are described for each of the chelators. Plots of logPapp versus ICE in a rodent model for both the 4?-O-alkylated-2,4-dihydroxy and 5?-O-alkylated-2,5-dihydroxy series produced an inverse parabola plot with r2 values of 0.97 and 0.81, respectively. The plots indicate an optimum logPapp/ICE relationship. Because of the nature of the data spread in the 4?-O-alkylated 2,4-dihydroxy series, it will be used to help assess the origin of nephrotoxicity in desferrithiocin analogues: is toxicity simply related to lipophilicity, ICE, or a combination of these properties?

Bergeron, Raymond J.; Wiegand, Jan; McManis, James S.; Bharti, Neelam; Singh, Shailendra



Antimicrobial activity of resveratrol analogues.  


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

Chalal, Malik; Klinguer, Agnès; Echairi, Abdelwahad; Meunier, Philippe; Vervandier-Fasseur, Dominique; Adrian, Marielle



Structural comparison between retro-inverso and parent peptides: molecular basis for the biological activity of a retro-inverso analogue of the immunodominant fragment of VP1 coat protein from foot-and-mouth disease virus.  


Antibodies induced against intact foot-and-mouth disease Virus (FMDV) particles bind to the retro-inverso analogue of fragment 141-159 of the viral coat protein VP1 of FMDV, variant A, equally well as to the parent peptide. A conformational investigation of this retro-inverso peptide was carried out by nmr spectroscopy and restrained molecular modeling in order to identify the structural basis for the antigenic mimicry between these retro-inverso and parent peptides. In 100% trifluoroethanol a well-defined left-handed alpha-helical region exists from residue 150 to residue 159, which is consistently present in all conformational families obtained from restrained modelling. A less-defined left-handed helical region is present in the tract 144-148, which is also consistent for all structures. Conformational flexibility exists about Gly149, which leads to two types of structures, either bent or linear. In the bent structures, a three-residue inverse tight turn is found, which can be classified as an inverse gamma-turn centered at Gly149. The overall structural features of the retro-inverso peptide are shown to be similar to those of the parent L-peptide. The two molecules, however, are roughly mirror images because they share inherently chiral secondary structure elements. By comparing these conformational conclusions with the x-ray structure of the Fab complex of a corresponding VP1 antigenic fragment, a rationale is proposed to account for the topological requirements of specific recognition that are implied by the equivalent antigenic activity of the natural and retro-inverso compounds. PMID:9095678

Carver, J A; Esposito, G; Viglino, P; Fogolari, F; Guichard, G; Briand, J P; Van Regenmortel, M H; Brown, F; Mascagni, P



Thymidine analogues for tracking DNA synthesis.  


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

Cavanagh, Brenton L; Walker, Tom; Norazit, Anwar; Meedeniya, Adrian C B



Elucidating diphosphoinositol polyphosphate function with nonhydrolyzable analogues.  


The diphosphoinositol polyphosphates (PP-IPs) represent a novel class of high-energy phosphate-containing messengers which control a wide variety of cellular processes. It is thought that PP-IPs exert their pleiotropic effects as allosteric regulators and through pyrophosphorylation of protein substrates. However, most details of PP-IP signaling have remained elusive because of a paucity of suitable tools. We describe the synthesis of PP-IP bisphosphonate analogues (PCP-IPs), which are resistant to chemical and biochemical degradation. While the two regioisomers 1PCP-IP5 and 5PCP-IP5 inhibited Akt phosphorylation with similar potencies, 1PCP-IP5 was much more effective at inhibiting its cognate phosphatase hDIPP1. Furthermore, the PCP analogues inhibit protein pyrophosphorylation because of their inability to transfer the ?-phosphoryl group, and thus enable the distinction between PP-IP signaling mechanisms. As such, the PCP analogues will find widespread applications for the structural and biochemical characterization of PP-IP signaling properties. PMID:24888434

Wu, Mingxuan; Chong, Lucy S; Capolicchio, Samanta; Jessen, Henning J; Resnick, Adam C; Fiedler, Dorothea



Rigor-like structures from muscle myosins reveal key mechanical elements in the transduction pathways of this allosteric motor.  


Unlike processive cellular motors such as myosin V, whose structure has recently been determined in a "rigor-like" conformation, myosin II from contracting muscle filaments necessarily spends most of its time detached from actin. By using squid and sea scallop sources, however, we have now obtained similar rigor-like atomic structures for muscle myosin heads (S1). The significance of the hallmark closed actin-binding cleft in these crystal structures is supported here by actin/S1-binding studies. These structures reveal how different duty ratios, and hence cellular functions, of the myosin isoforms may be accounted for, in part, on the basis of detailed differences in interdomain contacts. Moreover, the rigor-like position of switch II turns out to be unique for myosin V. The overall arrangements of subdomains in the motor are relatively conserved in each of the known contractile states, and we explore qualitatively the energetics of these states. PMID:17502101

Yang, Yuting; Gourinath, S; Kovács, Mihály; Nyitray, László; Reutzel, Robbie; Himmel, Daniel M; O'Neall-Hennessey, Elizabeth; Reshetnikova, Ludmilla; Szent-Györgyi, Andrew G; Brown, Jerry H; Cohen, Carolyn



Ligand scaffold optimization of a supramolecular hydrogenation catalyst: Analyzing the influence of key structural subunits on reactivity and selectivity  

PubMed Central

Results are reported for the catalytic asymmetric hydrogenation of two prototypical substrates with a series of more than 150 closely related supramolecular catalysts differing in only their ligand/catalyst scaffold. These modular catalysts are constructed from four subunits and vary widely in their reactivity (no reaction to quantitative yield) and enantioselectivity (racemic to 96% ee). Analysis of the ligand/catalyst scaffold optimization data reveals how each subunit contributes to the effectiveness of the modular supramolecular catalyst. The results suggest that a balance between key elements of rigidity and flexibility is required for the successful catalysts and, moreover, that this balance is required to enable effective fine-tuning via catalyst scaffold optimization.

Thacker, Nathan C.; Moteki, Shin A.; Takacs, James M.



Total synthesis and antiplasmodial activity of pohlianin C and analogues.  


The first synthesis of the glycine-rich cyclic octapeptide pohlianin C is reported, confirming the structure of this natural product. Screening against Plasmodium falciparum reveals moderate antiplasmodial activity, consistent with data obtained from the natural sample. In addition, the synthesis of three analogues reveals that the antiplasmodial activity of pohlianin C can be preserved or increased with simplified structures. PMID:24813731

Lawer, Aggie; Tai, Jonathan; Jolliffe, Katrina A; Fletcher, Sabine; Avery, Vicky M; Hunter, Luke



Solvent/solute Interactions Probed by Picosecond Transient Raman Spectroscopy: a Study of S(1) 1,4-DIPHENYL -1,3-BUTADIENE and its Structural Analogues  

NASA Astrophysics Data System (ADS)

Many important chemical/biochemical reactions involve a short-lived photochemical intermediate. From a practical standpoint, understanding the behavior of such a transient species would allow effective manipulation of many chemical and biochemical processes. In this study, Raman spectroscopy on a picosecond time scale is used to examine the character of the S_1 states of several simple probe molecules and the effect(s) that different solvents have on the behavior of the excited state species in solution. We present the S_1 Raman spectra of 1,4-diphenyl-1,3-butadiene (DPB) in the series of linear alkanes pentane, hexane, heptane, octane, decane, and dodecane. DPB has virtually degenerate electronic states in the vicinity of S_1 (2 ^1A_{rm g} and 1^1B _{rm u}). The electronic state probed by the transient Raman measurements exhibits both 2^1A_{ rm g} and 1^1B _{rm u} character (i.e. a "mixed" state). It appears that a state exhibiting more 2^1A_{ rm g} character is favored by more viscous solvents while a state of significant 1^1 B_{rm u} character is preferred by less viscous solvents. We also observe very broad features (>50 cm ^{-1}) in the S_1 Raman spectra that are associated with motions of the butadiene portion of the molecule. In order to verify that these broad bands arise from a distribution of s-trans conformers in DPB, we have obtained the transient Raman spectra of 1,4-diphenyl-1,3 - cyclopentadiene (DPCP), a "stiff" analogue of DPB. As predicted, the DPCP spectra contain only sharp bands. We also provide evidence for assigning the lowest excited singlet state of DPCP in solution as the 1B state. We evaluate the effect of geometrical constraints on the photophysics of DPCP by obtaining the S _1 Raman spectra of 1,2,3,4-tetraphenyl-1,3 -cyclopentadiene (TPCP) in solution. The addition of the extra phenyl rings to DPCP forces the molecule to take on a non-planar geometry. We confirm that the viscosity -dependent S_1 lifetime of TPCP is due to a photocyclization reaction.

Morris, Daniel Lamon, Jr.



A Model of Interaction between Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Apocynin Analogues by Docking Method  

PubMed Central

Some apocynin analogues have exhibited outstanding inhibition to NADPH oxidase. In this study, the key interactions between apocynin analogues and NADPH oxidase were analyzed by the docking method. The potential active site was first identified by the SiteID program combining with the key residue CYS378. Afterwards, the compounds in the training set were docked into NADPH oxidase (1K4U) under specific docking constraints to discuss the key interactions between ligands and the receptor. These key interactions were then validated by the consistence between the docking result and the experimental result of the test set. The result reveals that the Pi interaction between apocynin analogues and NADPH oxidase has a direct contribution to inhibition activities, except for H-bond formation and docking score. The key interactions might be valuable to discover and screen apocynin analogues as potent inhibitors of NADPH oxidase.

Jiang, Jie; Kang, Hongjun; Song, Xiaoliang; Huang, Sichao; Li, Sha; Xu, Jun



Boronyls as Key Structural Units in Boron Oxide Clusters: B(BO)2- and B(BO)3-  

SciTech Connect

BO- is isoelectronic with CN-.1 However, in comparison to CN-, which is an important ligand in inorganic and biomolecules, the chemistry of BO- is relatively unknown. The electron affinity (EA) of BO (2.51 eV)2,3 is much smaller than that of CN (3.86 eV),4 which may explain the fact that CN- is a stable anion in solution, but BO- is not. However, the electronic structure and bond strength of BO- are similar to those of CN-, suggesting that it may be a robust chemical unit and can retain its structural integrity in chemical compounds. In a recent study, we indeed found that BO behaves like a monovalent structural unit in its bonding to Au in AunBO- (n ) 1-3) clusters.5 Theoretical calculations also suggested that carbon boronyls (CBO)n (n ) 3-7) are stable species on the potential-energy surfaces.6 Here we report a photoelectron spectroscopy (PES) and theoretical study on two boron oxide clusters, B3O2 - and B4O3 -, which are shown to possess a D¥h (3ªg) linear and D3h (2A2¢¢) triangular structure, respectively, and can be viewed as two and three boronyl groups bonded to a single B atom.

Zhai, Hua Jin; Li, Si-Dian; Wang, Lai S.



Hippocampal Structure and Human Cognition: Key Role of Spatial Processing and Evidence Supporting the Efficiency Hypothesis in Females  

ERIC Educational Resources Information Center

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…

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.



Crystal structures of ?-glutamyltranspeptidase from Escherichia coli, a key enzyme in glutathione metabolism, and its reaction intermediate  

PubMed Central

?-Glutamyltranspeptidase (GGT) is a heterodimic enzyme that is generated from the precursor protein through posttranslational processing and catalyzes the hydrolysis of ?-glutamyl bonds in ?-glutamyl compounds such as glutathione and/or the transfer of the ?-glutamyl group to other amino acids and peptides. We have determined the crystal structure of GGT from Escherichia coli K-12 at 1.95 Å resolution. GGT has a stacked ???? fold comprising the large and small subunits, similar to the folds seen in members of the N-terminal nucleophile hydrolase superfamily. The active site Thr-391, the N-terminal residue of the small subunit, is located in the groove, from which the pocket for ?-glutamyl moiety binding follows. We have further determined the structure of the ?-glutamyl-enzyme intermediate trapped by flash cooling the GGT crystal soaked in glutathione solution and the structure of GGT in complex with l-glutamate. These structures revealed how the ?-glutamyl moiety and l-glutamate are recognized by the enzyme. A water molecule was seen on the carbonyl carbon of the ?-glutamyl-Thr-391 O? bond in the intermediate that is to be hydrolyzed. Notably the residues essential for GGT activity (Arg-114, Asp-433, Ser-462, and Ser-463 in E. coli GGT) shown by site-directed mutagenesis of human GGT are all involved in the binding of the ?-glutamyl moiety. The structure of E. coli GGT presented here, together with sequence alignment of GGTs, may be applicable to interpret the biochemical and genetic data of other GGTs.

Okada, Toshihiro; Suzuki, Hideyuki; Wada, Kei; Kumagai, Hidehiko; Fukuyama, Keiichi



Understanding complex structures in fold-and-thrust belts. Integration of geometric and growth strata analyses, paleomagnetism, AMS and analogue models in the Western termination of the Southern Pyrenees  

NASA Astrophysics Data System (ADS)

Classic 2D approaches have helped the understanding of the geometry and kinematics of fold-and-thrust belts belts (FAT belts) but are insufficient to unravel many natural cases. This is because deformation is 3D from the geometric point of view and, thus, cylindrical features may be considered as a simplification. On the other hand, deformation kinematics is usually complex, diachronic and poliphasic in real cases. Therefore, FAT belts have to be always considered in 4D. In this sense, the Southern Pyrenees is a perfect location to study the evolution of FAT belts because of the exceptional outcropping conditions of growth strata, the proven diachronic kinematics and the non-coaxial interference of deformation events. Within the vast catalogue of complex structures that includes superposed folding, conical and plunging folds, oblique thrust ramps, etc here, we have selected the westernmost termination of the South Pyrenean sole thrust to illustrate how the integration of geometric and kinematic analysis can help unraveling complex structures in FAT belts. The San Marzal pericline (4 km2 surface extension) is the lateral termination of the Sto. Domingo deca-kilometric fold. San Marzal looks like a large 70° plunging cylindrical structure. However the large magnitude (? 60-70°) of vertical axis rotations accommodated between its flanks cannot be explained without a conical geometry. In this work we will show how the structural analysis performed on this structure has disentangled its complex geometry. This analyses comprises several hundreds of bedding data, joints and veins and more than 150 standard paleomagnetic and AMS sites. Besides, we will show how the kinematic information derived from magnetostratigraphic sections (more than 8 km of sampled profiles) has helped to constraint the folding and rotation ages and velocities. Finally, all these complex geometric and kinematic features have inspired us to build an analogue model where we can explore the 3D distribution of strain ellipsoids.

Pueyo, Emilio L.; Sánchez, Elisa; Oliva-Urcia, Belén; José Ramón, Ma



Crystal Structures of the Lumazine Protein from Photobacterium kishitanii in Complexes with the Authentic Chromophore, 6,7-Dimethyl- 8-(1?-d-Ribityl) Lumazine, and Its Analogues, Riboflavin and Flavin Mononucleotide, at High Resolution?  

PubMed Central

Lumazine protein (LumP) is a fluorescent accessory protein having 6,7-dimethyl-8-(1?-d-ribityl) lumazine (DMRL) as its authentic chromophore. It modulates the emission of bacterial luciferase to shorter wavelengths with increasing luminous strength. To obtain structural information on the native structure as well as the interaction with bacterial luciferase, we have determined the crystal structures of LumP from Photobacterium kishitanii in complexes with DMRL and its analogues, riboflavin (RBF) and flavin mononucleotide (FMN), at resolutions of 2.00, 1.42, and 2.00 Å. LumP consists of two ? barrels that have nearly identical folds, the N-terminal and C-terminal barrels. The structures of LumP in complex with all of the chromophores studied are all essentially identical, except around the chromophores. In all of the structures, the chromophore is tethered to the narrow cavity via many hydrogen bonds in the N-terminal domain. These are absent in the C-terminal domain. Hydrogen bonding in LumP-FMN is decreased in comparison with that in LumP-RBF because the phosphate moiety of FMN protrudes out of the narrow cavity. In LumP-DMRL, the side chain of Gln65 is close to the ring system, and a new water molecule that stabilizes the ligand is observed near Ser48. Therefore, DMRL packs more tightly in the ligand-binding site than RBF or FMN. A docking simulation of bacterial luciferase and LumP suggests that the chromophore is located close enough for direct energy transfer to occur. Moreover, the surface potentials around the ligand-binding sites of LumP and bacterial luciferase exhibit complementary charge distributions, which would have a significant effect on the interaction between LumP and luciferase.

Sato, Yuichi; Shimizu, Satoshi; Ohtaki, Akashi; Noguchi, Keiichi; Miyatake, Hideyuki; Dohmae, Naoshi; Sasaki, Satoshi; Odaka, Masafumi; Yohda, Masafumi



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.  


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 PPAR?, NF?B, 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

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



Water is a key factor to alter the structure and electrochemical properties of carboxylate-bridged dimanganese(ii) complexes.  


The synthesis and physical properties of dimanganese(ii) compounds with varying numbers of water ligands housed in the four bulky carboxylate motifs, including the first complex with a parallelogram core {Mn2(?-OH2)2(?-O2CR)}(3+) unit, are described. The isolation of these complexes revealed how water could alter the structural and electrochemical properties of similar carboxylate-bridged dimanganese(ii) cores that may occur in a variety of active sites of Mn-containing metalloenzymes. These studies support the notion that water molecules in coordination spheres of active sites of metalloproteins are not a simple spectator medium but the modulation factor of structures and functions. PMID:24926561

Sivanesan, Dharmalingam; Kannan, Sethuraman; Thangadurai, Thangaian Daniel; Jung, Kwang-Deog; Yoon, Sungho



Growth and structure of pentacene films on graphite: Weak adhesion as a key for epitaxial film growth  

NASA Astrophysics Data System (ADS)

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.

Götzen, Jan; Käfer, Daniel; Wöll, Christof; Witte, Gregor



The Structure of the Flavoprotein Tryptophan-2-Monooxygenase, a Key Enzyme in the Formation of Galls in Plants†  

PubMed Central

The flavoprotein tryptophan 2-monooxygenase catalyzes the oxidative decarboxylation of tryptophan to yield indole-3-acetamide. This is the initial step in the biosynthesis of the plant growth hormone indole-acetic-acid by bacterial pathogens that cause crown gall and related diseases. The structure of the enzyme from Pseudomonas savastanoi has been determined by X-ray diffraction methods to a resolution of 1.95 Å. The overall structure of the protein shows that it has the same fold as the monoamine oxidase family of flavoproteins, with the greatest similarities to the L-amino acid oxidases. The location of bound indole-3-acetamide in the active site enables identification of residues responsible for substrate binding and specificity. Two residues in the enzyme are conserved in all members of the monoamine oxidase family, Lys365 and Trp466. The K365M mutation decreases the kcat and kcat/KTrp values by 60,000 and 2 million-fold, respectively. The deuterium kinetic isotope effect increases to 3.2, consistent with carbon-hydrogen bond cleavage becoming rate-limiting in the mutant enzyme. The W466F mutation decreases the kcat value less than 2-fold and the kcat/KTrp value only 5-fold, while the W466M mutation results in enzyme lacking flavin and detectable activity. This is consistent with a role for Trp466 in maintaining the structure of the flavin binding site in the more conserved FAD domain.

Gaweska, Helena M.; Taylor, Alexander B.; Hart, P. John; Fitzpatrick, Paul F.



Conformationally constrained analogues of 2-arachidonoylglycerol.  


Novel monocyclic analogues of 2-arachidonoylglycerol (2-AG) were designed in order to explore the pharmacophoric conformations of this endocannabinoid ligand at the key cannabinergic proteins. All 2-arachidonoyl esters of 1,2,3-cyclohexanetriol [meso-7 (AM5504), (+/-)-8 (AM5503), and meso-9 (AM5505)] were synthesized by regioselective acylation of 2,3-dihydroxycyclohexanone followed by selective reductions. The optically active isomers (+)-8 (AM4434) and (-)-8 (AM4435) were synthesized from (2S,3S)- and (2R,3R)-2,3-dihydroxycyclohexanone, respectively, via a chemoenzymatic route. These head group constrained and conformationally restricted analogues of 2-AG as well as the 1-keto precursors were evaluated as substrates for the endocannabinoid deactivating hydrolytic enzymes monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH), and also were tested for their affinities for CB1 and CB2 cannabinoid receptors. The observed biochemical differences between these ligands can help define the conformational requirements for 2-AG activity at each of the above endocannabinoid protein targets. PMID:17826996

Vadivel, Subramanian K; Vardarajan, Sundararaman; Duclos, Richard I; Wood, JodiAnne T; Guo, Jianxin; Makriyannis, Alexandros



Structure-activity relationships of novel cyclic alpha-MSH/beta-MSH hybrid analogues that lead to potent and selective ligands for the human MC3R and human MC5R.  


It has been shown by extensive studies that alpha-MSH bioactivity is critically dependent on the core or central tetrapeptide sequence, His-Phe-Arg-Trp, however with poor selectivity for the human MC3R-MC5R. The structure-activity relationships study here is aimed at identifying lead structures or templates of this core sequence by the use of different conformational constraints that might impart changes in its topography and thus promote differences in potency and selectivity at these receptors. Our peptide library consists of a novel series of cyclic alpha-MSH analogues that have disulfide bridges between Cys or Cys-like residues at positions 4 and 10, giving rise to 23-membered rings fused at the C-terminal end with the C-terminal fragment of beta-MSH (Pro-Pro-Lys-Asp). While such constraints of the peptide backbone with disulfide bridges of different chirality affect potency and selectivity at these receptors, further changes in the hydrophobicity at position 7 with either a D-Phe or D-Nal(2') and replacement of a His with a Pro in position 6 cause additional effects. Thus, the most interesting lead compounds that emerged from this study are (1) compound 5, Ac-c[Cys-Glu-His-D-Phe-Arg-Trp-D-Cys]-Pro-Pro-Lys-Asp-NH(2) (IC(50) = 10 nM), which is the first potent and highly selective antagonist ligand for the hMC5R (560-fold vs the MC3R and 1000-fold vs the MC4R); (2) compound 7, Ac-c[Cys-Glu-Pro-D-Nal(2')-Arg-Trp-Cys]-Pro-Pro-Lys-Asp-NH(2) (IC(50) = 31 nM), which is a highly selective antagonist analogue for the MC3R (560-fold vs the hMC4R and about 3000-fold vs the hMC5R; and (3) compound 9, Ac-c[Pen-Glu-His-D-Nal(2')-Arg-Trp-Cys]-Pro-Pro-Lys-Asp-NH(2) (IC(50) = 3 nM), which is more potent than 7 at the MC3R but not as selective. PMID:12904077

Balse-Srinivasan, Preeti; Grieco, Paolo; Cai, Minying; Trivedi, Dev; Hruby, Victor J



Synthesis and characterization of mitoQ and idebenone analogues as mediators of oxygen consumption in mitochondria  

PubMed Central

Analogues of mitoQ and idebenone were synthesized to define the structural elements that support oxygen consumption in the mitochondrial respiratory chain. Eight analogues were prepared and fully characterized, then evaluated for their ability to support oxygen consumption in the mitochondrial respiratory chain. While oxygen consumption was strongly inhibited by mitoQ analogues 2–4 in a chain length-dependent manner, modification of idebenone by replacement of the quinone methoxy groups by methyl groups (analogues 6 – 8) reduced, but did not eliminate, oxygen consumption. Idebenone analogues 6 – 8 also displayed significant cytoprotective properties toward cultured mammalian cells in which glutathione had been depleted by treatment with diethyl maleate.

Duveau, Damien Y.; Arce, Pablo M.; Schoenfeld, Robert A.; Raghav, Nidhi; Cortopassi, Gino A.; Hecht, Sidney M.



Crystal Structure Analysis of Human Glutamine : Fructose 6-Phosphate Amidotransferase, a Key Regulator in Type 2 Diabetes  

NASA Astrophysics Data System (ADS)

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.

Nakaishi, Yuichiro; Bando, Masahiko


Five key turning points in the American space industry in the past 20 years: Structure, innovation, and globalization shifts in the space sector  

NASA Astrophysics Data System (ADS)

Though unremarkable to some, the 1990s and 2000s saw important events and changes in the U.S. space sector. These changes were by no means preemptive but rather reactions to key events. This paper studies five moments over the two decades that have shaped the American space industry significantly. The author explains how these events have affected change and indicated shifting trends. The shifts examined are those in the American space industry's structure as well as its approach to innovation and to the globalization of the space sector.

Cornell, Ariane



Stepwise Organization of the ?-Structure Identifies Key Regions Essential for the Propagation and Cytotoxicity of Insulin Amyloid Fibrils.  


Amyloid fibrils are supramolecular assemblies, the deposition of which is associated with many serious diseases including Alzheimer, prion, and Huntington diseases. Several smaller aggregates such as oligomers and protofibrils have been proposed to play a role in early stages of the fibrillation process; however, little is known about how these species contribute to the formation of mature amyloid fibrils with a rigid cross-? structure. Here, we identified a new pathway for the formation of insulin amyloid fibrils at a high concentration of salt in which mature fibrils were formed in a stepwise manner via a prefibrillar intermediate: minute prefibrillar species initially accumulated, followed by the subsequent formation of thicker amyloid fibrils. Fourier transform infrared spectra suggested the sequential formation of two types of ?-sheets with different strength hydrogen bonds, one of which was developed concomitantly with the mutual assembly of the prefibrillar intermediate to form mature fibrils. Interestingly, fibril propagation and cellular toxicity appeared only after the later step of structural organization, and a comparison of ?-sheet regions between the prefibrillar intermediate and mature fibrils using proteolysis led to the proposal of specific regions essential for manifestation of these properties. PMID:24569992

Chatani, Eri; Imamura, Hiroshi; Yamamoto, Naoki; Kato, Minoru



Key microstructures controlling the mechanical properties of two-phase TiAl alloys with lamellar structures  

SciTech Connect

TiAl alloys with the base composition of Ti-47Al-2Cr-2Nb (at.%) were prepared by arc melting and drop casting, followed by hot extrusion above the {alpha}-transus temperature, T{sub {alpha}}. The hot extruded materials were then heat treated above and below T{sub {alpha}} in order to control microstructural features in these lamellar structures. Mechanical properties of these alloys were determined by tensile testing at temperatures to 1000 C. Tensile elongation at room temperature (RT) is strongly dependent on grain size, showing increased ductility with decreasing grain size. Strength at RT and elevated temperatures is sensitive to interlamellar spacing, showing increased strength with decreasing lamellar spacing. Hall-Petch relations hold well for yield strength at RT and elevated temperatures and for tensile elongation at RT. Tensile elongations of about 5% and yield strengths around 900 MPa are achieved by controlling both colony size and interlamellar spacing. Mechanical properties of the TiAl alloys with controlled lamellar structures produced directly by hot extrusion are much superior to those produced by conventional thermomechanical treatments.

Liu, C.T.; Maziasz, P.J.; Wright, J.L.



Design and synthesis of paracaseolide A analogues as selective protein tyrosine phosphatase 1B inhibitors.  


A series of structurally related analogues of the natural product paracaseolide A were synthesized and identified as potent PTP1B inhibitors. Among these analogues, compound 10 in particular showed improved PTP1B enzyme inhibitory activity, high selectivity for PTP1B over TC-PTP, and improved cellular effects. PMID:24752625

Yin, Jian-Peng; Tang, Chun-Lan; Gao, Li-Xin; Ma, Wei-Ping; Li, Jing-Ya; Li, Ying; Li, Jia; Nan, Fa-Jun



Optical properties of porphyrin analogues for solar cells: An NLO approach  

Microsoft Academic Search

The geometries, electronic structures, and optical properties of various ?-substituted Zn tetraarylporphyrin analogues were studied using density functional theory (DFT). Major differences in geometry and electronic properties were observed as a function of the acceptor moiety. Analogues containing cyanoacrylic acid had longer Zn–N21 bonds, narrower band gaps, and more stabilized energy levels than their methylenemalonic counterparts. Nonlinear optical (NLO) properties

Mannix P. Balanay; Dong Hee Kim



New Insight into the Transcarbamylase Family: The Structure of Putrescine Transcarbamylase, a Key Catalyst for Fermentative Utilization of Agmatine  

PubMed Central

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 ?-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.

Polo, Luis Mariano; Gil-Ortiz, Fernando; Cantin, Angel; Rubio, Vicente



Hydrocode modeling of the largest impact crater on Lutetia, a key to the inner structure of the asteroid  

NASA Astrophysics Data System (ADS)

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.

Oklay, N.; Vincent, J.-B.; Sierks, H.; Wünnemann, K.; Elbeshausen, D.



FD-891, a structural analogue of concanamycin A that does not affect vacuolar acidification or perforin activity, yet potently prevents cytotoxic T lymphocyte-mediated cytotoxicity through the blockage of conjugate formation  

PubMed Central

FD-891 belongs to a group of 18-membered macrolides, and is a structural analogue of a specific inhibitor of vacuolar type H+-ATPase, concanamycin A (CMA). In our previous work, we have shown that CMA specifically inhibits perforin-dependent cytotoxic T lymphocyte (CTL)-mediated cytotoxicity through the degradation and inactivation of perforin, although CMA does not affect Fas ligand (FasL)-dependent cytotoxicity. Here, we show that FD-891 potently prevents not only perforin-dependent but also FasL-dependent CTL-mediated killing pathways by blocking CTL–target conjugate formation. In contrast to CMA, FD-891 was unable to inhibit vacuolar acidification and only slightly decreased the perforin activity in lytic granules. FD-891 blocked granule exocytosis in response to anti-CD3, mainly owing to the lack of CTL binding to immobilized anti-CD3. The conjugate formation was markedly inhibited only when effector cells were pretreated with FD-891. Consistent with these observations, fluorescence-activated cell sorter (FACS) analysis for cell surface receptors revealed that FD-891 significantly reduced the expression of the T-cell receptor (TCR)/CD3 complex. These data suggest that the blockage of conjugate formation and subsequent target cell killing might be at least partly owing to FD-891-induced down-regulation of the TCR/CD3 complex.

Kataoka, T; Yamada, A; Bando, M; Honma, T; Mizoue, K; Nagai, K



[Effect of vitamin B1 structural analogue 3-decyloxycarbonylmethyl-4-methyl-5-(beta-hydroxyethyl) thiazole chloride on transmembrane current via ion channels formed by amphotericin B in bilayer lipid membrane].  


The structural analogue of vitamin B1 (thiamine)-3-decyloxycarbonylmethyl-4-methyl-5-(beta-hydroxyethyl) thiazole chloride (DMHT) introduced from the cis-side of cholesterol-containing phospholipid bilayer membrane reversibly reduced the conductance induced by amphotericin B channels reconstituted from the same side of membrane. Introduction of DMHT (0.1 mM) from the cis-side of membrane blocked the amphotericin B-created conductance in symmetric solution of 100 mM KCI by 84 +/- 2%. The conductance of one-sided amphotericin B channels remained unaffected, when DMHT was introduced separately to the opposite trans-side of membrane. The kinetics of amphotericin B channels inhibition with DMHT showed no cooperativity allowing to expect that negatively charged ionogenic groups of these channels formed one DMHT binding site per channel as the slope of blocking rate determined in double-log coordinates was 1.5. Relatively high pK of binding with amphotericin B channels (5.13) suggests that this site provides high-affinity interaction with DMHT. The comparative analysis of inhibition kinetics with the other blockers of amphotericin B channels--tetraethylammonium and tetramethylammonium has proved that DMHT is a comparable though much more potent substitute for both tetraalkylammonia. Hence, the DMHT was proposed as a novel powerful blocker for cation-selective channels with the size of the pore ranging between 0.28 nm and 0.385 nm. PMID:19873878

Shaturs'ky?, O Ia; Romanenko, O V; Himmel're?kh, N H



Determination of key structure-activity relationships in siRNA delivery with a mixed micelle system???  

PubMed Central

Short interfering ribonucleic acids (siRNAs) offer a highly specific and selective form of therapy for diseases with a genetic component; however the poor pharmacokinetic properties of the molecule have impeded its development into a therapeutic for use in vivo. Several different approaches have been taken to develop a successful siRNA delivery system but these systems lack the flexibility for easy optimisation. Here, we propose a polymeric nanoparticle (PNP) system consisting of two amphiphilic diblock copolymers which allow for the rapid determination of structure–activity relationships involving gene knockdown and toxicity. The diblock copolymers self-assemble into monodisperse micelles of defined hydrodynamic diameters ranging from 30 to 100 nm dependent on the copolymer ratio. A luciferase-based high throughput assay varying PNP composition, concentration and siRNA concentration allowed the rapid identification of efficient PNP formulations for adherent and suspension cell lines. Optimised PNPs efficiently knocked down a fusion oncogene in hard to transfect human leukaemic cells raising the possibility of targeting malignant cells in a cancer-specific fashion. This approach allows the optimum PNP formulation to be identified for different cell types and conditions.

Omedes Pujol, Marta; Coleman, Daniel J.L.; Allen, Christopher D.; Heidenreich, Olaf; Fulton, David A.



Determination of key structure-activity relationships in siRNA delivery with a mixed micelle system.  


Short interfering ribonucleic acids (siRNAs) offer a highly specific and selective form of therapy for diseases with a genetic component; however the poor pharmacokinetic properties of the molecule have impeded its development into a therapeutic for use in vivo. Several different approaches have been taken to develop a successful siRNA delivery system but these systems lack the flexibility for easy optimisation. Here, we propose a polymeric nanoparticle (PNP) system consisting of two amphiphilic diblock copolymers which allow for the rapid determination of structure-activity relationships involving gene knockdown and toxicity. The diblock copolymers self-assemble into monodisperse micelles of defined hydrodynamic diameters ranging from 30 to 100 nm dependent on the copolymer ratio. A luciferase-based high throughput assay varying PNP composition, concentration and siRNA concentration allowed the rapid identification of efficient PNP formulations for adherent and suspension cell lines. Optimised PNPs efficiently knocked down a fusion oncogene in hard to transfect human leukaemic cells raising the possibility of targeting malignant cells in a cancer-specific fashion. This approach allows the optimum PNP formulation to be identified for different cell types and conditions. PMID:24140749

Omedes Pujol, Marta; Coleman, Daniel J L; Allen, Christopher D; Heidenreich, Olaf; Fulton, David A



Total synthesis of sandramycin and its analogues via a multicomponent assemblage.  


The total synthesis of sandramycin has been accomplished by using a Staudinger/aza-Wittig/diastereoselective Ugi three-component reaction sequence as a key step to obtain a linear pentadepsipeptide. Subsequent [5 + 5] coupling of the penptapeptide, macrolactamization, and introduction of the quinaldin chromophores afforded sandramycin. Dihydroxy and diacetoxy analogues were also prepared, and the cytotoxic activity of these analogues against a range of human cancer cell lines was evaluated. PMID:24341513

Katayama, Katsushi; Nakagawa, Koji; Takeda, Hiroshi; Matsuda, Akira; Ichikawa, Satoshi



Structure and dynamics of ?-aryl amide and ketone enolates: THF, PMDTA, TMTAN, HMPA, and crypt-solvated lithium enolates, and comparison with phosphazenium analogues.  


A variety of multinuclear NMR techniques, in combination with X-ray diffraction methods, were used to probe the solution structure of ?-aryl lithium enolates of bis(4-fluorobenzyl) ketone (1-H), phenyl 4-fluorobenzyl ketone (2-H), and N,N-dimethyl 4-fluorophenylacetamide (3-H) in ethereal solvents and in the presence of cosolvent additives PMDTA, TMTAN, HMPA, and cryptand [2.1.1]. All three enolates were dimers in THF solution, and were converted to monomers by the triamine additives, PMDTA and TMTAN. The exchange of the triamine-solvated monomers with their ethereal-solvated dimer counterparts was probed by using dynamic NMR (DNMR). The cosolvent HMPA formed monomers along with minor amounts of lithiate species, (RO)(2)Li(-) and (RO)(3)Li(2-), which were also observed when cryptand [2.1.1] was used as a cosolvent, or when mixed lithium-phosphazenium enolate solutions were prepared. Dynamic exchange of lithiate species was investigated by DNMR spectroscopy. The barrier to rotation of the conjugated 4-fluorophenyl ring of these diverse enolate structures was measured and found to be consistent with a resonance picture where lower aggregation states lead to increased delocalization of negative charge. The lithium enolate aggregates identified were compared to the "naked" ?-4-fluorophenyl enolates generated with the phosphazene base P4. The barrier to aryl ring rotation was 2.7 kcal/mol higher for the phosphazenium enolate 3-Li·P4H compared to the dimer (3-Li)(2). Structural characterization of a phosphazenium enolate through X-ray crystallography was obtained for the first time. Additional aspects of the Schwesinger base P4 were investigated which included characterization of the solution exchange behavior of the protonated and unprotonated forms as well as determination of the solid state structure by X-ray diffraction. PMID:20735148

Kolonko, Kristopher J; Guzei, Ilia A; Reich, Hans J



Thalidomide analogues as anticancer drugs.  


The evolution of thalidomide as an effective treatment in several neoplasms has led to the search for compounds with increased antiangiogenic and anti-tumor effects, but decreased side-effects. The development of thalidomide analogues which retain the immunomodulatory effects of the parent compound, while minimizing the adverse reactions, brought about a class of agents termed the Immunomodulatory drugs (IMiDs). The IMiDs have undergone significant advances in recent years as evidenced by the recent FDA-approvals of one of the lead compounds, CC-5013 (lenalidomide), for 5q-myelodysplasia and for multiple myeloma (MM). Actimid (CC-4047), another IMiD lead compound, has also undergone clinical testing in MM. Apart from hematologic malignancies, these drugs are actively under investigation in solid tumor malignancies including prostate cancer, melanoma, and gliomas, in which potent activity has been demonstrated. The preclinical and clinical data relating to these analogues, as well as ENMD-0995, are reviewed herein. Encouraging results with these thalidomide analogues brought forth synthesis and screening of additional novel thalidomide analogues in the N-substituted and tetrafluorinated classes, including CPS11 and CPS49. This review also discusses the patents and preclinical findings for these agents. PMID:17975653

Aragon-Ching, Jeanny B; Li, Haiqing; Gardner, Erin R; Figg, William D



New routes towards reutericyclin analogues.  


A range of N-acylpyrrolo[3,4-c]isoxazoles and derived N-acyltetramides has been prepared via a nitrile oxide dipolar cycloaddition approach, as analogues of the acyltetramic acid metabolite reutericyclin, of interest for its antibiotic potential against Gram-positive bacteria including hospital-acquired infections of resistant Clostridium difficile. PMID:24382380

Jones, Raymond C F; Bullous, James P; Law, Carole C M; Elsegood, Mark R J



New phosphorus analogues of nitrogen classics-no carbon copies.  


Getting heavy: The recently prepared phosphorus analogues of two old acquaintances, urea and dinitrogen tetroxide, bear some structural resemblance to their archetypes but are no carbon copies. Their syntheses and chemical properties reveal rather certain peculiarities, which back the doctrine that the electronic properties of the heavier elements in a group differ from those of the lightest congener. PMID:24718995

Gudat, Dietrich



Naturally occurring crystalline phases: analogues for radioactive waste forms  

SciTech Connect

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.

Haaker, R.F.; Ewing, R.C.