Sample records for key structural analogues

  1. Total synthesis of vinblastine, vincristine, related natural products, and key structural analogues.

    PubMed

    Ishikawa, Hayato; Colby, David A; Seto, Shigeki; Va, Porino; Tam, Annie; Kakei, Hiroyuki; Rayl, Thomas J; Hwang, Inkyu; Boger, Dale L

    2009-04-01

    Full details of the development of a direct coupling of catharanthine with vindoline to provide vinblastine are described along with key mechanistic and labeling studies. Following an Fe(III)-promoted coupling reaction initiated by generation of a presumed catharanthine radical cation that undergoes a subsequent oxidative fragmentation and diastereoselective coupling with vindoline, addition of the resulting reaction mixture to an Fe(III)-NaBH(4)/air solution leads to oxidation of the C15'-C20' double bond and reduction of the intermediate iminium ion directly providing vinblastine (40-43%) and leurosidine (20-23%), its naturally occurring C20' alcohol isomer. The yield of coupled products, which exclusively possess the natural C16' stereochemistry, approaches or exceeds 80% and the combined yield of the isomeric C20' alcohols is >60%. Preliminary studies of Fe(III)-NaBH(4)/air oxidation reaction illustrate a generalizable trisubstituted olefin scope, identify alternatives to O(2) trap at the oxidized carbon, provide a unique entry into C20' functionalized vinblastines, and afford initial insights into the observed C20' diastereoselectivity. The first disclosure of the use of exo-catharanthine proceeding through Delta(19',20')-anhydrovinblastine in such coupling reactions is also detailed with identical stereochemical consequences. Incorporating either a catharanthine N-methyl group or a vindoline N-formyl group precludes Fe(III)-promoted coupling, whereas the removal of the potentially key C16 methoxy group of vindoline does not adversely impact the coupling efficiency. Extension of these studies provided a total synthesis of vincristine (2) via N-desmethylvinblastine (36, also a natural product), 16-desmethoxyvinblastine (44) and 4-desacetoxy-16-desmethoxyvinblastine (47) both of which we can now suggest are likely natural products produced by C. roseus, desacetylvinblastine (62) and 4-desacetoxyvinblastine (59), as well as a series of key analogues bearing systematic modifications in the vindoline subunit. Their biological evaluation provided additional insights into the key functionality within the vindoline subunit contributing to the activity and sets the foundation on which further, more deep-seated changes in the structures of 1 and 2 will be explored in future studies. PMID:19292450

  2. Total Synthesis of Vinblastine, Related Natural Products, and Key Analogues and Development of Inspired Methodology Suitable for the Systematic Study of Their Structure–Function Properties

    PubMed Central

    2015-01-01

    Conspectus Biologically active natural products composed of fascinatingly complex structures are often regarded as not amenable to traditional systematic structure–function studies enlisted in medicinal chemistry for the optimization of their properties beyond what might be accomplished by semisynthetic modification. Herein, we summarize our recent studies on the Vinca alkaloids vinblastine and vincristine, often considered as prototypical members of such natural products, that not only inspired the development of powerful new synthetic methodology designed to expedite their total synthesis but have subsequently led to the discovery of several distinct classes of new, more potent, and previously inaccessible analogues. With use of the newly developed methodology and in addition to ongoing efforts to systematically define the importance of each embedded structural feature of vinblastine, two classes of analogues already have been discovered that enhance the potency of the natural products >10-fold. In one instance, remarkable progress has also been made on the refractory problem of reducing Pgp transport responsible for clinical resistance with a series of derivatives made accessible only using the newly developed synthetic methodology. Unlike the removal of vinblastine structural features or substituents, which typically has a detrimental impact, the additions of new structural features have been found that can enhance target tubulin binding affinity and functional activity while simultaneously disrupting Pgp binding, transport, and functional resistance. Already analogues are in hand that are deserving of full preclinical development, and it is a tribute to the advances in organic synthesis that they are readily accessible even on a natural product of a complexity once thought refractory to such an approach. PMID:25586069

  3. Total synthesis of vinblastine, related natural products, and key analogues and development of inspired methodology suitable for the systematic study of their structure-function properties.

    PubMed

    Sears, Justin E; Boger, Dale L

    2015-03-17

    Biologically active natural products composed of fascinatingly complex structures are often regarded as not amenable to traditional systematic structure-function studies enlisted in medicinal chemistry for the optimization of their properties beyond what might be accomplished by semisynthetic modification. Herein, we summarize our recent studies on the Vinca alkaloids vinblastine and vincristine, often considered as prototypical members of such natural products, that not only inspired the development of powerful new synthetic methodology designed to expedite their total synthesis but have subsequently led to the discovery of several distinct classes of new, more potent, and previously inaccessible analogues. With use of the newly developed methodology and in addition to ongoing efforts to systematically define the importance of each embedded structural feature of vinblastine, two classes of analogues already have been discovered that enhance the potency of the natural products >10-fold. In one instance, remarkable progress has also been made on the refractory problem of reducing Pgp transport responsible for clinical resistance with a series of derivatives made accessible only using the newly developed synthetic methodology. Unlike the removal of vinblastine structural features or substituents, which typically has a detrimental impact, the additions of new structural features have been found that can enhance target tubulin binding affinity and functional activity while simultaneously disrupting Pgp binding, transport, and functional resistance. Already analogues are in hand that are deserving of full preclinical development, and it is a tribute to the advances in organic synthesis that they are readily accessible even on a natural product of a complexity once thought refractory to such an approach. PMID:25586069

  4. Structure of octreotide, a somatostatin analogue.

    PubMed

    Pohl, E; Heine, A; Sheldrick, G M; Dauter, Z; Wilson, K S; Kallen, J; Huber, W; Pfäffli, P J

    1995-01-01

    Octreotide, a synthetic somatostatin analogue, is an octapeptide with one disulfide bridge. Crystals of octreotide are orthorhombic, space group P2(1)2(1)2(1), a = 18.458 (5), b = 30.009 (7), c = 39.705 (27) A, with three molecules of octapeptide, one ordered oxalate dianion and 52 water molecules in the asymmetric unit. Complete protonation of the NH(2) groups (as assumed in the refinement) would require three oxalate dianions in the asymmetric unit for charge neutrality; a chemical analysis indicated that four are present. In either case they are so disordered that they cannot be distinguished from the water molecules. The 18 951 unique reflections (R(sym) = 0.026) used for structure solution and refinement were recorded with the EMBL imaging-plate scanner using synchrotron radiation. The structure was solved by Patterson interpretation, locating the three disulfide bridges, followed by tangent phase expansion and E-Fourier recycling. The anisotropic refinement against all F(2) data between 1.04 and 10.0 A resolution by blocked restrained full-matrix least-squares techniques converged to a conventional R index based on F of 0.084 [I > 2a(I) and 10.0 > d > 1.04 A] and wR2, the weighted R-index on F(2), of 0.246 (for all data). One peptide molecule adopts a flat beta-sheet structure; the other two possess different irregular backbone conformations, but are similar to each other. All three molecules have a distorted type II' beta-turn around the D-Trp-Lys region, but exhibit different side-chain conformations. The crystal structure is stabilized by a network of inter- and intramolecular hydrogen bonds. PMID:15299335

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

    PubMed

    Prévost, Sébastien; Thai, Karen; Schützenmeister, Nina; Coulthard, Graeme; Erb, William; Aggarwal, Varinder K

    2015-02-01

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

  6. Relationship between antimold activity and molecular structure of cinnamaldehyde analogues.

    PubMed

    Zhang, Yuanyuan; Li, Shujun; Kong, Xianchao

    2013-03-01

    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

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

    PubMed

    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

    2007-11-14

    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

  8. Super-secondary structure peptidomimetics: design and synthesis of an ?-? hairpin analogue

    PubMed Central

    Nevola, Laura; Rodriguez, Johanna M.; Thompson, Sam; Hamilton, Andrew D.

    2015-01-01

    The ?-? helix motif presents key recognition domains in protein-protein and protein-oligonucleotide binding, and is one of the most common super-secondary structures. Herein we describe the design, synthesis and structural characterization of an ?-? hairpin analogue based on a tetra-coordinated Pd(II) bis-(iminoisoquinoline) complex as a template for the display of two ?-helix mimics. This approach is exemplified by the attachment of two biphenyl peptidomimetics to reproduce the side-chains of the i and i+4 residues of two helices.

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

    PubMed Central

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

    2014-01-01

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

  10. Modern freshwater microbialite analogues for ancient dendritic reef structures

    NASA Technical Reports Server (NTRS)

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

    2000-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2013-12-01

    Impact cratering is the dominant geological process on the Moon, Near Earth Asteroids (NEAs) and the moons of Mars - the objectives for the new Solar System Exploration Research Virtual Institute (SSERVI). Led by members of the Canadian Lunar Research Network (CLRN), funded by the Canadian Space Agency, and with participants from the U.S., we carried out a series of analogue missions on Earth in order to prepare and train for future potential robotic and human sample return missions. Critically, these analogue missions were driven by the paradigm that operational and technical objectives are conducted while conducting new science and addressing real overarching scientific objectives. An overarching operational goal was to assess the utility of a robotic field reconnaissance mission as a precursor to a human sortie sample return mission. Here, we focus on the results and lessons learned from a robotic precursor mission and follow on human-robotic mission to the Mistastin Lake impact structure in Labrador, northern Canada (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.

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

    PubMed

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

    2014-08-27

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

  13. Synthesis and Structure activity relationships of EGCG Analogues, A Recently Identified Hsp90 Inhibitor

    PubMed Central

    Khandelwal, Anuj; Hall, Jessica

    2014-01-01

    Epigallocatechin-3-gallate (EGCG), the principal polyphenol isolated from green tea, was recently shown to inhibit Hsp90, however structure-activity relationships for this natural product have not yet been produced. Herein, we report the synthesis and biological evaluation of EGCG analogues to establish structure-activity relationships between EGCG and Hsp90. All four rings as well as the linker connecting the C- and the D-rings were systematically investigated, which led to the discovery of compounds that inhibit Hs90 and display improvement in efficacy over EGCG. Anti-proliferative activity of all the analogues was determined against MCF-7 and SKBr3 cell lines and Hsp90 inhibitory activity of four most potent analogues was further evaluated by western blot analyses and degradation of Hsp90-dependent client proteins. Prenyl substituted aryl ester of 3,5-dihydroxychroman-3-ol ring system was identified as novel scaffold that exhibit Hsp90 inhibitory activity. PMID:23834230

  14. A De Novo Approach to the Synthesis of Glycosylated Methymycin Analogues with Structural and Stereochemical Diversity

    PubMed Central

    Borisova, Svetlana A.; Guppi, Sanjeeva R.; Kim, Hak Joong; Wu, Bulan

    2010-01-01

    A divergent and highly stereoselective route to eleven glycosylated methymycin analogues has been developed. The key to the success of this method was the iterative use of the Pd-catalyzed glycosylation reaction and post-glycosylation transformation. This unique application of Pd-catalyzed glycosylation demonstrates the breath of ?/?-& D/L-glycosylation of macrolides that can be efficiently prepared using a de novo asymmetric approach to the carbohydrate portion. PMID:20958086

  15. Taurine and GABA release from mouse cerebral cortex slices: Effects of structural analogues and drugs

    Microsoft Academic Search

    Pirjo Kontro; Simo S. Oja

    1987-01-01

    The effects of structural analogues, excitatory amino acids and certain drugs on spontaneous and potassium-stimulated exogenous taurine and GABA release were investigated in mouse cerebral cortex slices using a superfusion system. Spontaneous efflux of both amino acids was rather slow but could be enhanced by their uptake inhibitors. Taurine efflux was facilitated by exogenous taurine, hypotaurine, ß-alanine and GABA, whereas

  16. Synthetic ceramide analogues as skin permeation enhancers: structure–Activity relationships

    Microsoft Academic Search

    Kate?ina Vávrová; Alexandr Hrabálek; Pavel Doležal; Lucie Šámalová; Karel Palát; Jarmila Zbytovská; Tomáš Holas; Jana Klimentová

    2003-01-01

    The study presents new information about the structure–activity relationships of the skin permeation enhancers. A series of ceramide analogues including eight different polar head groups and six different chain lengths was synthesised. The compounds were evaluated as permeation enhancers in vitro using porcine skin. The physico-chemical parameters of the tested compounds obtained by computer modelling were used to evaluate, by

  17. Novel biological effects of alloferon and its selected analogues: structure-activity study.

    PubMed

    Kuczer, Mariola; Czarniewska, El?bieta; Rosi?ski, Grzegorz

    2013-05-10

    The subject of this paper is a search for new biological properties of alloferon (H-His-Gly-Val-Ser-Gly-His-Gly-Gln-His-Gly-Val-His-Gly-OH) and a series of its analogues. The studies on structure/activity relationship in alloferon, the synthesis of a series of 28 analogues were performed. The analogues were modified at position 1 or 6, and other were oligopeptides with a shortened peptide sequence. Biological effects of the peptides were evaluated by the pro-apoptotic action in vivo on haemocytes of Tenebrio molitor and in the cardiotropic test in vitro on the heart of T. molitor and Zophobas atratus. In the in vivo bioassays, new biological activities of alloferon and its analogues were discovered. In haemocytotoxic bioassay, alloferon strongly induces T. molitor haemocytes to undergo apoptosis at a dose of 10 nM. Moreover, [Phe(p-NH2)(1)]-, [Tyr(6)]- and [1-10]-alloferon exhibit a two-fold increase of caspases activation in comparison with the alloferon. However, alloferon and its analogues show a weak cardiostimulatory activity in Z. atratus but the heart of T. molitor is not sensitive to these peptides. The results obtained here suggest that alloferon plays pleiotropic functions in insects. PMID:23499798

  18. Differential effects of spermine and its analogues on the structures of polynucleotides complexed with ethidium bromide.

    PubMed Central

    Delcros, J G; Sturkenboom, M C; Basu, H S; Shafer, R H; Szöllösi, J; Feuerstein, B G; Marton, L J

    1993-01-01

    The interactions of spermine and polyamine analogues with synthetic polynucleotides of various base sequences complexed with ethidium bromide (EB) were investigated using measurements of fluorescence intensity and steady-state fluorescence polarization. Spermine and polyamine analogues displaced some but not all of the EB bound to poly(dA-dT).poly(dA-dT) or poly(dG-dC).poly(dG-dC), suggesting that polyamines may stabilize these polynucleotides in a conformation with reduced affinity for EB. Modifications of the aliphatic backbone of spermine have pronounced effects on its ability to displace EB from poly(dA-dT).poly(dA-dT) but not from poly-(dG-dC).poly(dG-dC). Spermine and some but not all of the polyamine analogues caused fluorescence depolarization when they interacted with the complex of EB and poly(dA-dT).poly-(dA-dT). Neither spermine nor any of the analogues, however, induced fluorescence depolarization in the complex of EB with poly(dG-dC).poly(dG-dC) or poly(dA).poly(dT). This suggests that spermine and some spermine analogues induce structural changes specific to alternating A-T sequences. PMID:8471043

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

    PubMed

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

    2013-05-01

    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

  20. Isolation and structural characterisation of a propoxyphenyl-linked thiohomosildenafil analogue found in a herbal product.

    PubMed

    Kim, Nam Sook; Lee, Ji Hyune; Han, Kyoung Moon; Kim, Hyung Joo; Cho, Sooyeul; Han, Soon Young; Kim, Woo Seong

    2013-01-01

    A propoxyphenyl-linked thiohomosildenafil analogue, one of the sildenafil analogues, was found in an herbal product. It was isolated by semi-preparative high-performance liquid chromatography (HPLC). The structure was established based on a comparison of chromatographic and spectroscopic behaviour with other sildenafil analogues using HPLC with diode array detection, quadrupole time-of-flight mass spectrometry (Q-TOF/MS), and nuclear magnetic resonance (NMR) spectroscopy. The HPLC analysis showed separation from known sildenafil analogues with a similar chromatographic retention time. An [M + H](+) ion at m/z 519.22 was detected by mass spectrometry corresponding to an empirical formula of C24H34N6O3S2. The structure was similar to that of thiohomosildenafil, except that the ethoxy group attached to the phenyl ring was substituted for a propoxy group. It was assigned as 5-[2-propoxy-5-(4-ethylpiperazin-4-ylsulfonyl)phenyl]-3-methyl-1-n-propyl-4,5,dihydro-1H-pyrazole[7,1,d]pyrimidin-4-thione and named as propoxyphenyl-thiohomosildenafil because the structure was considerably similar to thiohomosildenafil. PMID:23984909

  1. Structure-Based Design Guides the Improved Efficacy of Deacylation Transition State Analogue Inhibitors of TEM-1 -Lactamase,#

    E-print Network

    Paetzel, Mark

    Inhibitors of TEM-1 -Lactamase,# Steven Ness, Richard Martin,§ Alois M. Kindler,§ Mark Paetzel, Marvin Gold 31, 2000 ABSTRACT: Transition state analogue boronic acid inhibitors mimicking the structures, as designed, compounds 1 and 2 are highly effective deacylation transition state analogue inhibitors of TEM-1

  2. Sensitivity of Volume-regulated Anion Current to Cholesterol Structural Analogues

    Microsoft Academic Search

    Victor G. Romanenko; George H. Rothblat; Irena Levitan

    2003-01-01

    Depletion of membrane cholesterol and substitution of endogenous cholesterol with its structural analogues was used to analyze the mechanism by which cholesterol regulates volume-regulated anion current (VRAC) in endothelial cells. Depletion of membrane cholesterol enhanced the development of VRAC activated in a swelling-independent way by dialyzing the cells either with GTPS or with low ionic strength solution. Using MCD-sterol complexes,

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

    SciTech Connect

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

    2012-05-09

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

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

    NASA Astrophysics Data System (ADS)

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

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

  5. Design, synthesis, biological and structural evaluation of functionalized resveratrol analogues as inhibitors of quinone reductase 2

    PubMed Central

    St. John, Sarah E.; Jensen, Katherine C.; Kang, SooSung; Chen, Yafang; Calamini, Barbara; Mesecar, Andrew D.; Lipton, Mark A.

    2013-01-01

    Resveratrol (3,5,4?-trihydroxylstilbene) has been proposed to elicit a variety of positive health effects including protection against cancer and cardiovascular disease. The highest affinity target of resveratrol identified so far is the oxidoreductase enzyme quinone reductase 2 (QR2), which is believed to function in metabolic reduction and detoxification processes; however, evidence exists linking QR2 to the metabolic activation of quinones, which can lead to cell toxicity. Therefore, inhibition of QR2 by resveratrol may protect cells against reactive intermediates and eventually cancer. With the aim of identifying novel inhibitors of QR2, we designed, synthesized, and tested two generations of resveratrol analogue libraries for inhibition of QR2. In addition, X-ray crystal structures of six of the resveratrol analogues in the active site of QR2 were determined. Several novel inhibitors of QR2 were successfully identified as well as a compound that inhibits QR2 with a novel binding orientation. PMID:23953689

  6. Structural analysis of glycosphingolipid analogues obtained by the saccharide primer method using CE-ESI-MS.

    PubMed

    Zhu, Xingyu; Hatanaka, Kenichi; Yamagata, Tatsuya; Sato, Toshinori

    2009-10-01

    A glycosphingolipid analogue (12-azidododecyl beta-lactoside) as a saccharide primer has been shown to be useful for the synthesis of oligosaccharide libraries by mammalian cells. In the present study, CE-ESI-MS was employed to elucidate the structure of glycosphingolipid analogues derived from 12-azidododecyl beta-lactoside (Lac-C12N3) by mammalian cells. MDCK cells and COLO201 cells were cultured with Lac-C12N3, and the glycosylated products secreted into the medium were collected and separated into acidic and neutral products by column chromatography. The acidic products could be directly analyzed by CE-ESI-MS, while the neutral products were converted to anionic derivatives via a reaction with propiolic acid. With this method, it was possible to analyze both acidic and neutral products glycosylated by MDCK cells and COLO201 cells at high sensitivity. PMID:19813238

  7. REASONING ABOUT FUNCTIONAL AND KEY DEPENDENCIES IN HIERARCHICALLY STRUCTURED DATA

    E-print Network

    Plotkin, Joshua B.

    REASONING ABOUT FUNCTIONAL AND KEY DEPENDENCIES IN HIERARCHICALLY STRUCTURED DATA CARMEM SATIE HARA like to thank my advisors, Susan Davidson and Wenfei Fan for their guidance and advice. I have no doubt;ABSTRACT REASONING ABOUT FUNCTIONAL AND KEY DEPENDENCIES IN HIERARCHICALLY STRUCTURED DATA Carmem Satie

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

    PubMed

    Takeda, Takashi; Akutagawa, Tomoyuki

    2015-02-20

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

  9. Structure-function relationship studies of PTH(1-11) analogues containing sterically hindered dipeptide mimetics.

    PubMed

    Fiori, Nereo; Caporale, Andrea; Schievano, Elisabetta; Mammi, Stefano; Geyer, Armin; Tremmel, Peter; Wittelsberger, Angela; Woznica, Iwona; Chorev, Michael; Peggion, Evaristo

    2007-08-01

    The N-terminal 1-34 fragment of parathyroid hormone (PTH) is fully active in vitro and in vivo and reproduces all biological responses characteristic of the native intact PTH. In order to develop safer and non-parenteral PTH-like bone anabolic agents, we have studied the effect of introducing conformationally constrained dipeptide mimetics into the N-terminal portion of PTH in an effort to generate miniaturized PTH-mimetics. To this end, we have synthesized and conformationally and biologically characterized PTH(1-11) analogues containing 3R-carboxy-6S-amino-7,5-bicyclic thiazolidinlactam (7,5-bTL), a rigidified dipeptide mimetic unit. The wild type sequence of PTH(1-11) is H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-NH(2). The following pseudo-undecapeptides were prepared: [Ala(1), 7,5-bTL(3, 4), Nle(8), Arg(11)]hPTH(1-11)NH(2) (I); [Ala(1), 7,5-bTL(6, 7), Nle(8), Arg(11)]hPTH(1-11)NH(2) (II); [Ala(1), Nle(8), 7,5-bTL(9, 10), Arg(11)]hPTH(1-11)NH(2) (III). In aqueous solution containing 20% TFE, only analogue I exhibited the typical CD pattern of the alpha-helical conformation. NMR experiments and molecular dynamics calculations located the alpha-helical stretch in the sequence Ile(5)-His(9). The dipeptide mimetic unit 7,5-bTL induces a type III beta-turn, occupying the positions i - 1 and i of the turn. Analogue II exhibited an equilibrium between a type I beta-turn and an alpha-helix, and analogue III did not show any ordered structure. Biological tests revealed poor activity for all analogues (EC(50) > 0.1 mM). Apparently, the relative side-chain orientation of Val(2), Ile(5) and Met(8) can be critical for effective analogue-receptor interaction. Considering helicity as an essential property to obtain active PTH agonists, one must decorate the correctly positioned dipeptide mimetic azabicycloalkane scaffold with substitutions corresponding to the displaced amino acids. PMID:17617795

  10. New structural form of a tetranuclear lanthanide hydroxo cluster: Dy4 analogue display slow magnetic relaxation.

    PubMed

    Jami, Ananda Kumar; Baskar, Viswanathan; Sañudo, E Carolina

    2013-03-01

    A series of tetranuclear lanthanide (Ln = Tb, Dy, Ho) hydroxo clusters has been synthesized by reaction of LnCl3·6H2O (Ln = Tb (1), Dy (2), Ho (3)) with o-vanilin based schiff base ligand 2-(2,3 dihydroxpropyl imino methyl) 6-methoxy phenol (H3L) in methanol and in the presence of triethylamine as base. The solid state structures of all the products were established by single crystal X-ray diffraction technique. Magnetism studies reveal that Dy4 analogue exhibits slow magnetic relaxation at low temperatures. PMID:23428076

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

    PubMed Central

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

    2014-01-01

    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. PMID:24692664

  12. Weed Identification: Using Plant Structures as a Key 

    E-print Network

    Baumann, Paul A.

    2002-04-15

    Weed identification is necessary to the success of any weed control program. Frequently, simple plant keys or "picture book identification guides are used to identify weeds. This handbook, which identifies and labels plant structures, can help one...

  13. Weed Identification: Using Plant Structures as a Key (Spanish) 

    E-print Network

    Baumann, Paul A.

    1999-08-30

    Weed identification is necessary to the success of any weed control program. Frequently, simple plant keys or "picture book identification guides are used to identify weeds. This handbook, which identifies and labels plant structures, is intended...

  14. Cellular Localization of Dieldrin and Structure–Activity Relationship of Dieldrin Analogues in Dopaminergic Cells

    PubMed Central

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

    2015-01-01

    The incidence of 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

  15. Synthesis of structurally diverse benzosuberene analogues and their biological evaluation as anti-cancer agents

    PubMed Central

    Tanpure, Rajendra P.; George, Clinton S.; Strecker, Tracy E.; Devkota, Laxman; Tidmore, Justin K.; Lin, Chen-Ming; Herdman, Christine A.; MacDonough, Matthew T.; Sriram, Madhavi; Chaplin, David J.; Trawick, Mary Lynn; Pinney, Kevin G.

    2014-01-01

    Diversely functionalized, fused aryl-alkyl ring systems hold a prominent position as well-established molecular frameworks for a variety of anti-cancer agents. The benzosuberene (6,7 fused, also referred to as dihydro-5H-benzo[7]annulene and benzocycloheptene) ring system has emerged as a valuable molecular core component for the development of inhibitors of tubulin assembly, which function as antiproliferative anti-cancer agents and, in certain cases, as vascular disrupting agents (VDAs). Both a phenolic-based analogue (known as KGP18, compound 39) and its corresponding amine-based congener (referred to as KGP156, compound 45), which demonstrate strong inhibition of tubulin assembly (low micromolar range) and potent cytotoxicity (picomolar range for KGP18 and nanomolar range for KGP156) are noteworthy examples of such benzosuberene-based compounds. In order to extend the structure-activity relationship (SAR) knowledge base related to benzosuberene anti-cancer agents, a series of eleven analogues (including KGP18) were prepared in which the methoxylation pattern on the pendant aryl ring as well as functional group incorporation on the fused aryl ring were varied. The synthetic approach to these compounds featured a sequential Wittig olefination, reduction, Eaton's reagent-mediated cyclization strategy to achieve the core benzosuberone intermediate, and represented a higher-yielding synthesis of KGP18 (which we prepared previously through a ring-expansion strategy). Incorporation of a fluorine or chlorine atom at the 1-position of the fused aryl ring or replacement of one of the methoxy groups with hydrogen (on the pendant aryl ring of KGP18) led to benzosuberene analogues that were both strongly inhibitory against tubulin assembly (IC50 approximately 1.0 M) and strongly cytotoxic against selected human cancer cell lines (for example, GI50 = 5.47 nM against NCI-H460 cells with fluorobenzosuberene analogue 37). A water-soluble phosphate prodrug salt of KGP18 (referred to as KGP265, compound 44) and a water-soluble serinamide salt (compound 48) of KGP156 were also synthesized and evaluated in this study. PMID:24183586

  16. Quad Trees: A Data Structure for Retrieval on Composite Keys

    Microsoft Academic Search

    Raphael A. Finkel; Jon Louis Bentley

    1974-01-01

    The quad tree is a data structure appropriate for storing information to be retrieved on composite keys. We discuss the specific case of two-dimensional retrieval, although the structure is easily generalised to arbitrary dimensions. Algorithms are given both for staightforward insertion and for a type of balanced insertion into quad trees. Empirical analyses show that the average time for insertion

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

    NASA Astrophysics Data System (ADS)

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

    2014-05-01

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

  18. Key Factors for Successful Generation of Protein–Fragment Structures

    Microsoft Academic Search

    Jark Böttcher; Anja Jestel; Reiner Kiefersauer; Stephan Krapp; Susanna Nagel; Stefan Steinbacher; Holger Steuber

    2011-01-01

    In the past two decades, fragment-based approaches have evolved as a predominant strategy in lead discovery. The availability of structural information on the interaction geometries of binding fragments is key to successful structure-guided fragment-to-lead evolution. In this chapter, we illustrate methodological advances for protein–fragment crystal structure generation in order to offer general lessons on the importance of fragment properties and

  19. Structure activity relationship study of burkholdine analogues toward simple antifungal agents.

    PubMed

    Konno, Hiroyuki; Abumi, Kanako; Sasaki, Yasuhiro; Yano, Shigekazu; Nosaka, Kazuto

    2015-08-15

    Cyclic and linear lipopeptides, burkholdine analogues, were synthesized by conventional Fmoc-SPPS and cyclisation with DIPC/HOBt in the solution phase. Synthesized peptides were evaluated for antifungal activities with MIC values against Saccharomyces cerevisiae and Aspergillus oryzae. As a result, the stereochemistry of the amino acid residues and sequences of burkholdine analogues exerted a significant influence on antifungal activities. In addition, we found a linear burkholdine analogue with moderate antifungal activities. PMID:26077490

  20. A Novel Transition State Analogue Inhibitor of Guanase Based on Azepinomycin Ring Structure: Synthesis and Biochemical Assessment of Enzyme Inhibition

    PubMed Central

    Chakraborty, Saibal; Shah, Niti H.; Fishbein, James C.; Hosmane, Ramachandra S.

    2010-01-01

    Synthesis and biochemical inhibition studies of a novel transition state analogue inhibitor of guanase bearing the ring structure of azepinomycin have been reported. The compound was synthesized in five steps from a known compound and biochemically screened against the rabbit liver guanase. The compound exhibited competitive inhibition profile with a Ki of 16.7 ± 0.5 µM. PMID:21183343

  1. Synthesis of lipid A monosaccharide analogues containing acidic amino acid: Exploring the structural basis for the endotoxic and antagonistic activities

    Microsoft Academic Search

    Masao Akamatsu; Yukari Fujimoto; Mikayo Kataoka; Yasuo Suda; Shoichi Kusumoto; Koichi Fukase

    2006-01-01

    For elucidation of the structural and conformational requirements on the endotoxic and antagonistic activity of lipid A derivatives, we designed and synthesized lipid A analogues containing acidic amino acid residues in place of the non-reducing end phosphorylated glucosamine. Definite switching of the endotoxic or antagonistic activity was observed depending on the difference of the acidic groups (phosphoric acid or carboxylic

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

    PubMed Central

    Gupta, Malaya; Majumder, Upal Kanti

    2010-01-01

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

  3. Structure of the Cytochrome b6f Complex: Quinone Analogue Inhibitors as Ligands of Heme cn

    PubMed Central

    Yamashita, E.; Zhang, H.; Cramer, W. A.

    2007-01-01

    A native structure of the cytochrome b6f complex with improved resolution was obtained from crystals of the complex grown in the presence of divalent cadmium. Two Cd2+ binding sites with different occupancy were determined: (i) a higher affinity site, Cd1, which bridges His143 of cytochrome f and the acidic residue, Glu75, of cyt b6; in addition, Cd1 is coordinated by 1-2 H2O or 1-2 Cl- ; (ii) a second site, Cd2, of lower affinity for which three identified ligands are Asp58 (subunit IV), Glu3 (PetG subunit) and Glu4 (PetM subunit). Binding sites of quinone analogue inhibitors were sought in order to map the pathway of transfer of the lipophilic quinone across the b6f complex and to further define the function of the novel heme cn. Two sites were found for the chromone ring of the tridecyl-stigmatellin (TDS) quinone analogue inhibitor, one near the p-side [2Fe-2S] cluster. A second TDS site was unexpectedly found on the n-side of the complex facing the quinone exchange cavity as an axial ligand of heme cn. A similar binding site proximal to heme cn was found for the n-side quinone analogue inhibitor, NQNO. Binding of these inhibitors required their addition to the complex before lipid that is used to facilitate crystallization. The similar binding of NQNO and TDS as axial ligands to heme cn implies that this heme utilizes plastoquinone as a natural ligand, thus defining an electron transfer complex consisting of hemes bn, cn, and PQ, and the pathway of n-side reduction of the PQ pool. The NQNO binding site provides an explanation for several effects associated with its inhibitory action: the large negative shift in midpoint redox potential of heme cn, the increased amplitude of light-induced reduction of heme bn, and an altered EPR spectrum attributed to interaction between hemes cn and bn. A decreased extent of heme cn reduction by reduced ferredoxin in the presence of NQNO allows observation of the heme cn Soret band in a chemical difference spectrum. PMID:17498743

  4. Cycle Structure of the DES for Keys Having Palindromic (or Antipalindromic) Sequences of Round Keys

    Microsoft Academic Search

    Judy H. Moore; Gustavus J. Simmons

    1987-01-01

    Certain DES keys have been called weak or semiweak based upon the number of distinct round keys which they produce. For the weak keys, all 16 round keys are identical and encryption is the same as decryption. For the semiweak keys, there are only two distinct round keys but no specific weakness of the DES with these keys has been

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

    PubMed

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

    2015-05-01

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

  6. New analogues of Cucurbita maxima trypsin inhibitor III (CMTI III) with simplified structure.

    PubMed

    Rolka, K; Kupryszewski, G; Rózycki, J; Ragnarsson, U; Zbyryt, T; Otlewski, J

    1992-10-01

    Seven new analogues of trypsin inhibitor CMTI III were obtained by solid-phase peptide synthesis. Three analogues contained only two, instead of three, disulfide bridges, whereas the molecules of the next four analogues were shortened at the N- and/or C-terminus. The elimination of one disulfide bridge in CMTI III induces a decrease in the association equilibrium constants by 6-7 orders of magnitude, whereas the removal of one, two or three amino-acid residues at the N- and/or C-terminus does not significantly affect the activity. PMID:1418676

  7. Structural bisphenol analogues differentially target steroidogenesis in murine MA-10 Leydig cells as well as the glucocorticoid receptor.

    PubMed

    Roelofs, Maarke J E; van den Berg, Martin; Bovee, Toine F H; Piersma, Aldert H; van Duursen, Majorie B M

    2015-03-01

    Although much information on the endocrine activity of bisphenol A (BPA) is available, a proper human hazard assessment of analogues that are believed to have a less harmful toxicity profile is lacking. Here the possible effects of BPA, bisphenol F (BPF), bisphenol S (BPS), as well as the brominated structural analogue and widely used flame retardant tetrabromobisphenol A (TBBPA) on human glucocorticoid and androgen receptor (GR and AR) activation were assessed. BPA, BPF, and TBBPA showed clear GR and AR antagonism with IC50 values of 67 ?M, 60 ?M, and 22 nM for GR, and 39 ?M, 20 ?M, and 982 nM for AR, respectively, whereas BPS did not affect receptor activity. In addition, murine MA-10 Leydig cells exposed to the bisphenol analogues were assessed for changes in secreted steroid hormone levels. Testicular steroidogenesis was altered by all bisphenol analogues tested. TBBPA effects were more directed towards the male end products and induced testosterone synthesis, while BPF and BPS predominantly increased the levels of progestagens that are formed in the beginning of the steroidogenic pathway. The MA-10 Leydig cell assay shows added value over the widely used H295R steroidogenesis assay because of its fetal-like characteristics and specificity for the physiologically more relevant testicular ?4 steroidogenic pathway. Therefore, adding an in vitro assay covering fetal testicular steroidogenesis, such as the MA-10 cell line, to the panel of tests used to screen potential endocrine disruptors, is highly recommendable. PMID:25576683

  8. Structure-activity relationships for antibacterial to antifungal conversion of kanamycin to amphiphilic analogues.

    PubMed

    Fosso, Marina; AlFindee, Madher N; Zhang, Qian; Nziko, Vincent de Paul Nzuwah; Kawasaki, Yukie; Shrestha, Sanjib K; Bearss, Jeremiah; Gregory, Rylee; Takemoto, Jon Y; Chang, Cheng-Wei Tom

    2015-05-01

    Novel fungicides are urgently needed. It was recently reported that the attachment of an octyl group at the O-4? position of kanamycin B converts this antibacterial aminoglycoside into a novel antifungal agent. To elucidate the structure-activity relationship (SAR) for this phenomenon, a lead compound FG03 with a hydroxyl group replacing the 3?-NH2 group of kanamycin B was synthesized. FG03's antifungal activity and synthetic scheme inspired the synthesis of a library of kanamycin B analogues alkylated at various hydroxyl groups. SAR studies of the library revealed that for antifungal activity the O-4? position is the optimal site for attaching a linear alkyl chain and that the 3?-NH2 and 6?-OH groups of the kanamycin B parent molecule are not essential for antifungal activity. The discovery of lead compound, FG03, is an example of reviving clinically obsolete drugs like kanamycin by simple chemical modification and an alternative strategy for discovering novel antimicrobials. PMID:25826012

  9. The Manicouagan impact structure as a terrestrial analogue site for lunar and martian planetary science

    NASA Astrophysics Data System (ADS)

    Spray, John G.; Thompson, Lucy M.; Biren, Marc B.; O'Connell-Cooper, Catherine

    2010-03-01

    The 90 km diameter, late Triassic Manicouagan impact structure of Québec, Canada, is a well-preserved, undeformed complex crater possessing an anorthositic central uplift and a 55 km diameter melt sheet. As such, it provides a valuable terrestrial analogue for impact structures developed on other planetary bodies, especially the Moon and Mars, which are currently the focus of exploration initiatives. The scientific value of Manicouagan has recently been enhanced due to the production, between 1994 and 2006, of ˜18 km of drill core from 38 holes by the mineral exploration industry. Three of these holes are in excess of 1.5 km deep, with the deepest reaching 1.8 km. Here we combine recent field work, sampling and the drill core data with previous knowledge to provide insight into processes occurring at Manicouagan and, by inference, within extraterrestrial impact structures. Four areas of comparative planetology are discussed: impact melt sheets, central uplifts, impact-generated hydrothermal regimes and footwall breccias. Human training and instrument testing opportunities are also considered. The drill core reveals that the impact melt and clast-bearing impact melts in the centre of the structure reach thicknesses of 1.4 km. The 1.1 km thick impact melt has undergone differentiation to yield a lower monzodiorite, a transitional quartz monzodiorite and an upper quartz monzonite sequence. This calls into question the previous citing of Manicouagan as an exemplar of a relatively large crater possessing an undifferentiated melt sheet, which was used as a rationale for assigning different composition lunar impact melts and clast-bearing impact melts to separate cratering events. The predominantly anorthositic central uplift at Manicouagan is comparable to certain lunar highlands material, with morphometric analogies to the King, Tycho, Pythagoras, Jackson, and Copernicus impact structures, which have similar diameters and uplift structure. Excellent exposure of the Manicouagan uplift facilitates mapping and an appraisal of its formation and collapse mechanisms, enhanced by drill core data from the centre of the structure. Recent field studies at the edge of the central island at Manicouagan, and multiple drill core sections through footwall lithologies, provide insight into allochthonous (clastic and suevitic) and autochthonous breccia formation, as well as shock effects. The hydrothermal regimes developed at Manicouagan are akin to systems proposed for Noachian (>3.5 Ga) Mars that involve alteration of impact melts via meteoritic and surface waters, with the generation of phyllosilicates, zeolites, hematite, sulfates and sulfides that can contribute to martian soil formation and sedimentation processes.

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

    PubMed

    Jeon, Ju-Hyun; Lee, Hoi-Seon

    2014-08-27

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

  11. Synthesis of ethyleneoxide modified 3-carboranyl thymidine analogues and evaluation of their biochemical, physicochemical, and structural properties

    Microsoft Academic Search

    Jayaseharan Johnsamuel; Nisha Lakhi; Ashraf S. Al-Madhoun; Youngjoo Byun; Junhua Yan; Staffan Eriksson; Werner Tjarks

    2004-01-01

    Eleven 3-carboranyl thymidine analogues (3CTAs) containing highly hydrophilic and flexible ethyleneoxide moieties were synthesized as potential agents for boron neutron capture therapy (BNCT) and their biochemical and physicochemical properties were evaluated. Based on specific structural features, this library of 3CTAs was divided into three subgroups. The first group contained 3CTAs with 1–4 ethyleneoxide units between the thymidine (Thd) scaffold and

  12. Stereoselective synthesis of beta-substituted phenylalanine-beta-phenylisoserine-derived tripeptides using N-cinnamoyl-L-proline as template: synthesis of structural analogues of HIV protease inhibitors.

    PubMed

    Saha, Biswajit; Nandy, Jyoti Prokash; Shukla, Shalini; Siddiqui, Iffat; Iqbal, Javed

    2002-11-01

    N-Cinnamoyl-L-proline can be used as a template on which beta-substituted phenylalanine and beta-phenylisoserine residues can be synthesized leading to tripeptide derivatives as structural analogues of HIV protease inhibitors. PMID:12398514

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

    Microsoft Academic Search

    Jürg Nievergelt; Hans Hinterberger; Kenneth C. Sevcik

    1981-01-01

    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.

  14. Synthesis, crystal structure and anti-inflammatory properties of curcumin analogues.

    PubMed

    Liang, Guang; Yang, Shulin; Zhou, Huiping; Shao, Lili; Huang, Kexin; Xiao, Jian; Huang, Zhifeng; Li, Xiaokun

    2009-02-01

    Curcuminoids have been reported to possess multifunctional bioactivities, especially the ability to inhibit proinflammatory induction. Since it has been suggested that the seven-carbon beta-diketone linker in curcumin is responsible for its instability, nine mono-carbonyl five-carbon linker containing analogues were designed and synthesized. Their bioactivity against lipopolysaccharide-induced TNF-alpha amd IL-6 secretion was evaluated by using mouse J774.1 macrophages. The results showed that the 3'-methoxyl plays an important role in bioactivity and cyclohexanone containing analogues exhibited stronger inflammatory inhibition than acetone and cyclopentanone analogues. Subsequently the most active analogue 3c was determined using single-crystal X-ray diffraction. X-ray analysis and comparison with curcumin reveals that the presence of cyclohexanone in 3c, which remotely resembles the 6-membered ring in the enol tautomer in curcumin, may play an important role in the bioactivity. It is suggested that five-carbon linker analogues containing a cyclohexane ring which are synthetically assessable may be pharmacologically important. PMID:18336957

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

    PubMed Central

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

    2010-01-01

    In our continuation of the structure-based design of anti-trypanosomatid drugs, parasite-selective adenosine analogues were identified as low micromolar inhibitors of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Crystal structures of Trypanosoma brucei, Trypanosoma cruzi, Leishmania mexicana, and human GAPDH’s provided details of how the adenosyl moiety of NAD+ interacts with the proteins, and this facilitated the understanding of the relative affinities of a series of adenosine analogues for the various GAPDH’s. From exploration of modifications of the naphthalenemethyl and benzamide substituents of a lead compound, N6-(1-naphthalenemethyl)-2?-deoxy-2?-(3-methoxybenzamido)adenosine (6e), N6-(substituted-naphthalenemethyl)-2?-deoxy-2?-(substituted-benzamido)adenosine analogues were investigated. N6-(1-Naphthalenemethyl)-2?-deoxy-2?-(3,5-dimethoxybenzamido)adenosine (6m), N6-[1-(3-hydroxy-naphthalene)methyl]-2?-deoxy-2?-(3,5-dimethoxybenzamido)adenosine (7m), N6-[1-(3-methoxy-naphthalene)methyl]-2?-deoxy-2?-(3,5-dimethoxybenzamido)adenosine (9m), N6-(2-naphthalene-methyl)-2?-deoxy-2?-(3-methoxybenzamido)adenosine (11e), and N6-(2-naphthalenemethyl)-2?-deoxy-2?-(3,5-dimethoxybenzamido)adenosine (11m) demonstrated a 2- to 3-fold improvement over 6e and a 7100- to 25000-fold improvement over the adenosine template. IC50’s of these compounds were in the range 2–12 ?M for T. brucei, T. cruzi, and L. mexicana GAPDH’s, and these compounds did not inhibit mammalian GAPDH when tested at their solubility limit. To explore more thoroughly the structure–activity relationships of this class of compounds, a library of 240 N6-(substituted)-2?-deoxy-2?-(amido)adenosine analogues was generated using parallel solution-phase synthesis with N6 and C2? substituents chosen on the basis of computational docking scores. This resulted in the identification of 40 additional compounds that inhibit parasite GAPDH’s in the low micromolar range. We also explored adenosine analogues containing 5?-amido substituents and found that 2?,5?-dideoxy-2?-(3,5-dimethoxy-benzamido)-5?-(diphenylacetamido)adenosine (49) displays an IC50 of 60–100 ?M against the three parasite GAPDH’s. PMID:11405646

  16. Silicon Analogues of Triarylmethanol Hosts. Inclusion Properties and Host–guest Structures: A Comparative Study

    Microsoft Academic Search

    Edwin Weber; Wilhelm Seichter; Konstantinos Skobridis; Dimitrios Alivertis; Vassiliki Theodorou; Petra Bombicz; Ingeborg Csöregh

    2006-01-01

    The simple triarylmethanol hosts, 2 and 4, and their silicon analogues, 1 and 3, have been studied for comparison of the formation of crystalline inclusion compounds. Clathrate formation experiments showed\\u000a that replacement of the carbinol C atoms in 2 and 4 by Si atoms to give 1 and 3 resulted in a distinct increase of the capability to form inclusion

  17. A Facile Total Synthesis of ent-17?-Estradiol and Structurally–Related Analogues

    PubMed Central

    Cai, Zu Yun; Covey, Douglas F.

    2013-01-01

    A facile six-step synthesis (15.2% yield) of ent-17?-estradiol from readily accessible precursors is described. The preparation of analogues with 2-alkyl substitutents, double bond unsaturation in the C-ring, a cis C, D-ring fusion and modified substituents at C17 is also reported. PMID:17257636

  18. Properties of IRMOF-14 and its analogues M-IRMOF-14 (M = Cd, alkaline earth metals): electronic structure, structural stability, chemical bonding, and optical properties.

    PubMed

    Yang, Li-Ming; Ravindran, Ponniah; Vajeeston, Ponniah; Tilset, Mats

    2012-04-14

    The chemical bonding, electronic structure, and optical properties of the experimentally available metal-organic framework IRMOF-14 and its metal-substituted analogues M-IRMOF-14 (M = Zn, Cd, Be, Mg, Ca, Sr, Ba), which contain a pyrene-2,7-dicarboxylate linker group, have been systematically investigated using DFT calculations. The unit cell volume and atomic positions were optimized with the Perdew-Burke-Ernzerhof (PBE) functional and showed good agreement between experimental and theoretical equilibrium structural parameters for Zn-IRMOF-14. The calculated bulk moduli indicate that the whole M-IRMOF-14 series are soft materials. The estimated band gap from DOS calculations for the M-IRMOF-14 series is ca. 2.5 eV, essentially independent of the metal ion and indicative of nonmetallic character. The band gap value is distinctly different from those calculated previously for the M-IRMOF-1 (benzene-1,4-dicarboxylate linker; ca. 3.5 eV) and M-IRMOF-10 (biphenyl-4,4'-dicarboxylate linker; ca. 3.0 eV) series and this confirms that the identity of the linker is a key parameter to control band gaps in an isoreticular series of main-group MOFs. In view of potential uses of MOFs in organic semiconducting devices such as field-effect transistors, solar cells, and organic light-emitting devices, the linear optical properties of these materials were also investigated. Comparisons are made with the M-IRMOF-1 and M-IRMOF-10 series. PMID:22382620

  19. Bismethylene triphosphate nucleotides of uridine 4-phosphate analogues: a new class of anionic pyrimidine nucleotide analogues.

    PubMed

    Taylor, Scott D; Mirzaei, Farzad; Bearne, Stephen L

    2008-02-15

    Cytidine-5'-triphosphate synthase (CTPS) catalyzes the formation of cytidine triphosphate (CTP) from glutamine, uridine 5'-triphosphate (UTP), and adenosine 5'-triphosphate (ATP). This reaction proceeds via formation of the high-energy intermediate UTP-4-phosphate (UTP-4-P). Stable analogues of UTP-4-P may be potent inhibitors of CTPS and useful as lead structures for the development of anticancer and antiviral agents. Several bismethylene triphosphate (BMT) nucleotides of uridine 4-phosphate (U-4-P) analogues have been prepared. A key step was the selective methanolysis, with the aid of a tin catalyst, of the 5' ester moiety of 2',3',5'-tri-O-acetyl or tri-O-benzoyl U-4-P analogues. We believe this represents the first general approach to the selective cleavage of 5' benzoyl esters in benzoylated nucleosides. Mitsunobu coupling of these 5'-deprotected U-4-P analogues to an unsymmetrical, protected BMT bearing a free phosphonic acid moiety at one of the terminal positions gave fully protected BMT-U-4-P analogues. Global deprotection of these species was achieved using TMSBr followed by treatment with NH4OH-MeOH or NH4OH-pyridine. The resulting BMT nucleotides represent a new class of anionic pyrimidine nucleotide analogues. PMID:18215061

  20. Effects of taurine analogues on chloride channel conductance of rat skeletal muscle fibers: a structure-activity relationship investigation

    Microsoft Academic Search

    S. Pierno; D. Tricarico; A. Luca; F. Campagna; A. Carotti; G. Casini; D. Conte Camerino

    1994-01-01

    In rat skeletal muscle, taurine was proposed to interact with a low affinity binding site on sarcolemmal phospholipids near chloride channel, increasing chloride conductance (GCI). In an attempt to evaluate the structure-activity relationship between taurine and its binding site, a series of N-azacycloalkenyl analogues of taurine (A: N-(1'aza-cyclopenten-2'yl)-2-aminoethane sulfonic acid; B: N-(1'-aza-cyclopenten-2'-yl)-2-aminoethane sulfonic acid; C: N-(1'aza-cyclopenten-2'-yl)-3-amino-propane sulfonic acid; D: N-(1'aza-cyclopenten-2'-yl)-3-aminopropane

  1. Structural Analogues of Smoothened Intracellular Loops as Potent Inhibitors of Hedgehog Pathway and Cancer Cell Growth

    PubMed Central

    Remsberg, Jarrett R.; Lou, Hong; Tarasov, Sergey G.; Dean, Michael; Tarasova, Nadya I.

    2014-01-01

    Smoothened is a critical component of the Hedgehog pathway that is essential for stem cell renewal and is dysregulated in many cancer types. We have found synthetic analogues of the second and third intracellular loops of smoothened to be potent inhibitors of the Hedgehog pathway. Palmitoylated peptides as short as 10 residues inhibited melanoma cells growth with IC50 in the low nanomolar range. The compounds are promising drug candidates and convenient tools for solving mechanisms of Hedgehog signaling. PMID:17685505

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

    ERIC Educational Resources Information Center

    Nitinawarat, Sirin

    2010-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2014-03-01

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

  4. Effects of taurine analogues on chloride channel conductance of rat skeletal muscle fibers: a structure-activity relationship investigation.

    PubMed

    Pierno, S; Tricarico, D; De Luca, A; Campagna, F; Carotti, A; Casini, G; Conte Camerino, D C

    1994-04-01

    In rat skeletal muscle, taurine was proposed to interact with a low affinity binding site on sarcolemmal phospholipids near chloride channel, increasing chloride conductance (GCl). In an attempt to evaluate the structure-activity relationship between taurine and its binding site, a series of N-azacycloalkenyl analogues of taurine (A: N-(1'aza-cyclohepten-2'yl)-2-aminoethane sulfonic acid; B: N-(1'-aza-cyclopenten-2'-yl)-2-aminoethane sulfonic acid; C: N-(1'-aza-cyclohepten-2'-yl)-3-amino-propane sulfonic acid; D: N-(1'aza-cyclopenten-2'-yl)-3-aminopropane sulfonic acid) have been synthetized and tested in vitro on rat extensor digitorum longus (EDL) muscle. In spite of the presence of a bulky and lipophilic 5 or 7 membered heterocycle linked to the taurine amino group, analogues A and B determined an increase of GCl, although less potently than taurine. Also 3-amino-propane sulfonic acid (homotaurine), tested in comparison, showed less activity in increasing GCl with respect to taurine, probably for the increased distance between charged groups. Taurine analogues C and D, which differ from compounds A and B for an additional methylene group, showed much lower activity in increasing GCl. It has been reported that guanidinoethane sulfonate (GES) displaces taurine from the low affinity site on sarcolemma by only 7%. This compound, characterized by lower charge density on the guanidinium cationic head, applied in vitro on EDL muscle, show reduced taurine-like activity in increasing GCl.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8058113

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

    PubMed

    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

    2013-02-28

    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

  6. Simplified cyclic analogues of bastadin-5. Structure-activity relationships for modulation of the RyR1/FKBP12 Ca2+ channel complex.

    PubMed

    Masuno, Makoto N; Pessah, Isaac N; Olmstead, Marilyn M; Molinski, Tadeusz F

    2006-07-27

    Bastadin-5, a brominated macro-dilactam from the marine sponge Ianthella basta, enhances release of Ca2+ from stores within the sarcoplasmic reticulum (SR) of muscle and nonmuscle cells by modulating RyR1/FKBP12 complex. Analogues of bastadin-5 present desirable targets for SAR studies to shed light on the gating mechanism and locus of bastadin-5 binding on these heteromeric channels that mediate essential steps in early coupling of membrane excitation to Ca2+ signaling cascades. Simple, ring-constrained analogues of bastadin-5 were synthesized from substituted benzaldehydes in a convergent manner, featuring an efficient S(N)Ar macroetherification, and evaluated in an assay that measures [3H]-ryanodine that is known to correlate with the functional open state of the Ca2+ channel. The simplified 14-membered ring, atropisomeric analogue (+/-)-7, like bastadin-5, enhanced ryanodine binding to the RyR1/FKBP12 complex (EC50 11 microM), however, unexpectedly, the corresponding achiral 18-membered ring analogue 14 potently inhibited binding (IC50 6 microM) under the same conditions. Structure-activity relationships of both families of cyclic analogues showed activity in a ryanodine binding assay that varied with substitutions of the Br atom on the trisubstituted aryl ring by various functional groups. The most active analogues were those that conserved the dibromocatechol ether moiety that corresponds to the 'western edge' of the bastadin-5 structure. These data suggest that cyclic analogues of bastadin-5 interact with the channel complex in a complex manner that can either enhance or inhibit channel activity. PMID:16854055

  7. Modified Method of rRNA Structure Analysis Reveals Novel Characteristics of Box C/D RNA Analogues

    PubMed Central

    Filippova, J. A.; Stepanov, G. A.; Semenov, D. V.; Koval, O. A.; Kuligina, E. V.; Rabinov, I. V.; Richter, V. A.

    2015-01-01

    Ribosomal RNA (rRNA) maturation is a complex process that involves chemical modifications of the bases or sugar residues of specific nucleotides. One of the most abundant types of rRNA modifications, ribose 2’-O-methylation, is guided by ribonucleoprotein complexes containing small nucleolar box C/D RNAs. Since the majority of 2’-O-methylated nucleotides are located in the most conserved regions of rRNA that comprise functionally important centers of the ribosome, an alteration in a 2’-O-methylation profile can affect ribosome assembly and function. One of the key approaches for localization of 2’-O-methylated nucleotides in long RNAs is a method based on the termination of reverse transcription. The current study presents an adaptation of this method for the use of fluorescently labeled primers and analysis of termination products by capillary gel electrophoresis on an automated genetic analyzer. The developed approach allowed us to analyze the influence of the synthetic analogues of box C/D RNAs on post-transcriptional modifications of human 28S rRNA in MCF-7 cells. It has been established that the transfection of MCF-7 cells with a box C/D RNA analogue leads to an enhanced modification level of certain native sites of 2’-O-methylation in the target rRNA. The observed effect of synthetic RNAs on the 2’-O-methylation of rRNA in human cells demonstrates a path towards targeted regulation of rRNA post-transcriptional maturation. The described approach can be applied in the development of novel diagnostic methods for detecting diseases in humans.

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

    PubMed

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

    2015-03-18

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

  9. Synthesis, structure elucidation, in vitro biological activity, toxicity, and Caco-2 cell permeability of lipophilic analogues of alpha-conotoxin MII.

    PubMed

    Blanchfield, Joanne T; Dutton, Julie L; Hogg, Ronald C; Gallagher, Oliver P; Craik, David J; Jones, Alun; Adams, David J; Lewis, Richard J; Alewood, Paul F; Toth, Istvan

    2003-03-27

    The alpha-conotoxin MII is a two disulfide bridge containing, 16 amino acid long peptide toxin isolated from the marine snail Conus magus. This toxin has been found to be a highly selective and potent inhibitor of neuronal nicotinic acetylcholine receptors (nAChRs) of the subtype alpha3beta2. To improve the bioavailability of this peptide, two lipidic analogues of MII have been synthesized, the first by coupling 2-amino-d,l-dodecanoic acid (Laa) to the N terminus (LaaMII) and the second by replacing Asn5 in the MII sequence with this lipoamino acid (5LaaMII). Both lipidic linear peptides were then oxidized under standard conditions. (1)H NMR shift analysis of these peptides and comparison with the native MII peptide showed that the tertiary structure of the N-conjugated analogue, LaaMII, was consistent with that of the native conotoxin, whereas the 5LaaMII analogue formed the correct disulfide bridges but failed to adopt the native helical tertiary structure. The N terminus conjugate was also found to inhibit nAChRs of the subtype alpha3beta2 with equal potency to the parent peptide, whereas the 5LaaMII analogue showed no inhibitory activity. The active LaaMII analogue was found to exhibit significantly improved permeability across Caco-2 cell monolayers compared to the native MII, and both peptides showed negligible toxicity. PMID:12646037

  10. Novel Pt(II) anticancer agents and their Pd(II) analogues: syntheses, crystal structures, reactions with nucleobases and cytotoxicities

    Microsoft Academic Search

    Christian Mock; Ina Puscasu; Michael J Rauterkus; Gesche Tallen; Johannes E. A Wolff; Bernt Krebs

    2001-01-01

    Five novel cisplatin analogues as well as their equivalent palladium compounds were prepared using the chelating ligands 2-(2-pyridyl)benzimidazole (pbi), 2-(2-pyridyl)-5,6-dimethylbenzimidazole (pdbi), 2-(2-pyrazyl)-5,6-dimethylbenzimidazole (padbi), bis(pyridine-2-yl)methane (bpm), and (2,2?-dipyridyl)propylamine (dppa). The reactions of [Pt(dppa)(H2O)2]2+ with the model nucleobase 3-methylpyridone (3-MeP) and [Pd(bpm)(H2O)2]2+ with the model nucleobase 1-methylthymine (1-MeT) were studied. The products were characterised by X-ray structure analysis. The resulting compound bis(?-3-methyl-2-pyridone-N3-O4)bis[((2,2?-dipyridyl)propylamine)platinum(II)]·tetrafluoroborate

  11. Preparation and Crystal Structure of a Rhenium Analogue of the Cationic Renal Agent, Tc-99m Diaminocyclohexane

    PubMed Central

    Hansen, Lory; Taylor, Andrew; Lachicotte, Rene

    2000-01-01

    We report here a chemical study on a Re analogue of one of the few cationic Tc-99m tracers previously investigated as an agent for effective renal plasma flow (ERPF) measurement. Cationic Tc-99m tracers have the potential for overcoming problems associated with common anionic Tc-99m tracers in patients who have developed a uremic state. The Tc-99m-DACH tracer, prepared from 1,2-diaminocyclohexane (1,2-DACH), is the only cationic renal agent tested in humans and has seven possible isomers. The complex isolated from the reaction of the racemic mixture, (±)-trans-1,2-DACH, and ReIO2(PPh3)2 after conversion to the BPh4- salt was found by X-ray crystallography to be the meso isomer, trans-[ReO2 (trans-R,R-1,2-DACH)(trans-S,S-l,2-DACH)][BPh4]·MeOH·2H2O (1). The structural parameters for 1 are normal. The complex is highly symmetrical, suggesting that the analogous meso Tc-99m-DACH agent is also symmetrical. Studies of other Tc-99m-DACH agents that were made from cis-1,2-DACH or individual trans-1,2-DACH enantiomers show that the biodistribution is not very dependent on the starting 1,2-DACH ligand stereochemistry; these agents must be less symmetrical than the meso Tc-99m-DACH agent analogue of 1. Thus, the overall charge and lipophilicity (similar for all Tc-99m-DACH isomers) exert a greater influence on biodistribution than the specific structural features of the different Tc-99m-DACH isomers. PMID:18475937

  12. [Reversible metalation of a bis-disulfide analogue of the Cys*-X-Cys* hepcidin binding site: structural characterisation of the related copper complex].

    PubMed

    Desbenoit, N; Galardon, E; Deschamps, P; Roussel, P; Vaulont, S; Artaud, I; Tomas, A

    2010-11-01

    Hepcidin, a 25-amino-acid peptide secreted by the liver, distributed in the plasma and excreted in urine, is a key central regulator of body iron homeostasis. This hormone decreases export of cellular iron by binding to ferroportin, an iron exporter present at the basolateral surface of enterocytes and macrophages (the sites of dietary iron absorption and iron recycling, respectively), inducing its internalization and degradation. Hepcidin contains eight cysteine residues that form four disulfide bridges, which stabilize a hairpin-shaped structure with two beta sheets. We noticed in the sequence of hepcidin a Cys*-X-Cys* motif which can act as a metal binding site able to trap iron and/or copper. We have tested this hypothesis using a pseudopeptidic synthetic bis-disulfide analogue and we have shown that direct metalation of such ligand leads to the formation of a copper(III) complex with the typical N(2)S(2) donor set. This compound crystallizes in the orthorhombic system, space group Imma. The Cu(III) configuration is square planar, built up from two carboximado-N and two thiolato-S donors. This complex is converted back to the bis-disulfide, with release of the copper salt, upon oxidation with iodine. PMID:21073997

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

    Microsoft Academic Search

    Jianhui Feng; Mingfeng Li; Yanzhao Huang; Yi Xiao; Annalisa Pastore

    2010-01-01

    To understand how symmetric structures of many proteins are formed from asymmetric sequences, the proteins with two repeated beta-trefoil domains in Plant Cytotoxin B-chain family and all presently known beta-trefoil proteins are analyzed by structure-based multi-sequence alignments. The results show that all these proteins have similar key structural residues that are distributed symmetrically in their structures. These symmetric key structural

  14. Molecular Structure of the Rat Vitamin D Receptor Ligand Binding Domain Complexed with 2-Carbon-Substituted Vitamin D3 Hormone Analogues and a

    E-print Network

    Pike, J. Wesley

    Molecular Structure of the Rat Vitamin D Receptor Ligand Binding Domain Complexed with 2-Carbon-Substituted Vitamin D3 Hormone Analogues and a LXXLL-Containing Coactivator Peptide, Janeen L. Vanhooke,*,| Matthew M of the ligand binding domain (LBD) of the rat vitamin D receptor in ternary complexes with a synthetic LXXLL

  15. Development of a Mycobacterium smegmatis transposon mutant array for characterising the mechanism of action of tuberculosis drugs: Findings with isoniazid and its structural analogues.

    PubMed

    Campen, Richard L; Ackerley, David F; Cook, Gregory M; O'Toole, Ronan F

    2015-07-01

    The development of new drugs is required to control human tuberculosis (TB). This study examined whether drug hypersensitive mutants could be used to reveal novel aspects of the mechanism of action of a TB drug. A transposon mutant collection with an estimated 1.1-fold genome coverage (7680 mutants) was constructed in Mycobacterium smegmatis and screened in high-throughput against isoniazid. Hypersensitive transposants with mutations in genes known to influence the mode of action of isoniazid were isolated. To further investigate the role of one of these genes, nudC, the corresponding mutant was tested for sensitivity towards isoniazid structural analogues. Overexpression of nudC, as well as inhA which encodes a known target of isoniazid, increased M. smegmatis resistance to isoniazid, but failed to increase resistance to three of the analogues, NSC27607, NSC33759, and NSC40350. In contrast, overexpression of katG resulted in increased sensitivity to each of the isoniazid analogues tested including NSC27607, NSC33759, and NSC40350. This provides evidence that the latter isoniazid analogues are activated by KatG in a NudC-independent manner and that InhA may not be their primary target. In summary, characterisation of drug hypersensitive mutants detected genes involved in the mode of action of isoniazid. Furthermore, it identified isoniazid analogues which are resilient to both InhA- and NudC-dependent mechanisms of resistance. PMID:25936537

  16. CONSIDERATION OF REACTION INTERMEDIATES IN STRUCTURE-ACTIVITY RELATIONSHIPS: A KEY TO UNDERSTANDING AND PREDICTION

    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...

  17. STRUCTURE OF MATERIALSSTRUCTURE OF MATERIALS The Key to its Properties

    E-print Network

    Subramaniam, Anandh

    -METAL SEMI-CONDUCTOR INSULATOR GAS BAND STRUCTURE AMORPHOUS ATOMIC STATE / VISCOSITY SOLID LIQUID LIQUID (Crystalline) Component · Vacancies · Dislocations · Phase Transformation · Voids · Cracks · Stress corrosion

  18. Synthesis of ethyleneoxide modified 3-carboranyl thymidine analogues and evaluation of their biochemical, physicochemical, and structural properties.

    PubMed

    Johnsamuel, Jayaseharan; Lakhi, Nisha; Al-Madhoun, Ashraf S; Byun, Youngjoo; Yan, Junhua; Eriksson, Staffan; Tjarks, Werner

    2004-09-15

    Eleven 3-carboranyl thymidine analogues (3CTAs) containing highly hydrophilic and flexible ethyleneoxide moieties were synthesized as potential agents for boron neutron capture therapy (BNCT) and their biochemical and physicochemical properties were evaluated. Based on specific structural features, this library of 3CTAs was divided into three subgroups. The first group contained 3CTAs with 1-4 ethyleneoxide units between the thymidine (Thd) scaffold and a carborane cluster. The second group of 3CTAs contained a pentylene spacer between Thd and the carborane and 2-4 ethyleneoxide units additionally attached to the carborane cluster. The third group contained three 3CTAs all with pentylene spacers and four ethylene units but with different carborane cages. The ethyleneoxide modified 3CTAs were good substrates of thymidine kinase 1 (TK1) and poor substrates of human mitochondrial thymidine kinase 2 (TK2) as determined in phosphoryl transfer assays. In the first group of 3CTAs, all the compounds were efficiently phosphorylated regardless of varying spacer lengths (37-42% of the activity of Thd). The second group of 3CTAs was less effectively phosphorylated (17-26% of the activity of Thd) probably due to a less favorable sterical orientation of Thd within the active site of TK1 and/or an increased lipophilicity compared with the first group. In the third group of structural isomers, no significant differences in phosphorylation rates were observed (17-25%). A structure-function hypothesis explaining these results is presented. PMID:15336255

  19. Synthesis, solution and crystal structure of the coenzyme B12 analogue Co?-2'-fluoro-2',5'-dideoxyadenosylcobalamin.

    PubMed

    Hunger, Miriam; Wurst, Klaus; Kräutler, Bernhard

    2015-07-01

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

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

    ERIC Educational Resources Information Center

    Sjoberg, Daniel

    2008-01-01

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

  1. Cytotoxic and antioxidant effects of methoxylated stilbene analogues on HepG2 hepatoma and Chang liver cells: Implications for structure activity relationship.

    PubMed

    Hasiah, A H; Ghazali, A R; Weber, J F F; Velu, S; Thomas, N F; Inayat Hussain, S H

    2011-02-01

    Stilbenes possess a variety of biological activities including chemopreventive activity. This study was conducted to evaluate the structural activity relationships of six methoxylated stilbene analogues with respect to their cytotoxic effects and antioxidant activities on HepG2 hepatoma and Chang liver cells. The cytotoxic and total antioxidant activities of six stilbene analogues were determined by MTT and Ferric Reducing Antioxidant Power (FRAP) assays, respectively. We found that the cis-methoxylated stilbene: (Z)-3,4,4'-trimethoxystilbene was the most potent and selective antiproliferative agent (IC?? 89 µM) in HepG2 cells. For the total antioxidant activity, compounds possessing hydroxyl groups at the 4' position namely (E)-3-methoxy-4'-hydroxystilbene, (E)-3,5-dimethoxy-4'-hydroxystilbene (pterostilbene), (E)-4-methoxy-4'-hydroxystilbene showed the highest antioxidant activity. Structure activity relationship studies of these compounds demonstrated that the cytotoxic effect and antioxidant activities of the tested compounds in this study were structurally dependent. PMID:20385705

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

    SciTech Connect

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

    2010-09-03

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

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

    PubMed

    Quiñonero, David

    2015-01-01

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

  4. DATA NORMALIZATION : A KEY FOR STRUCTURAL HEALTH MONITORING

    SciTech Connect

    Farrar, C. R. (Charles R.); Sohn, H. (Hoon); Worden, K.

    2001-01-01

    Structural health monitoring (SHM) is the implementation of a damage detection strategy for aerospace, civil and mechanical engineering infrastructure. Typical damage experienced by this infrastructure might be the development of fatigue cracks, degradation of structural connections, or bearing wear in rotating machinery. For SHM strategies that rely on vibration response measurements, the ability to normalize the measured data with respect to varying operational and environmental conditions is essential if one is to avoid false-positive indications of damage. Examples of common normalization procedure include normalizing the response measurements by the measured inputs as is commonly done when extracting modal parameters. When environmental cycles influence the measured data, a temporal normalization scheme may be employed. This paper will summarize various strategies for performing this data normalization task. These strategies fall into two general classes: (1) Those employed when measures of the varying environmental and operational parameters are available; (2) Those employed when such measures are not available. Whenever data normalization is performed, one runs the risk that the damage sensitive features to be extracted from the data will be obscured by the data normalization procedure. This paper will summarize several normalization procedures that have been employed by the authors and issues that have arose when trying to implement them on experimental and numerical data.

  5. Structural Basis of Thiamine Pyrophosphate Analogues Binding to the Eukaryotic Riboswitch

    E-print Network

    Halazonetis, Thanos

    bacteria and several archaea and is, so far, the only riboswitch identified in eukaryotes.18,3 TPP shown to exert an antibiotic effect via interaction with TPP-specific riboswitches in bacteria (Figure 1B). Overall, it is very similar to the lower resolution structure,14 except for the conforma

  6. New Mexico structural zone - An analogue of the Colorado mineral belt

    USGS Publications Warehouse

    Sims, P.K.; Stein, H.J.; Finn, C.A.

    2002-01-01

    Updated aeromagnetic maps of New Mexico together with current knowledge of the basement geology in the northern part of the state (Sangre de Cristo and Sandia-Manzano Mountains)-where basement rocks were exposed in Precambrian-cored uplifts-indicate that the northeast-trending Proterozoic shear zones that controlled localization of ore deposits in the Colorado mineral belt extend laterally into New Mexico. The shear zones in New Mexico coincide spatially with known epigenetic precious- and base-metal ore deposits; thus, the mineralized belts in the two states share a common inherited basement tectonic setting. Reactivation of the basement structures in Late Cretaceous-Eocene and Mid-Tertiary times provided zones of weakness for emplacement of magmas and conduits for ore-forming solutions. Ore deposits in the Colorado mineral belt are of both Late Cretaceous-Eocene and Mid-Tertiary age; those in New Mexico are predominantly Mid-Tertiary in age, but include Late Cretaceous porphyry-copper deposits in southwestern New Mexico. The mineralized belt in New Mexico, named the New Mexico structural zone, is 250-km wide. The northwest boundary is the Jemez subzone (or the approximately equivalent Globe belt), and the southeastern boundary was approximately marked by the Santa Rita belt. Three groups (subzones) of mineral deposits characterize the structural zone: (1) Mid-Tertiary porphyry molybdenite and alkaline-precious-metal deposits, in the northeast segment of the Jemez zone; (2) Mid-Tertiary epithermal precious-metal deposits in the Tijeras (intermediate) zone; and (3) Late Cretaceous porphyry-copper deposits in the Santa Rita zone. The structural zone was inferred to extend from New Mexico into adjacent Arizona. The structural zone provides favorable sites for exploration, particularly those parts of the Jemez subzone covered by Neogene volcanic and sedimentary rocks. ?? 2002 Published by Elsevier Science B.V.

  7. 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)

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

    2012-12-01

    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.

  8. Detecting key structural features within highly recombined genes.

    PubMed

    Wertz, John E; McGregor, Karen F; Bessen, Debra E

    2007-01-26

    Many microorganisms exhibit high levels of intragenic recombination following horizontal gene transfer events. Furthermore, many microbial genes are subject to strong diversifying selection as part of the pathogenic process. A multiple sequence alignment is an essential starting point for many of the tools that provide fundamental insights on gene structure and evolution, such as phylogenetics; however, an accurate alignment is not always possible to attain. In this study, a new analytic approach was developed in order to better quantify the genetic organization of highly diversified genes whose alleles do not align. This BLAST-based method, denoted BLAST Miner, employs an iterative process that places short segments of highly similar sequence into discrete datasets that are designated "modules." The relative positions of modules along the length of the genes, and their frequency of occurrence, are used to identify sequence duplications, insertions, and rearrangements. Partial alleles of sof from Streptococcus pyogenes, encoding a surface protein under host immune selection, were analyzed for module content. High-frequency Modules 6 and 13 were identified and examined in depth. Nucleotide sequences corresponding to both modules contain numerous duplications and inverted repeats, whereby many codons form palindromic pairs. Combined with evidence for a strong codon usage bias, data suggest that Module 6 and 13 sequences are under selection to preserve their nucleic acid secondary structure. The concentration of overlapping tandem and inverted repeats within a small region of DNA is highly suggestive of a mechanistic role for Module 6 and 13 sequences in promoting aberrant recombination. Analysis of pbp2X alleles from Streptococcus pneumoniae, encoding cell wall enzymes that confer antibiotic resistance, supports the broad applicability of this tool in deciphering the genetic organization of highly recombined genes. BLAST Miner shares with phylogenetics the important predictive quality that leads to the generation of testable hypotheses based on sequence data. PMID:17257051

  9. Synthesis of a Ring Expanded Bryostatin Analogue

    PubMed Central

    Trost, Barry M.; Yang, Hanbiao; Thiel, Oliver R.; Frontier, Alison J.; Brindle, Cheyenne S.

    2008-01-01

    A ring expanded bryostatin analogue was synthesized by utilizing a Ru-catalyzed tandem tetrahydropyran formation, a Pd-catalyzed tandem dihydropyran formation, and a ring-closing metathesis (RCM) as key steps. The analogue possesses potent anti-tumor activity against the NCI-ADR cancer cell line with an IC50 of 123 nM. PMID:17279751

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

    Microsoft Academic Search

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

    1998-01-01

    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

  11. Identification of a Key Structural Element for Protein Folding Within b-Hairpin Turns

    E-print Network

    Blaber, Michael

    Identification of a Key Structural Element for Protein Folding Within b-Hairpin Turns Jaewon Kim position in defined b-hairpin turns within human acidic fibroblast growth factor, and demonstrate identified that Gly at the i þ 3 position within a subset of b-hairpin turns is a key contributor towards

  12. Structure-Based Design of ?-Carboline Analogues as Potent and Specific BET Bromodomain Inhibitors.

    PubMed

    Ran, Xu; Zhao, Yujun; Liu, Liu; Bai, Longchuan; Yang, Chao-Yie; Zhou, Bing; Meagher, Jennifer L; Chinnaswamy, Krishnapriya; Stuckey, Jeanne A; Wang, Shaomeng

    2015-06-25

    Small-molecule inhibitors of bromodomain and extra terminal proteins (BET), including BRD2, BRD3, and BRD4 proteins have therapeutic potential for the treatment of human cancers and other diseases and conditions. In this paper, we report the design, synthesis, and evaluation of ?-carboline-containing compounds as a new class of small-molecule BET inhibitors. The most potent inhibitor (compound 18, RX-37) obtained from this study binds to BET bromodomain proteins (BRD2, BRD3, and BRD4) with Ki values of 3.2-24.7 nM and demonstrates high selectivity over other non-BET bromodomain-containing proteins. Compound 18 potently and selectively inhibits cell growth in human acute leukemia cell lines harboring the rearranged mixed lineage leukemia 1 gene. We have determined a cocrystal structure of 18 in complex with BRD4 BD2 at 1.4 Å resolution, which provides a solid structural basis for the compound's high binding affinity and for its further structure-based optimization. Compound 18 represents a promising lead compound for the development of a new class of therapeutics for the treatment of human cancer and other conditions. PMID:26080064

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

    PubMed

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

    2012-10-15

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

  14. Key structure of brij for overcoming multidrug resistance in cancer.

    PubMed

    Tang, Jingling; Wang, Yongjun; Wang, Dun; Wang, Yuhua; Xu, Zhenghong; Racette, Kelly; Liu, Feng

    2013-02-11

    Multidrug resistance (MDR) is a major barrier to the chemotherapy treatment of many cancers. However, some nonionic surfactants, for example, Brij, have been shown to restore the sensitivity of MDR cells to such drugs. The aim of this study was to explore the reversal effect of Brij on MDR tumor cells and elucidate its potential mechanism. Our data indicate that the structure of Brij surfactants plays an important role in overcoming MDR in cancer, that is, modified hydrophilic-lipophilic balance (MHLB, the ratio of the number (n) of hydrophilic repeating units of ethylene oxide (EO) to the number (m) of carbons in the hydrophobic tail (CH(2))). Cell viability of cells treated with paclitaxel (PTX) nanocrystals (NCs) formulated with Brij showed positive correlations with MHLB (R(2) = 0.8195); the higher the ratio of Brij to PTX in NCs, the higher cytotoxicity induced by the PTX NCs. Significant increases in intracellular accumulation of (3)H-PTX (P-gp substrate) were observed in an MDR cell line (H460/taxR cells) treated with Brij 78 (MHLB = 1.11) and Brij 97 (MHLB = 0.6). After treatments with Brij 78 and Brij 97, the levels of intracellular ATP were decreased and verapamil-induced ATPase activities of P-gp were inhibited in multidrug resistant cells. The responses of the cells to Brij 78 and Brij 97 in ATP depletion studies correlated with the cell viability induced by PTX/Brij NCs and intracellular accumulation of (3)H-PTX. Brij 78 and Brij 97 could not alter the levels of P-gp expression detected by Western blotting. These findings may provide some insight into the likelihood of further development of more potent P-gp inhibitors for the treatment of MDR in cancer. PMID:23311629

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

    SciTech Connect

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

    2007-01-01

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

  16. Structure of a complex between a cap analogue and mRNA guanylyl transferase demonstrates the structural chemistry of RNA capping.

    PubMed

    Hâkansson, K; Wigley, D B

    1998-02-17

    Paramecium bursaria Chlorella virus PBCV-1 mRNA guanylyl transferase (capping enzyme) has been complexed with an mRNA cap analogue G[5']ppp[5']G and crystallized. The crystals belong to space group C2221 with unit cell dimensions a = 78.4 A, b = 164.1 A, c = 103.3 A, and diffraction data to 3.1 A has been collected by using synchrotron radiation. The structure has been solved by molecular replacement by using each of the two domains in the previously determined structure of the enzyme in complex with GTP. The conformation is open with respect to the active site cleft, and all contacts between enzyme and ligand are mediated by domain 1. One of the guanine bases is bound in the same pocket that is utilized by GTP. The conformation of the ligand positions the beta phosphate and the active site lysine on opposite sides of the alpha phosphate. This geometry is optimal for nucleophilic substitution reactions and has previously been found for GTP in the closed conformational form of the capping enzyme, where the lysine can be guanylylated upon treatment with excess manganese(II) ions. The remainder of the cap analogue runs along the conserved active site Lys82 Thr83 Asp84 Gly85 Ile86 Arg87 motif, and the second guanine, corresponding to the 5' RNA base, is stacked against the hydrophobic Ile86. The ligand displays approximate 2-fold symmetry with intramolecular hydrogen bonding between the 2' and 3' hydroxyls of the two ribose rings. PMID:9465045

  17. Direct Measurement of Time-Frequency Analogues of Sub-Planck Structures

    E-print Network

    Ludmila Praxmeyer; Chih-Cheng Chen; Popo Yang; Shang-Da Yang; Ray-Kuang Lee

    2015-05-27

    Exploiting the correspondence between Wigner distribution function and a frequency-resolved optical gating (FROG) measurement, we experimentally demonstrate existence of the chessboard-like interference patterns with a time-bandwidth product smaller than that of a transform-limited pulse in the phase space representation of compass states. Using superpositions of four electric pulses as realization of compass states, we have shown via direct measurements that displacements leading to orthogonal states can be smaller than limits set by uncertainty relations. In the experiment we observe an exactly chronocyclic correspondence to the sub-Planck structure in the interference pattern appearing for superposition of two Sch\\"{o}dinger-cat-like states in a position-momentum phase space.

  18. Direct Measurement of Time-Frequency Analogues of Sub-Planck Structures

    E-print Network

    Praxmeyer, Ludmila; Yang, Popo; Yang, Shang-Da; Lee, Ray-Kuang

    2015-01-01

    Exploiting the correspondence between Wigner distribution function and a frequency-resolved optical gating (FROG) measurement, we experimentally demonstrate existence of the chessboard-like interference patterns with a time-bandwidth product smaller than that of a transform-limited pulse in the phase space representation of compass states. Using superpositions of four electric pulses as realization of compass states, we have shown via direct measurements that displacements leading to orthogonal states can be smaller than limits set by uncertainty relations. In the experiment we observe an exactly chronocyclic correspondence to the sub-Planck structure in the interference pattern appearing for superposition of two Sch\\"{o}dinger-cat-like states in a position-momentum phase space.

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

    PubMed

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

    1987-08-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2013-09-01

    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.

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

    NASA Astrophysics Data System (ADS)

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

    2015-04-01

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

  2. Protein three-dimensional structure and molecular recognition: a story of soft locks and keys

    Microsoft Academic Search

    R. Sowdhamini; N. Srinivasan; K. Guruprasad; S. Rufino; V. Dhanaraj; S. P. Wood; J. Emsley; H. E. White; Tom Blundell

    1995-01-01

    One hundred years ago Emil Fischer proposed a descriptive but provocative analogy for molecular recognition: the lock and key hypothesis. At a time when little was known of the molecular structures of even the relatively simple substrates of enzymes, let alone the complex structures of proteins, this gave an extraordinarily useful visual image of enzyme action. Similar recognition processes, such

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

    PubMed

    Furet, P; Imbach, P; Fürst, P; Lang, M; Noorani, M; Zimmermann, J; García-Echeverria, C

    2001-05-21

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

  4. Structural and Immunological Characterisation of Heteroclitic Peptide Analogues Corresponding to the 600–612 Region of the HIV Envelope gp41 Glycoprotein

    Microsoft Academic Search

    Angélique Phan Chan Du; David Limal; Vincent Semetey; Hayet Dali; Michel Jolivet; Claude Desgranges; Manh Thông Cung; Jean-Paul Briand; Marie-Christine Petit; Sylviane Muller

    2002-01-01

    The conformational and immunological properties of different analogues corresponding to the 600–612 disulfide loop of the human immunodeficiency virus (HIV) gp41 glycoprotein envelope were studied. Fourteen analogues were designed and synthesised; namely, a series of seven analogues in which the disulfide bond was replaced by a lactam bridge and a series of seven analogues in which one residue of each

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

    PubMed Central

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

    2011-01-01

    ?-Conotoxin KIIIA (?-KIIIA) blocks mammalian voltage-gated sodium channels (VGSCs) and is a potent analgesic following systemic administration in mice. Previous structure-activity studies of ?-KIIIA identified a helical pharmacophore for VGSC blockade. This suggested a route for designing truncated analogues of ?-KIIIA by incorporating the key residues into an ?-helical scaffold. As (i, i+4) lactam bridges constitute a proven approach for stabilizing ?-helices, we designed and synthesized six truncated analogues of ?-KIIIA containing single lactam bridges at various locations. The helicity of these lactam analogues was analysed by NMR spectroscopy, and their activities were tested against mammalian VGSC subtypes NaV1.1 through 1.7. Two of the analogues, Ac-cyclo9/13[Asp9,Lys13]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. PMID:21962108

  6. Synthetic, structural and biological studies of the ubiquitin system: synthesis and crystal structure of an analogue containing unnatural amino acids.

    PubMed Central

    Love, S G; Muir, T W; Ramage, R; Shaw, K T; Alexeev, D; Sawyer, L; Kelly, S M; Price, N C; Arnold, J E; Mee, M P; Mayer, R J

    1997-01-01

    Ubiquitin is a 76-amino acid protein involved in the targeting for destruction of proteins in the cell. The protein can readily be synthesized chemically affording an extra dimension to studies of protein stability. Ubiquitin with various modifications to the hydrophobic core has been synthesized. In particular, two core amino acids have been replaced by aminobutyric acid (Val-26) and norvaline (for Ile-30) and the product crystallized. The refined crystal structure shows an overall contraction of the molecule and the side chain of Nva-30 rotates relative to Ile-30. However, the side chain rotation is not sufficient to compensate for the effect of the loss of the methyl group and hence a small cavity is introduced into the structure, which decreases the stability of the protein. The biological behaviour of the modified protein is unaltered. The observed changes in stability are of the magnitude expected for the removal of methyl groups from the hydrophobic core of a protein. Interestingly, the effect appears to be independent of the position of the removed methyl group. The intact structure, but not its stability, is important for recognition by the biological conjugating system. PMID:9169606

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

    PubMed

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

    2015-07-01

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

  8. Deposits of depletive high-density turbidity currents: a flume analogue of bed geometry, structure and texture

    Microsoft Academic Search

    Jaco H. Baas; WESSEL VAN KESTERENand; George Postma

    2004-01-01

    Flume experiments were performed to study the flow properties and depositional characteristics of high-density turbidity currents that were depletive and quasi-steady to waning for periods of several tens of seconds. Such currents may serve as an analogue for rapidly expanding flows at the mouth of submarine channels. The turbidity currents carried up to 35 vol.% of fine-grained natural sand, very

  9. Novel structural analogues of piperine as inhibitors of the NorA efflux pump of Staphylococcus aureus

    Microsoft Academic Search

    Ashwani Kumar; Inshad Ali Khan; Surrinder Koul; Jawahir Lal Koul; Subhash Chandra Taneja; Intzar Ali; Furqan Ali; Sandeep Sharma; Zahid Mehmood Mirza; Manoj Kumar; Pyare Lal Sangwan; Pankaj Gupta; Niranjan Thota; Ghulam Nabi Qazi

    2008-01-01

    Results: Based on the efflux inhibition assay, a library of 200 compounds was screened. Three piperine analogues, namely SK-20, SK-56 and SK-29, were found to be the most potent inhibitors of the NorA efflux pump. These inhibitors acted in a synergistic manner with ciprofloxacin, by substantially increasing its activity against both NorA-overexpressing and wild-type S. aureus isolates. These ana- logues

  10. Interaction of delta sleep-inducing peptide and its analogues with cellular membranes: A structure-function analysis

    Microsoft Academic Search

    I. I. Mikhaleva; G. T. Rikhireva; I. A. Prudchenko; I. N. Golubev

    2006-01-01

    The possibility of a correlation between the membrane properties of the delta sleep-inducing peptide (DSIP) and its analogues\\u000a and their biological activity in vivo was examined by a comparative study of the membrane effects of these peptides. The peptides\\u000a exhibiting biological activity in vivo were shown to cause a statistically reliable disordering of lipids in thrombocyte plasma\\u000a membranes similar to

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

    NASA Astrophysics Data System (ADS)

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

    2015-04-01

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

  12. Key factors for successful generation of protein-fragment structures requirement on protein, crystals, and technology.

    PubMed

    Böttcher, Jark; Jestel, Anja; Kiefersauer, Reiner; Krapp, Stephan; Nagel, Susanna; Steinbacher, Stefan; Steuber, Holger

    2011-01-01

    In the past two decades, fragment-based approaches have evolved as a predominant strategy in lead discovery. The availability of structural information on the interaction geometries of binding fragments is key to successful structure-guided fragment-to-lead evolution. In this chapter, we illustrate methodological advances for protein-fragment crystal structure generation in order to offer general lessons on the importance of fragment properties and the most appropriate crystallographic setup to evaluate them. We analyze elaborate protocols, methods, and clues applied to challenging complex formation projects. The results should assist medicinal chemists to select the most promising targets and strategies for fragment-based crystallography as well as provide a tutorial to structural biologists who attempt to determine protein-fragment structures. PMID:21371587

  13. FormatesThe Analogue of Azide: Structural and Magnetic Properties of M(HCOO)2(4,4-bpy),nH2O (M ) Mn, Co, Ni; n ) 0, 5)

    E-print Network

    Gao, Song

    FormatesThe Analogue of Azide: Structural and Magnetic Properties of M(HCOO)2(4,4-bpy),nH2O (M ) Mn group P41212. They are of three-dimensional diamondoid structure connected by anti-anti formate with 4,4-bpy in the cavities of the framework reinforcing the intermetallic connections; the diamond- like net

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

    NASA Astrophysics Data System (ADS)

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

    2012-11-01

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

  15. Comparative studies of structural, thermal, optical, and electrochemical properties of azines with different end groups with their azomethine analogues toward application in (opto)electronics.

    PubMed

    Sek, Danuta; Siwy, Mariola; Bijak, Katarzyna; Grucela-Zajac, Marzena; Malecki, Grzegorz; Smolarek, Karolina; Bujak, Lukasz; Mackowski, Sebastian; Schab-Balcerzak, Ewa

    2013-10-10

    Two series of azines and their azomethine analogues were prepared via condensation reaction of benzaldehyde, 2-hydroxybenzaldehyde, 4-pyridinecarboxaldehyde, 2-thiophenecarboxaldehyde, and 4-(diphenylamino)benzaldehyde with hydrazine monohydrate and 1,4-phenylenediamine, respectively. The structures of given compounds were characterized by FTIR, (1)H NMR, and (13)C NMR spectroscopy as well as elemental analysis. Optical, electrochemical, and thermal properties of all compounds were investigated by means of differential scanning calorimetry (DSC), UV-vis spectroscopy, stationary and time-resolved photoluminescence spectroscopy, and cycling voltammetry (CV). Additionally, the electronic properties, that is, orbital energies and resulting energy gap were calculated theoretically by density functional theory (DFT). Influence of chemical structure of the compounds on their properties was analyzed. PMID:23957579

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

    SciTech Connect

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

    1987-12-29

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

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

    SciTech Connect

    Ida, Tomoyo [Osaka University, Toyonaka, Osaka 560-0043 (Japan); Suzuki, Hideyuki [Kyoto Institute of Technology, Goshokaido-cho, Matsugasaki, Sakyo-ku, Kyoto 606-8585 (Japan); Fukuyama, Keiichi [Osaka University, Toyonaka, Osaka 560-0043 (Japan); Hiratake, Jun [Kyoto University, Uji, Kyoto 611-0011 (Japan); Wada, Kei, E-mail: keiwada@med.miyazaki-u.ac.jp [University of Miyazaki, Miyazaki 889-1692 (Japan); Osaka University, Toyonaka, Osaka 560-0043 (Japan)

    2014-02-01

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

  18. Pseudocyanides of sanguinarine and chelerythrine and their series of structurally simple analogues as new anticancer lead compounds: Cytotoxic activity, structure-activity relationship and apoptosis induction.

    PubMed

    Cao, Fang-Jun; Yang, Rui; Lv, Chao; Ma, Qun; Lei, Ming; Geng, Hui-Ling; Zhou, Le

    2015-01-25

    6-Cyano dihydrosanguinarine (CNS) and 6-cyano dihydrochelerythrine (CNC) are respectively artificial derivatives of sanguinarine and chelerythrine, two anticancer quaternary benzo[c]phenanthridine alkaloids (QBAs) while 1-cyano-2-aryl-1,2,3,4-tetrahydroisoquinolines (CATHIQs) are a class of structurally simple analogues of CNS or CNC. This study investigated the inhibition activity of CNS, CNC and CATHIQs on cancer cells, apoptosis induction as well as their preliminary SAR. The results showed that CNS and 18 out of CATHIQs showed IC50 values of 0.53 and 0.62-2.24?M against NB4 and 1.53 and 2.99-11.17?M against MKN-45 cells, respectively, superior to a standard anticancer drug cis-platinum with IC50 of 2.39 and 11.36?M. CNC showed a higher activity against NB4 cells (IC50=1.85?M) and a moderate activity against MKN-45 cells (IC50=12.72?M). Among all CATHIQs, 2 and 17 gave the highest activity against NB4 cells and MKN-45 cells (IC50=0.62 and 2.99?M), respectively. DAPI staining, AO/EB staining and ultrastructure analysis of cells demonstrated that CATHIQs were able to induce apoptosis of the cells in a concentration-dependent manner. SAR showed that substitution patterns on the N-aromatic ring significantly influenced the activity of CATHIQs. The general trend was that the introduction of electron-withdrawing substituents like halogen atom, nitro, trifluoromethyl led to a significant improvement of the activity, while the presence of electron-donating groups like methyl, methoxyl caused a reduction of the activity. In most cases, the 2' site was the most favorable substitution position for the improvement of the activity. Thus, the present results strongly suggested that QBA-type pseudocyanides may serve as potential alternatives of anticancer QBAs while CATHIQs should be a class of promising lead compounds for the development of new QBA-like-type anticancer drugs. CNS exhibited the highest cytotoxicities with IC50 values of 0.53?M on NB4 cells and 1.53?M on MKN-45 cells. PMID:25444843

  19. Strong nonadditivity as a key structure-activity relationship feature: distinguishing structural changes from assay artifacts.

    PubMed

    Kramer, Christian; Fuchs, Julian E; Liedl, Klaus R

    2015-03-23

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

  20. Natural analogues of nuclear waste glass corrosion.

    SciTech Connect

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

    1999-01-06

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

  1. Synthesis and Antibacterial Activities of Yanglingmycin Analogues.

    PubMed

    Li, Long-Bo; Dan, Wen-Jia; Tan, Fang-Fang; Cui, Li-Hui; Yuan, Zhi-Peng; Wu, Wen-Jun; Zhang, Ji-Wen

    2014-10-30

    The synthesis of Yanglingmycin and its enantiomer, along with eighteen Yanglingmycin analogues is reported. The structures were confirmed mainly by analyses of NMR spectral data. Antibacterial activity assays showed that Yanglingmycin and some of its analogues exhibited significant antibacterial activities against two important agricultural pathogenic bacteria, Ralstonia solanacearum and Pseudomonas syringae pv. actinidiae, with MIC values ranging from 3.91 to 15.62 ?g/mL. The antibacterial activities exhibited by Yanglingmycin and its analogues are promising, suggesting potential in the development of compounds for novel bactericides. PMID:25355464

  2. Synthesis and antibacterial activities of Yanglingmycin analogues.

    PubMed

    Li, Long-Bo; Dan, Wen-Jia; Tan, Fang-Fang; Cui, Li-Hui; Yuan, Zhi-Peng; Wu, Wen-Jun; Zhang, Ji-Wen

    2015-01-01

    The synthesis of Yanglingmycin and its enantiomer, along with eighteen Yanglingmycin analogues is reported. The structures were confirmed mainly by analyses of NMR spectral data. Antibacterial activity assays showed that Yanglingmycin and some of its analogues exhibited significant antibacterial activities against two important agricultural pathogenic bacteria, Ralstonia solanacearum and Pseudomonas syringae pv. actinidiae, with minimum inhibitory concentration (MIC) values ranging from 3.91 to 15.62?µg/mL. The antibacterial activities exhibited by Yanglingmycin and its analogues are promising, suggesting potential in the development of compounds for novel bactericides. PMID:25743192

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

    NASA Astrophysics Data System (ADS)

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

    2012-04-01

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

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

    PubMed

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

    2012-03-21

    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

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

    PubMed

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

    2010-09-01

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

  6. 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)

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

    2007-08-01

    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.

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

    NASA Astrophysics Data System (ADS)

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

    2015-05-01

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

  8. Automatic analogue modulation recognition

    Microsoft Academic Search

    A. K. Nandi; E. E. Azzouz

    1995-01-01

    For several reasons, modulation recognition is extremely important in communication intelligence (COMINT). In this paper, a global procedure for recognition of analogue modulation types is developed. Computer simulations for different types of band-limited analogue modulated signals corrupted by band-limited Gaussian noise have been carried out. Expressions for the instantaneous amplitude and phase as well as the Fourier transform of different

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

    NASA Astrophysics Data System (ADS)

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

    2015-05-01

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

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

    PubMed

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

    2015-02-19

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

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

    NASA Astrophysics Data System (ADS)

    Lloyd, Jonathan

    2015-04-01

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

  12. Pyrazolate-Bridging Dinucleating Ligands Containing Hydrogen-Bond Donors: Synthesis and Structure of Their Cobalt Analogues

    E-print Network

    Hendrich, Mike

    Pyrazolate-Bridging Dinucleating Ligands Containing Hydrogen-Bond Donors: Synthesis and Structure to new urea-pyrazolate dinucleating ligands are described. Metal complexes of these ligands have hydrogen

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

    EPA Science Inventory

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

  14. Nonstationary analogue black holes

    NASA Astrophysics Data System (ADS)

    Eskin, Gregory

    2014-12-01

    We study the existence of analogue nonstationary spherically symmetric black holes. The prime example is the acoustic model see Unruh (1981 Phys. Rev. Lett. 46 1351). We consider also a more general class of metrics that could be useful in other physical models of analogue black and white holes. We give examples of the appearance of black holes and of disappearance of white holes. We also discuss the relation between the apparent and the event horizons for the case of analogue black holes. In the end we study the inverse problem of determination of black or white holes by boundary measurements for the spherically symmetric nonstationary metrics.

  15. Nonstationary analogue black holes

    E-print Network

    Gregory Eskin

    2014-11-26

    We study the existence of analogue nonstationary spherically symmetric black holes. The prime example is the acoustic model (cf. [V], [U]). We consider also a more general class of metrics that could be useful in other physical models of analogue black and white holes. We give examples of the appearance of black holes and of disappearance of white holes. We also discuss the relation between the apparent and the event horizons for the case of analogue black holes. In the end we study the inverse problem of determination of black or white holes by boundary measurements for the spherically symmetric nonstationary metrics.

  16. Near-atomic resolution structures of urate oxidase complexed with its substrate and analogues: the protonation state of the ligand.

    PubMed

    Gabison, Laure; Chiadmi, Mohamed; El Hajji, Mohamed; Castro, Bertrand; Colloc'h, Nathalie; Prangé, Thierry

    2010-06-01

    Urate oxidase (uricase; EC 1.7.3.3; UOX) from Aspergillus flavus catalyzes the oxidation of uric acid in the presence of molecular oxygen to 5-hydroxyisourate in the degradation cascade of purines; intriguingly, catalysis proceeds using neither a metal ion (Fe, Cu etc.) nor a redox cofactor. UOX is a tetrameric enzyme with four active sites located at the interface of two subunits; its structure was refined at atomic resolution (1 A) using new crystal data in the presence of xanthine and at near-atomic resolution (1.3-1.7 A) in complexes with the natural substrate (urate) and two inhibitors: 8-nitroxanthine and 8-thiouric acid. Three new features of the structural and mechanistic behaviour of the enzyme were addressed. Firstly, the high resolution of the UOX-xanthine structure allowed the solution of an old structural problem at a contact zone within the tetramer; secondly, the protonation state of the substrate was determined from both a halochromic inhibitor complex (UOX-8-nitroxanthine) and from the H-atom distribution in the active site, using the structures of the UOX-xanthine and the UOX-uric acid complexes; and thirdly, it was possible to extend the general base system, characterized by the conserved catalytic triad Thr-Lys-His, to a large water network that is able to buffer and shuttle protons back and forth between the substrate and the peroxo hole along the reaction pathway. PMID:20516624

  17. 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.

    PubMed

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

    2013-11-01

    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

  18. Science Data Management During Real-Time Geological Lunar Analogue Missions to the Sudbury and Mistastin Lake Impact Structures: Recommendations for Future Ground Data Systems

    NASA Astrophysics Data System (ADS)

    Mader, M. M.; McCullough, E.; Beauchamp, M.; Clayton, J.; Marion, C. L.; Moores, J.; Pickersgill, A. E.; Preston, L. J.; Shankar, B.; Osinski, G. R.; Ilsr Team

    2012-03-01

    Simulating planetary missions on Earth can help test data management procedures and help identify needs and gaps in current ground data systems. We present lessons learned from three lunar analogue missions funded by the Canadian Space Agency.

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

    PubMed

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

    2015-07-17

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

  20. Four trifluoromethylnitrobenzene analogues.

    PubMed

    Lynch, Daniel E; McClenaghan, Ian

    2004-01-01

    The crystal structures of four trifluoromethylnitrobenzene analogues (CF(3))C(6)H(3)(NO(2))[C(4)H(8)N(2)]R (where C(4)H(8)N(2) is piperazinyl and R is ethyl carboxylate, CO(2)C(2)H(5), or phenyl, C(6)H(5)), have been determined, and their conformations and packing arrangements are compared. The four compounds are ethyl 4-[4-nitro-2-(trifluoromethyl)phenyl]piperazine-1-carboxylate, (I), and ethyl 4-[2-nitro-4-(trifluoromethyl)phenyl]piperazine-1-carboxylate, (II), both C(14)H(16)F(3)N(3)O(4), and 1-[4-nitro-2-(trifluoromethyl)phenyl]-4-phenylpiperazine, (III), and 1-[2-nitro-4-(trifluoromethyl)phenyl]-4-phenylpiperazine, (IV), both C(17)H(16)F(3)N(3)O(2). All molecules adopt a rod-like conformation, while the asymmetric units of (II) and (IV) contain two unique molecules that pack as monodirectional pairs. All molecules pack with C-H...O/F close contacts to all but one of the O atoms and to five of the 18 F atoms. PMID:14712031

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  2. 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 ( H PKIH) analogues

    Microsoft Academic Search

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

    2003-01-01

    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 the HPKIH analogues is maintained even after

  3. Pharmacophore modeling and 3D quantitative structure-activity relationship analysis of febrifugine analogues as potent antimalarial agent.

    PubMed

    Sen, Debanjan; Chatterjee, Tapan Kumar

    2013-01-01

    Febrifugine and its derivatives are effective against Plasmodium falciparum. Using PHASE algorithm, a five-point pharmacophore model with two hydrogen bond acceptor (A), one positively ionizable (P) and two aromatic rings (R), was developed to derive a predictive ligand-based statistically significant 3D-quantitative structure-activity relationship (QSAR) model (r(2) = 0.972, SD = 0.3, F = 173.4, Q(2) = 0.712, RMSE = 0.3, Person-R = 0.94, and r(2) pred = 0.8) to explicate the structural attributes crucial for antimalarial activity. The developed pharmacophore model and 3D QSAR model can be a substantial tool for virtual screening and related antimalarial drug discovery research. PMID:23662282

  4. Pharmacophore modeling and 3D quantitative structure-activity relationship analysis of febrifugine analogues as potent antimalarial agent

    PubMed Central

    Sen, Debanjan; Chatterjee, Tapan Kumar

    2013-01-01

    Febrifugine and its derivatives are effective against Plasmodium falciparum. Using PHASE algorithm, a five-point pharmacophore model with two hydrogen bond acceptor (A), one positively ionizable (P) and two aromatic rings (R), was developed to derive a predictive ligand-based statistically significant 3D-quantitative structure-activity relationship (QSAR) model (r2 = 0.972, SD = 0.3, F = 173.4, Q2 = 0.712, RMSE = 0.3, Person-R = 0.94, and r2pred = 0.8) to explicate the structural attributes crucial for antimalarial activity. The developed pharmacophore model and 3D QSAR model can be a substantial tool for virtual screening and related antimalarial drug discovery research. PMID:23662282

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

    PubMed

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

    2004-01-01

    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

  6. Action of intrathecal capsaicin and its structural analogues on the content and release of spinal substance P: selectivity of action and relationship to analgesia.

    PubMed

    Jhamandas, K; Yaksh, T L; Harty, G; Szolcsanyi, J; Go, V L

    1984-07-23

    Intrathecal injections of capsaicin (CAP) and 4 other homovanillic acid (HMV) derivatives related to the structure of CAP were carried out. Capsaicin, 1-nonenoylvanillylamide (NVA), HMV-dodecylamide (DCA) (but not HMV-cyclohexylamide (CHA) or HMV-hexadecylamide (HDC] reduced the spinal content of substance P (SP), as measured by radioimmunoassay (RIA), and increased the tail-flick latency. Similar injection of kainic acid and piperine reduced levels of SP but failed to affect the tail-flick latency. None of the agents used affected spinal levels of cholecystokinin (CCK) or vasoactive intestinal peptide (VIP) as measured by RIA. In experiments using in vivo superfusion of the rat spinal cord, CAP, DCA and NVA were found to stimulate release of SP. Capsaicin had no effect on the levels of CCK or VIP immunoreactivity in the spinal superfusate. A tachyphylaxis to the effect of CAP and DCA on spinal SP release was demonstrated. Pretreatment with either agent blocked the releasing effect of the second. Pretreatment with an inactive analogue (HDC) had no effect on the subsequent activity of CAP. Kainic acid and piperine did not induce release of SP from the spinal cord. The relative selectivity of spinally administered capsaicinoids with regard to their effects on the content and release of peptides known to be contained in primary afferents and the presence of a similar structure-activity relationship for depletion and release of SP, desensitization and antinociception suggest the presence of a specific receptor site associated with a specific population of primary afferents through which pain information may pass. Whether SP is an 'afferent pain transmitter' is not clear, but at the least, it appears to serve as a marker for a population of afferents acted upon by spinally administered capsaicinoids. PMID:6205719

  7. Impact of a heteroatom in a structure-activity relationship study on analogues of phenyl glycidyl ether (PGE) from epoxy resin systems.

    PubMed

    Niklasson, Ida B; Delaine, Tamara; Luthman, Kristina; Karlberg, Ann-Therese

    2011-04-18

    Epoxy resins are among the most common causes of occupational contact dermatitis. They are normally used in so-called epoxy resin systems (ERS). These commercial products are combinations of epoxy resins, curing agents, modifiers, and reactive diluents. The most frequently used resins are diglycidyl ethers based on bisphenol A (DGEBA) and bisphenol F (DGEBF). In this study, we have investigated the contact allergenic properties of a series of analogues to the reactive diluent phenyl glycidyl ether (PGE), all with similar basic structures but with varying heteroatoms or with no heteroatom present. The chemical reactivity of the compounds in the test series toward the hexapeptide H-Pro-His-Cys-Lys-Arg-Met-OH was investigated. All epoxides were shown to bind covalently to both cysteine and proline residues. The percent depletion of nonreacted peptide was also studied resulting in ca. 60% depletion when using either PGE, phenyl 2,3-epoxypropyl sulfide (2), or N-(2,3-epoxypropyl)aniline (3), and only 15% when using 1,2-epoxy-4-phenylbutane (4) at the same time point. The skin sensitization potencies of the epoxides using the murine local lymph node assay (LLNA) were evaluated in relation to the observed physicochemical and reactivity properties. To enable determination of statistical significance between structurally closely related compounds, a nonpooled LLNA was performed. It was found that all investigated compounds containing a heteroatom in the ?-position to the epoxide were strong sensitizers, congruent with the reactivity data, indicating that the impact of a heteroatom is crucial for the sensitizing capacity for this type of epoxides. PMID:21370839

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

    PubMed

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

    2015-07-17

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

  9. Nitrogen analogues of Thiele's hydrocarbon.

    PubMed

    Su, Yuanting; Wang, Xingyong; Li, Yuantao; Song, You; Sui, Yunxia; Wang, Xinping

    2015-01-26

    A series of bis[N,N-di-(4-methoxylphenyl)amino]arene dications 1(2+) -3(2+) have been synthesized and characterized. Their electronic structures were investigated by various experiments assisted by theoretical calculations. It was found that they are singlets in the ground state and that their diradical character is dependent on the bridging moiety. 3(2+) has a smaller singlet-triplet energy gap and its excited triplet state is thermally readily accessible. The work provides a nitrogen analogue of Thiele's hydrocarbon with considerable diradical character. PMID:25504531

  10. Cytotoxic Spliceostatins from Burkholderia sp. and Their Semisynthetic Analogues.

    PubMed

    He, Haiyin; Ratnayake, Anokha S; Janso, Jeffrey E; He, Min; Yang, Hui Y; Loganzo, Frank; Shor, Boris; O'Donnell, Christopher J; Koehn, Frank E

    2014-08-01

    The spliceostatin class of natural products was reported to be potent cytotoxic agents via inhibition of the spliceosome, a key protein complex in the biosynthesis of mature mRNA. As part of an effort to discover novel leads for cancer chemotherapy, we re-examined this class of compounds from several angles, including fermentation of the producing strains, isolation and structure determination of new analogues, and semisynthetic modification. Accordingly, a group of spliceostatins were isolated from a culture broth of Burkholderia sp. FERM BP-3421, and their structures identified by analysis of spectroscopic data. Semisynthesis was performed on the major components 4 and 5 to generate ester and amide derivatives with improved in vitro potency. With their potent activity against tumor cells and unique mode of action, spliceostatins can be considered potential leads for development of cancer drugs. PMID:25098528

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

    PubMed

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

    2015-06-25

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed

    Fang, Ming-Chih; Cadwallader, Keith R

    2014-09-01

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

  14. Novel Sorafenib-Based Structural Analogues: In Vitro Anticancer Evaluation of t-MTUCB and t-AUCMB

    PubMed Central

    Wecksler, Aaron T.; Hwang, Sung Hee; Wettersten, Hiromi I.; Gilda, Jennifer E.; Patton, Amy; Leon, Leonardo J.; Carraway, Kermit L.; Gomes, Aldrin V.; Baar, Keith; Weiss, Robert H.; Hammock, Bruce D.

    2014-01-01

    In the current study, we performed a mechanistic study on the cytotoxicity of two compounds, t-AUCMB and t-MTUCB, that are structurally similar to sorafenib. These compounds display strong cytotoxic responses in various cancer cell lines, despite significant differences in the induction of apoptotic events such as caspase activation and lactate dehydrogenase release in hepatoma cells. Both compounds induce autophagosome formation and LC3I cleavage, but there was little observable effect on mTORC1 or the downstream targets, S6K1 and 4E-BP1. In addition, there was an increase in activity of upstream signaling through the IRS1/PI3K/Akt signaling pathway, suggesting that unlike sorafenib, both compounds induce mTOR-independent autophagy. The observed autophagy correlates with mitochondrial membrane depolarization, AIF release, and oxidative stress-induced glutathione depletion. However, there were no observable changes in the ER-stress markers such as, Bip, IRE?, p-eIP2, and the lipid peroxidation marker, 4-HNE, suggesting ER-independent oxidative stress. Finally, these compounds do not possess the multikinase inhibitory activity of sorafenib, which may be reflected in their difference in ability to halt cell cycle progression compared to sorafenib. Our findings indicate that both compounds have anti-cancer effects comparable to sorafenib in multiple cell line, but they induce significant differences in apoptotic responses and appear to induce mTOR-independent autophagy. t-AUCMB and t-MTUCB, represent novel chemical probes that are capable of inducing mTOR-independent autophagy and apoptosis to differing degrees, and thus may be potential tools for further understanding the link between these two cellular stress responses. PMID:24525589

  15. Propionate analogues of zearalenone bind to Hsp90.

    PubMed

    Ugele, Markus; Sasse, Florenz; Knapp, Stefan; Fedorov, Oleg; Zubriene, Asta; Matulis, Daumantas; Maier, Martin E

    2009-09-01

    By replacement of an acetate with propionate through organic synthesis a range of zearalenone analogues were prepared. As key steps in the synthesis of the analogues we used the Noyori hydrogenation of methyl acetoacetate followed by Frater alkylation of the enantiomeric 3-hydroxybutyrates. This converted the second acetate to a propionate. Through the derived alkyne, chain extension led to 3-methylundec-10-en-2-ol derivatives. These were condensed with 2,4-dimethoxy-6-vinylbenzoic acid. Ring-closing metathesis of the obtained esters led to macrolactones, which were deproteced to give the zearalenone analogues. Several of the analogues showed cytotoxicity against the L929 mouse fibroblast cell line comparable to zearalenone (9 microM) itself. In the thermal-shift assay, two analogues 35 and ent-35 displayed stronger binding than the natural product geldanamycin to the chaperone Hsp90. PMID:19637143

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

    NASA Astrophysics Data System (ADS)

    Zwaan, Frank; Schreurs, Guido

    2015-04-01

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

  17. Effects of Vegetation Structure and Elevation on Lower Keys Marsh Rabbit Density

    E-print Network

    Dedrickson, Angela

    2012-02-14

    The Lower Keys marsh rabbit (Sylvilagus palustris hefneri, LKMR), 1 of 3 subspecies of Sylvilagus palustris, is endemic to the Lower Florida Keys. The LKMR is listed as an endangered species due to predation by feral and free roaming domestic cats...

  18. Microbial growth promotion studies of exochelin MN and analogues thereof

    Microsoft Academic Search

    Li Dong; Marvin J. Miller; Ute Möllmann

    2004-01-01

    The ability of exochelin MN and three synthetic analogues to promote the growth of various strains of mycobacteria and Gram-negative bacteria was investigated. The results indicated that growth promotion ability of these compounds depends either on ligand exchange with mycobactin or on the exochelin permease. Despite stronger iron complexing capacity, the structural analogues showed weaker growth promotion ability than exochelin

  19. The response of greek key proteins to changes in connectivity depends on the nature of their secondary structure.

    PubMed

    Kemplen, Katherine R; De Sancho, David; Clarke, Jane

    2015-06-19

    What governs the balance between connectivity and topology in regulating the mechanism of protein folding? We use circular permutation to vary the order of the helices in the all-? Greek key protein FADD (Fas-associated death domain) to investigate this question. Unlike all-? Greek key proteins, where changes in the order of secondary structure cause a shift in the folding nucleus, the position of the nucleus in FADD is unchanged, even when permutation reduces the complexity significantly. We suggest that this is because local helical contacts are so dominant that permutation has little effect on the entropic cost of forming the folding nucleus whereas, in all-? Greek key proteins, all interactions in the nucleus are long range. Thus, the type of secondary structure modulates the sensitivity of proteins to changes in connectivity. PMID:25861761

  20. The Response of Greek Key Proteins to Changes in Connectivity Depends on the Nature of Their Secondary Structure

    PubMed Central

    Kemplen, Katherine R.; De Sancho, David; Clarke, Jane

    2015-01-01

    What governs the balance between connectivity and topology in regulating the mechanism of protein folding? We use circular permutation to vary the order of the helices in the all-? Greek key protein FADD (Fas-associated death domain) to investigate this question. Unlike all-? Greek key proteins, where changes in the order of secondary structure cause a shift in the folding nucleus, the position of the nucleus in FADD is unchanged, even when permutation reduces the complexity significantly. We suggest that this is because local helical contacts are so dominant that permutation has little effect on the entropic cost of forming the folding nucleus whereas, in all-? Greek key proteins, all interactions in the nucleus are long range. Thus, the type of secondary structure modulates the sensitivity of proteins to changes in connectivity. PMID:25861761

  1. Ultradeep Pyrosequencing and Molecular Modeling Identify Key Structural Features of Hepatitis B Virus RNase H, a Putative Target

    E-print Network

    Boyer, Edmond

    Ultradeep Pyrosequencing and Molecular Modeling Identify Key Structural Features of Hepatitis B, Francea ; National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology, Hôpital against hepatitis B virus (HBV) and have a high barrier to resis- tance. However, delayed responses have

  2. Numerical and Experimental Investigation of Reinforced Concrete Key Structural Components of the New San Francisco-Oakland Bay Bridge

    E-print Network

    Hines, Eric

    ABAQUS. The concrete model allows for strain soften- ing in compression and cracking in tension using by a stiff footing fixed to the reaction floor and at the top by a heavily post-tensioned cap beam- 1 - Numerical and Experimental Investigation of Reinforced Concrete Key Structural Components

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

    ERIC Educational Resources Information Center

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

    2010-01-01

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

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

    PubMed Central

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

    2013-01-01

    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. PMID:23946854

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

    PubMed Central

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

    2013-01-01

    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. PMID:23297801

  6. Effects of Vegetation Structure and Elevation on Lower Keys Marsh Rabbit Density 

    E-print Network

    Dedrickson, Angela

    2012-02-14

    .) and buttonwood. Herbaceous halophytic plant species within the transition zone also change as elevation increases and transition from glasswort (Salicornia spp.), key grass (Monanthochloe littoralis), and saltwort (Batis maritima) to sea daisy (Borrichia...

  7. Structure-Activity Relationships for a Novel Series of Citalopram (1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile) Analogues at Monoamine Transporters

    PubMed Central

    Zhang, Peng; Cyriac, George; Kopajtic, Theresa; Zhao, Yongfang; Javitch, Jonathan A.; Katz, Jonathan L.; Newman, Amy Hauck

    2010-01-01

    (±)-Citalopram (1, 1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile), and its eutomer, escitalopram (S(+)-1) are selective serotonin reuptake inhibitors (SSRIs) that are used clinically to treat anxiety and depression. To further explore structure-activity relationships at the serotonin transporter (SERT), a series of (±)-4- and 5-substituted citalopram analogues were designed, synthesized and evaluated for binding at the SERT, dopamine transporter (DAT) and norepinephrine transporter (NET) in native rodent tissue. Many of these analogues showed high SERT binding affinities (Ki = 1–40 nM) and selectivities over both NET and DAT. Selected enantiomeric pairs of analogues were synthesized and both retained enantioselectivity as with S- and R-1, wherein S > R at the SERT. In addition, the enantiomeric pairs of 1 and 5 were tested for binding at the homologous bacterial Leucine transporter (LeuT), wherein low affinities and the absence of enantioselectivity suggested distinctive binding sites for these compounds at SERT as compared to LeuT. These novel ligands will provide molecular tools to elucidate drug-protein interactions at the SERT and to relate those to behavioral actions, in vivo. PMID:20672825

  8. A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem Cells

    Microsoft Academic Search

    Bradley E. Bernstein; Tarjei S. Mikkelsen; Xiaohui Xie; Michael Kamal; Dana J. Huebert; James Cuff; Ben Fry; Alex Meissner; Marius Wernig; Kathrin Plath; Rudolf Jaenisch; Alexandre Wagschal; Robert Feil; Stuart L. Schreiber; Eric S. Lander

    2006-01-01

    SUMMARY The most highly conserved noncoding ele- ments (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding de- velopmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development. We explored this by examining histone methylation in mouse embryonic stem (ES) cells across 56 large HCNE-rich loci. We identified a specific

  9. Sila-substitution of alkyl nitrates: synthesis, structural characterization, and sensitivity studies of highly explosive (nitratomethyl)-, bis(nitratomethyl)-, and tris(nitratomethyl)silanes and their corresponding carbon analogues.

    PubMed

    Evangelisti, Camilla; Klapötke, Thomas M; Krumm, Burkhard; Nieder, Anian; Berger, Raphael J F; Hayes, Stuart A; Mitzel, Norbert W; Troegel, Dennis; Tacke, Reinhold

    2010-06-01

    A series of analogous nitratomethyl compounds of carbon and silicon of the formula types Me(3)ElCH(2)ONO(2) (1a/1b), Me(2)El(CH(2)ONO(2))(2) (2a/2b), MeEl(CH(2)ONO(2))(3) (3a/3b), (CH(2))(4)El(CH(2)ONO(2))(2) (4a/4b), and (CH(2))(5)El(CH(2)ONO(2))(2) (5a/5b) were synthesized [El = C (a), Si (b); (CH(2))(4)El = (sila)cyclopentane-1,1-diyl; (CH(2))(5)El = (sila)cyclohexane-1,1-diyl]. All compounds were characterized by using NMR, IR, and Raman spectroscopy and mass spectrometry. In addition, the crystal structures of Me(2)C(CH(2)ONO(2))(2) (2a), (CH(2))(4)C(CH(2)ONO(2))(2) (4a), Me(2)Si(CH(2)ONO(2))(2) (2b), and (CH(2))(5)Si(CH(2)ONO(2))(2) (5b) were determined by single-crystal X-ray diffraction. The gas-phase structures of the C/Si analogues 1a and 1b were determined by electron diffraction and compared with the results of quantum chemical calculations at different levels of theory. The thermal stabilities of the C/Si pairs 1a/1b-5a/5b were investigated by using DSC. In addition, their friction and impact sensitivities were measured with standard BAM methods. The extreme sensitivities of the silicon compounds 1b-5b compared to those of the corresponding carbon analogues 1a-5a were discussed in terms of the structures of the C/Si analogues and possible geminal Si...O interactions. PMID:20433159

  10. Key Structures and Interactions for Binding of Mycobacterium tuberculosis Protein Kinase B Inhibitors from Molecular Dynamics Simulation.

    PubMed

    Punkvang, Auradee; Kamsri, Pharit; Saparpakorn, Patchreenart; Hannongbua, Supa; Wolschann, Peter; Irle, Stephan; Pungpo, Pornpan

    2015-07-01

    Substituted aminopyrimidine inhibitors have recently been introduced as antituberculosis agents. These inhibitors show impressive activity against protein kinase B, a Ser/Thr protein kinase that is essential for cell growth of M. tuberculosis. However, up to now, X-ray structures of the protein kinase B enzyme complexes with the substituted aminopyrimidine inhibitors are currently unavailable. Consequently, structural details of their binding modes are questionable, prohibiting the structural-based design of more potent protein kinase B inhibitors in the future. Here, molecular dynamics simulations, in conjunction with molecular mechanics/Poisson-Boltzmann surface area binding free-energy analysis, were employed to gain insight into the complex structures of the protein kinase B inhibitors and their binding energetics. The complex structures obtained by the molecular dynamics simulations show binding free energies in good agreement with experiment. The detailed analysis of molecular dynamics results shows that Glu93, Val95, and Leu17 are key residues responsible to the binding of the protein kinase B inhibitors. The aminopyrazole group and the pyrimidine core are the crucial moieties of substituted aminopyrimidine inhibitors for interaction with the key residues. Our results provide a structural concept that can be used as a guide for the future design of protein kinase B inhibitors with highly increased antagonistic activity. PMID:25354564

  11. Synthesis and structure-activity relationship studies of conformationally flexible tetrahydroisoquinolinyl triazole carboxamide and triazole substituted benzamide analogues as ?2 receptor ligands.

    PubMed

    Bai, Suping; Li, Shihong; Xu, Jinbin; Peng, Xin; Sai, Kiran; Chu, Wenhua; Tu, Zhude; Zeng, Chenbo; Mach, Robert H

    2014-05-22

    Two novel classes of compounds targeting the sigma-2 (?2) receptor were synthesized, and their bioactivities to binding ?1 and ?2 receptors were measured. Four novel triazole carboxamide analogues, 24d, 24e, 24f, and 39c, demonstrated high affinity and selectivity for the ?2 receptor. These data suggest (11)C-labeled versions of these compounds may be potential ?2-selective radiotracers for imaging the proliferative status of solid tumors. PMID:24821398

  12. Cytotoxic Etherphospholipid Analogues

    Microsoft Academic Search

    Dinko Berkovic

    1998-01-01

    1.Alkyllyso-derivatives of physiologic cell membrane phospholipids show remarkable cytostatic and cytotoxic activity on many malignant tumor cell lines and tumors in vitro and in vivo. Three of these etherphospholipid analogues have already been tested in clinical phase II studies and one of these compounds, hexadecylphosphocholine (HePC), is now commercially available as a drug for the treatment of mammary carcinoma in

  13. Quantum Analogue Computing

    E-print Network

    Vivien M. Kendon; Kae Nemoto; William J. Munro

    2010-01-13

    We briefly review what a quantum computer is, what it promises to do for us, and why it is so hard to build one. Among the first applications anticipated to bear fruit is quantum simulation of quantum systems. While most quantum computation is an extension of classical digital computation, quantum simulation differs fundamentally in how the data is encoded in the quantum computer. To perform a quantum simulation, the Hilbert space of the system to be simulated is mapped directly onto the Hilbert space of the (logical) qubits in the quantum computer. This type of direct correspondence is how data is encoded in a classical analogue computer. There is no binary encoding, and increasing precision becomes exponentially costly: an extra bit of precision doubles the size of the computer. This has important consequences for both the precision and error correction requirements of quantum simulation, and significant open questions remain about its practicality. It also means that the quantum version of analogue computers, continuous variable quantum computers (CVQC) becomes an equally efficient architecture for quantum simulation. Lessons from past use of classical analogue computers can help us to build better quantum simulators in future.

  14. Student Value Structures: Key to Interpersonal Interaction in the College Community.

    ERIC Educational Resources Information Center

    Paulin, Kenneth C.; Bittner, John R.

    This study attempts to discover whether personal value structures are present at the personality level of student interaction (1) when there are no specific issues confronting the student, or (2) when issues are present and interaction results in linkage of the student value structure with a particular issue. Based on the results of a differential…

  15. The crystal structure of the ternary complex of T.thermophilus seryl-tRNA synthetase with tRNA(Ser) and a seryl-adenylate analogue reveals a conformational switch in the active site.

    PubMed Central

    Cusack, S; Yaremchuk, A; Tukalo, M

    1996-01-01

    The low temperature crystal structure of the ternary complex of Thermus thermophilus seryl-tRNA synthetase with tRNA(Ser) (GGA) and a non-hydrolysable seryl-adenylate analogue has been refined at 2.7 angstrom resolution. The analogue is found in both active sites of the synthetase dimer but there is only one tRNA bound across the two subunits. The motif 2 loop of the active site into which the single tRNA enters interacts within the major groove of the acceptor stem. In particular, a novel ring-ring interaction between Phe262 on the extremity of this loop and the edges of bases U68 and C69 explains the conservation of pyrimidine bases at these positions in serine isoaccepting tRNAs. This active site takes on a significantly different ordered conformation from that observed in the other subunit, which lacks tRNA. Upon tRNA binding, a number of active site residues previously found interacting with the ATP or adenylate now switch to participate in tRNA recognition. These results shed further light on the structural dynamics of the overall aminoacylation reaction in class II synthetases by revealing a mechanism which may promote an ordered passage through the activation and transfer steps. Images PMID:8654381

  16. Analogues of methotrexate.

    PubMed

    Montgomery, J A; Piper, J R; Elliott, R D; Temple, C; Roberts, E C; Shealy, Y F

    1979-07-01

    Analogues of methotrexate (MTX) were prepared by alkylation of side-chain precursors with 6-(bromomethyl)-2,4-pteridinediamine followed, where necessary, by saponification of the intermediate esters and, in two cases, by electrophilic substitution reactions in the pyridine ring portion of 3-deazamethotrexate. Effects of the various modifications on their ability to inhibit dihydrofolate reductase, cytotoxicity, and activity against L1210 leukemia in mice were examined in light of recent findings concerning active transport of MTX and related compounds and the binding features of the MTX-dihydrofolate reductase complex. PMID:448685

  17. The investigation of blind continental earthquake sources through analogue and numerical models

    NASA Astrophysics Data System (ADS)

    Bonini, L.; Toscani, G.; Seno, S.

    2012-04-01

    One of the most challenging topic in earthquake geology is to characterize the seismogenic sources, i.e. the potential causative faults of earthquakes. The main seismogenic layer is located in the upper brittle crust. Nevertheless it does not mean that a fault take up the whole schizosphere: i.e. from the brittle-plastic transition to the surface. Indeed, latest damaging earthquakes were generated by blind or "hidden" faults: 23 Oct. 2011, Van earthquake (Mw 7.1, Turkey); 3 Sep 2010, Darfield earthquake (Mw 7.1, New Zealand); 12 January 2010 Haiti earthquake (Mw 7.0); 6 April 2009 L'Aquila earthquake (Mw 6.3, Italy). Therefore understand how a fault grows and develops is a key question to evaluate the seismogenic potential of an area. Analogue model was used to understand kinematics and geometry of the geological structures since the beginning of the modern geology. On the other hand, numerical model develops much more during the last thirty years. Nowadays we can use these two methods working together providing mutual interactions. In the two-three most recent years we tried to use both numerical and analogue models to investigate the long-term and short-term evolution of a blind normal fault. To do this we improved the Analogue Model Laboratory of the University of Pavia with a laser scanner, a stepper motor and other high resolution tools in order to detect the distribution of the deformation mainly induced by blind faults. The goal of this kind of approach is to mimic the effects of the faults movements in a scaled model. We selected two seismogenic source cases: the causative fault of the 1908 Messina earthquake (Mw 7.1) and that of the 2009 L'Aquila earthquake (Mw 6.3). In the first case we investigate the long term evolution of this structure using a set of analogue models and afterwards a numerical model of our sandbox allow us to investigate stress and strain partitioning. In the second case we performed only an analogue model of short-term evolution of the L'Aquila seismogenic source comparing our result with pre-existing numerical models. In both cases we obtain mutual advantages using together experimental results. We believe that the analogue modelling approach coupled with numerical modelling applied to the study of active faults can provide useful insights to investigate the seismic potential of a structure with important appliances also for the seismic risk assessment.

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

    SciTech Connect

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

    2010-01-01

    The key regulatory step in the biosynthesis of abscisic acid (ABA), a hormone central to the regulation of several important processes in plants, is the oxidative cleavage of the 11,12 double bond of a 9-cis-epoxycarotenoid. The enzyme viviparous14 (VP14) performs this cleavage in maize (Zea mays), making it a target for the rational design of novel chemical agents and genetic modifications that improve plant behavior through the modulation of ABA levels. The structure of VP14, determined to 3.2-{angstrom} resolution, provides both insight into the determinants of regio- and stereospecificity of this enzyme and suggests a possible mechanism for oxidative cleavage. Furthermore, mutagenesis of the distantly related CCD1 of maize shows how the VP14 structure represents a template for all plant carotenoid cleavage dioxygenases (CCDs). In addition, the structure suggests how VP14 associates with the membrane as a way of gaining access to its membrane soluble substrate.

  19. Crystal structure of ATP sulfurylase from Saccharomyces cerevisiae, a key enzyme in sulfate activation

    PubMed Central

    Ullrich, Tobias C.; Blaesse, Michael; Huber, Robert

    2001-01-01

    ATP sulfurylases (ATPSs) are ubiquitous enzymes that catalyse the primary step of intracellular sulfate activation: the reaction of inorganic sulfate with ATP to form adenosine-5?-phosphosulfate (APS) and pyrophosphate (PPi). With the crystal structure of ATPS from the yeast Saccharomyces cerevisiae, we have solved the first structure of a member of the ATP sulfurylase family. We have analysed the crystal structure of the native enzyme at 1.95 ? resolution using multiple isomorphous replacement (MIR) and, subsequently, the ternary enzyme product complex with APS and PPi bound to the active site. The enzyme consists of six identical subunits arranged in two stacked rings in a D3 symmetric assembly. Nucleotide binding causes significant conformational changes, which lead to a rigid body structural displacement of domains III and IV of the ATPS monomer. Despite having similar folds and active site design, examination of the active site of ATPS and comparison with known structures of related nucleotidylyl transferases reveal a novel ATP binding mode that is peculiar to ATP sulfuryl-ases. PMID:11157739

  20. Protective activity of (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol analogues against diisopropylfluorophosphate neurotoxicity: preliminary structure-activity relationship and pharmacophore modeling.

    PubMed

    Eterovi?, Vesna A; Del Valle-Rodriguez, Angelie; Pérez, Dinely; Carrasco, Marimée; Khanfar, Mohammad A; El Sayed, Khalid A; Ferchmin, Pedro A

    2013-08-01

    Diisopropylfluorophosphate (DFP) is an organophosphorous insecticide used as a surrogate for the more toxic chemical warfare nerve agent sarin. DFP produces neurotoxicity in vivo and irreversibly decreases the area of population spikes recorded from the CA1 region of acute hippocampal slices. (1S,2E,4R,6R,7E,11E)-2,7,11-Cembratriene-4,6-diol (1) is a neuroprotective natural cembranoid that reverses DFP-induced damage both in vivo and in the hippocampal slice. Cembranoid 1 acts by noncompetitive inhibition of the ?7 nicotinic acetylcholine receptor. This study aims at establishing a preliminary structure-activity relationship to define the neuroprotective cembranoid pharmacophores using the hippocampal slice assay and pharmacophore modeling. Fourteen natural, semisynthetic, or biocatalytic cembranoid analogues 2-15 related to 1 were tested for their capacity to protect the population spikes from DFP-induced damage and intrinsic toxicity. Twelve cembranoids caused significant reversal of DFP toxicity; only 3 active analogues displayed minor intrinsic toxicity at 10 ?M. The C-4 epimer of 1 (2) and the 4-O-methyl ether analogue of 1 (3), were totally devoid of neuroprotective activity. The results suggested a model for cembranoid binding where the hydrophobic ring surface binds to a hydrophobic (Hbic) patch on the receptor molecule and an electronegative atom (oxygen or sulfur) in proper spatial relationship to the ring surface interacts with an electropositive group in the receptor binding site. A pharmacophore model consisting of 1 hydrogen bond acceptor (HBA), 2 Hbic, and 10 exclusion spheres was established using HipHop-REFINE and supported the above mentioned pharmacophoric hypothesis. PMID:23769165

  1. Protective activity of (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol analogues against diisopropylfluorophosphate neurotoxicity: Preliminary structure-activity relationship and pharmacophore modeling

    PubMed Central

    Eterovi?, Vesna A.; Valle-Rodriguez, Angelie Del; Pérez, Dinely; Carrasco, Marimée; Khanfar, Mohammad A.; El Sayed, Khalid A.; Ferchmin, Pedro A.

    2013-01-01

    Diisopropylfluorophosphate (DFP) is an organophosphorous insecticide used as a surrogate for the more toxic chemical warfare nerve agent sarin. DFP produces neurotoxicity in vivo and irreversibly decreases the area of population spikes recorded from the CA1 region of acute hippocampal slices. (1S,2E,4R,6R,7E,11E)-2,7,11-Cembratriene-4,6-diol (1) is a neuroprotective natural cembranoid that reverses DFP-induced damage both in vivo and in the hippocampal slice. Cembranoid 1 acts by noncompetitive inhibition of the ?7 nicotinic acetylcholine receptor. This study aims at establishing a preliminary structure-activity relationship to define the neuroprotective cembranoid pharmacophores using the hippocampal slice assay and pharmacophore modeling. Fourteen natural, semisyntheti or biocatalytic cembranoid analogues 2-15 related to 1 were tested for their capacity to protect the population spikes from DFP-induced damage and intrinsic toxicity. Twelve cembranoids caused significant reversal of DFP toxicity; only 3 active analogues displayed minor intrinsic toxicity at 10 ?M. The C-4 epimer of 1 (2) and the 4-O-methyl ether analogue of 1 (3), were totally devoid of neuroprotective activity. The results suggested a model for cembranoid binding where the hydrophobic ring surface binds to a hydrophobic (Hbic) patch on the receptor molecule and an electronegative atom (oxygen or sulfur) in proper spatial relationship to the ring surface interacts with an electropositive group in the receptor binding site. A pharmacophore model consisting of 1 hydrogen bond acceptor (HBA), 2 Hbic, and 10 exclusion spheres was established using HipHop-REFINE and supported the above mentioned pharmacophoric hypothesis. PMID:23769165

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

    PubMed Central

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

    2013-01-01

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

  3. 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.

    PubMed

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

    2011-08-15

    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

  4. Identification of key structural characteristics of Schisandra chinensis lignans involved in P-glycoprotein inhibition.

    PubMed

    Slanina, Ji?í; Páchniková, Gabriela; Carnecká, Martina; Porubová Koubíková, Ludmila; Adámková, Lenka; Humpa, Otakar; Smejkal, Karel; Slaninová, Iva

    2014-10-24

    The aim of the present study was to determine the structural requirements for dibenzocyclooctadiene lignans essential for P-glycoprotein inhibition. Altogether 15 structurally related lignans isolated from Schisandra chinensis or prepared by modification of their backbone were investigated, including three pairs of enantiomers. P-Glycoprotein inhibition was quantified using a doxorubicin accumulation assay in human promyelotic leukemia HL60/MDR cells overexpressing P-glycoprotein. A preliminary quantitative structure-activity relationship analysis revealed three main structural features involved in P-glycoprotein inhibition: a 1,2,3-trimethoxy moiety, a 6-acyloxy group, and the absence of a 7-hydroxy group. The most effective inhibitors, (-)-gomisin N (1) and (+)-deoxyschizandrin [(+)-2], were selected for further evaluation of their effects. Both these lignans restored the cytotoxic effect of doxorubicin in HL60/MDR cells and when combined with a subtoxic concentration of this compound increased the proportion of G2/M cells significantly, which is a usual response to treatment with this anticancer drug. PMID:25302569

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

    ERIC Educational Resources Information Center

    Rymarz, Richard

    2013-01-01

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

  6. Structure Activity Relationship of Uridine 5?-Diphosphoglucose (UDP-Glucose) Analogues as Agonists of the Human P2Y14 Receptor

    PubMed Central

    Ko, Hyojin; Fricks, Ingrid; Ivanov, Andrei A.; Harden, T. Kendall; Jacobson, Kenneth A.

    2012-01-01

    UDP-glucose (UDPG) and derivatives are naturally-occurring agonists of the Gi protein-coupled P2Y14 receptor, which occurs in the immune system. We synthesized and characterized pharmacologically novel analogues of UDPG modified on the nucleobase, ribose, and glucose moieties, as the basis for designing novel ligands in conjunction with modeling. The recombinant human P2Y14 receptor expressed in COS-7 cells was coupled to phospholipase C through an engineered G?-q/i protein. Most modifications of the uracil or ribose moieties abolished activity; this is among the least permissive P2Y receptors. However, a 2-thiouracil modification in 15 (EC50 49 ± 2 nM) enhanced the potency of UDPG (but not UDP-glucuronic acid) by 7-fold. 4-Thio analogue 13 was equipotent to UDPG, but S-alkylation was detrimental. Compound 15 was docked in a rhodposin-based receptor homology model, which correctly predicted potent agonism of UDP-fructose, UDP-mannose, and UDP-inositol. The hexose moiety of UDPG interacts with multiple H-bonding and charged resides and provides a fertile region for agonist modification. PMID:17407275

  7. The duration of Fgf8 isthmic organizer expression is key to patterning different tectal-isthmo-cerebellum structures.

    PubMed

    Sato, Tatsuya; Joyner, Alexandra L

    2009-11-01

    The isthmic organizer and its key effector molecule, fibroblast growth factor 8 (Fgf8), have been cornerstones in studies of how organizing centers differentially pattern tissues. Studies have implicated different levels of Fgf8 signaling from the mid/hindbrain boundary (isthmus) as being responsible for induction of different structures within the tectal-isthmo-cerebellum region. However, the role of Fgf8 signaling for different durations in patterning tissues has not been studied. To address this, we conditionally ablated Fgf8 in the isthmus and uncovered that prolonged expression of Fgf8 is required for the structures found progressively closer to the isthmus to form. We found that cell death cannot be the main factor accounting for the loss of brain structures near the isthmus, and instead demonstrate that tissue transformation underlies the observed phenotypes. We suggest that the remaining Fgf8 and Fgf17 signaling in our temporal Fgf8 conditional mutants is sufficient to ensure survival of most midbrain/hindbrain cells near the isthmus. One crucial role for sustained Fgf8 function is in repressing Otx2 in the hindbrain, thereby allowing the isthmus and cerebellum to form. A second requirement for sustained Fgf8 signaling is to induce formation of a posterior tectum. Finally, Fgf8 is also required to maintain the borders of expression of a number of key genes involved in tectal-isthmo-cerebellum development. Thus, the duration as well as the strength of Fgf8 signaling is key to patterning of the mid/hindbrain region. By extrapolation, the length of Fgf8 expression could be crucial to Fgf8 function in other embryonic organizers. PMID:19793884

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

    PubMed Central

    2011-01-01

    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. PMID:22102754

  9. A mimicking enzyme analogue for chemical sensors.

    PubMed

    Zen, J M; Kumar, A S

    2001-10-01

    An artificial enzyme analogue of Nafion/lead-ruthenium oxide pyrochlore (Py) chemically modified electrode (NPyCME) is synthesized by in situ precipitation through blocking of Nafion's hydrophilic zones. The catalytically active Py sites covered with a hydrophobic core of Nafion resemble an enzymatic structure. Moreover, the NPyCME obeys the Michaelis-Menten mechanism for the oxidation of many organic and biological molecules. This Account highlights aspects of the preparation, characterization, and application of the NPyCME. PMID:11601961

  10. Key Sites for P2X Receptor Function and Multimerization: Overview of Mutagenesis Studies on a Structural Basis

    PubMed Central

    Hausmann, Ralf; Kless, Achim; Schmalzing, Günther

    2015-01-01

    P2X receptors constitute a seven-member family (P2X1-7) of extracellular ATP-gated cation channels of widespread expression. Because P2X receptors have been implicated in neurological, inflammatory and cardiovascular diseases, they constitute promising drug targets. Since the first P2X cDNA sequences became available in 1994, numerous site-directed mutagenesis studies have been conducted to disclose key sites of P2X receptor function and oligomerization. The publication of the 3-Å crystal structures of the zebrafish P2X4 (zfP2X4) receptor in the homotrimeric apo-closed and ATP-bound open states in 2009 and 2012, respectively, has ushered a new era by allowing for the interpretation of the wealth of molecular data in terms of specific three-dimensional models and by paving the way for designing more-decisive experiments. Thanks to these structures, the last five years have provided invaluable insight into our understanding of the structure and function of the P2X receptor class of ligandgated ion channels. In this review, we provide an overview of mutagenesis studies of the pre- and post-crystal structure eras that identified amino acid residues of key importance for ligand binding, channel gating, ion flow, formation of the pore and the channel gate, and desensitization. In addition, the sites that are involved in the trimerization of P2X receptors are reviewed based on mutagenesis studies and interface contacts that were predicted by the zfP2X4 crystal structures. PMID:25439586

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

    SciTech Connect

    Thompson, M.R. (Pacific Northwest Lab., Richland, WA (USA)); Ebner, J.R. (Monsanto Co., St. Louis, MO (USA))

    1990-04-01

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

  12. Limitations and extensions of the lock-and-key principle: differences between gas state, solution and solid state structures.

    PubMed

    Schneider, Hans-Jörg

    2015-01-01

    The lock-and-key concept is discussed with respect to necessary extensions. Formation of supramolecular complexes depends not only, and often not even primarily on an optimal geometric fit between host and guest. Induced fit and allosteric interactions have long been known as important modifications. Different binding mechanisms, the medium used and pH effects can exert a major influence on the affinity. Stereoelectronic effects due to lone pair orientation can lead to variation of binding constants by orders of magnitude. Hydrophobic interactions due to high-energy water inside cavities modify the mechanical lock-and-key picture. That optimal affinities are observed if the cavity is only partially filled by the ligand can be in conflict with the lock-and-key principle. In crystals other forces than those between host and guest often dominate, leading to differences between solid state and solution structures. This is exemplified in particular with calixarene complexes, which by X-ray analysis more often than other hosts show guest molecules outside their cavity. In view of this the particular problems with the identification of weak interactions in crystals is discussed. PMID:25815592

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

    NASA Astrophysics Data System (ADS)

    François, Thomas; Burov, Evgueni

    2014-05-01

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

  14. Syntheses of Cyclotriveratrylene Analogues and Their Long Elusive Triketone Congeners

    PubMed Central

    2015-01-01

    Although interest in cyclotriveratrylene and its analogues has been significant, limitations in the ability to adjust its structure fully have hampered studies into their complete range of properties. A unique strategy to synthesize a previously unobtainable cyclotriveratrylene analogue and a procedure which adjusts the inner methylene bridges of that material to a triketone is reported. A second triketone synthesis and computational studies indicate the parameters needed for success. PMID:24987807

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

    NASA Astrophysics Data System (ADS)

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

    2013-04-01

    Land and soil conservation topics, the final mandate of the United Convention to Combat desertification in drylands, have been diagnosed as still suffering from a lack of guidance. On the contrary, climate change and biodiversity issues -the other two big subjects of the Rio Conventions- seem to progress and may benefit from the advice of international panels. Arguably the weakness of policy measures and hence the application of scientific knowledge by land users and stakeholders could be the expression of an inadequate research organization and a lack of ability to channel their findings. In order to better understand the size, breadth and depth of the scientific communities involved in providing advice to this convention and to other bodies, this study explores the corpus of international publications dealing with land and/or with soils. A database of several thousands records including a significant part of the literature published so far was performed using the Web of Science and other socio-economic databases such as FRANCIS and CAIRN. We extracted hidden information using bibliometric methods and data mining applied to these scientific publications to map the key actors (laboratories, teams, institutions) involved in research on land and on soils. Several filters were applied to the databases in combination with the word "desertification". The further use of Tetralogie software merges databases, analyses similarities and differences between keywords, disciplines, authors and regions and identifies obvious clusters. Assessing their commonalities and differences, the visualisation of links and gaps between scientists, organisations, policymakers and other stakeholders is possible. The interpretation of the 'clouds' of disciplines, keywords, and techniques will enhance the understanding of interconnections between them; ultimately this will allow diagnosing some of their strengths and weaknesses. This may help explain why land and soil degradation remains a serious global problem that lacks sufficient attention. We hope that this study will contribute to clarify the scientific landscape at stake to remediate possible weaknesses in the future.

  16. MOBILIZING COMMUNITIES AROUND HIV PREVENTION FOR YOUTH: HOW THREE COALITIONS APPLIED KEY STRATEGIES TO BRING ABOUT STRUCTURAL CHANGES

    PubMed Central

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

    2010-01-01

    Increasingly, HIV prevention efforts must focus on altering features of the social and physical environment to reduce risks associated with HIV acquisition and transmission. Community coalitions provide a vehicle for bringing about sustainable structural changes. This article shares lessons and key strategies regarding how three community coalitions located in Miami and Tampa, Florida, and San Juan, Puerto Rico engaged their respective communities in bringing about structural changes affecting policies, practices and programs related to HIV prevention for 12–24-year-olds. Outcomes of this work include increased access to HIV testing and counseling in the juvenile correctional system (Miami), increased monitoring of sexual abuse between young women and older men within public housing, and support services to deter age discordant relationships (Tampa) and increased access to community-based HIV testing (San Juan). PMID:20166784

  17. Synthesis and biological activity of two C-7 methyl analogues of vitamin d.

    PubMed

    Sokolowska, Katarzyna; Carballa, Diego; Seoane, Samuel; Pérez-Fernández, Román; Mouriño, Antonio; Sicinski, Rafal R

    2015-01-01

    Two novel vitamin D analogues of the hormone 1?,25-(OH)2D3 modified at C-7, namely, 7-methyl-1?,25-(OH)2D3 (12) and 7-methyl-1?,25-(OH)2-19-nor-D3 (26), were synthesized and biologically evaluated to gain further insights into the structure-function relationships of vitamin D. Key steps in the synthesis of 12 include the functionalization at C-7 by an efficient regioselective hydrostannylation of an allene precursor, and the construction of the triene framework by a palladium-catalyzed intramolecular cyclization-Suzuki-Miyaura coupling cascade. Since the calcitriol analogue 12 was prone to conversion into its previtamin D form by thermal equilibration, the corresponding 19-nor-compound 26 was also synthesized. The diene moiety of compound 26 was constructed by a modified Julia coupling. UV data as well as X-ray analysis indicate that introduction of the methyl group at C-7 results in a significant deviation from planarity of the 5,7-diene moiety. The new vitamin D analogues 12 and 26 retained good VDR binding ability. PMID:25396296

  18. Soil parent material is a key determinant of the bacterial community structure in arable soils.

    PubMed

    Ulrich, Andreas; Becker, Regina

    2006-06-01

    The bacterial community composition in soil and rhizosphere taken from arable field sites, differing in soil parent material and soil texture, was analyzed using terminal restriction fragment length polymorphism (T-RFLP) of 16S rRNA genes. Nine sandy to silty soils from North-East Germany could clearly be distinguished from each other, with a relatively low heterogeneity in the community structure within the field replicates. There was a relationship between the soil parent material, i.e. different glacial and aeolian sediments, and the clustering of the profiles from different sites. A site-specific grouping of T-RFLP profiles was also found for the rhizosphere samples of the same field sites that were planted with potatoes. The branching of the rhizosphere profiles corresponded partly with the soil parent material, whereas the effect of the plant genotype was negligible. Selected terminal restriction fragments differing in their relative abundance within the nine soils were analyzed based on the cloning of the 16S rRNA genes of one soil sample. A high phylogenetic diversity observed to include Acidobacteria, Betaproteobacteria, Bacteroidetes, Verrucomicrobia, and Gemmatimonadetes. The assignment of three out of the seven selected terminal restriction fragments to members of Acidobacteria suggested that this group seems to participate frequently in the shifting of community structures that result from soil property changes. PMID:16689875

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

    PubMed Central

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

    2014-01-01

    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

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

    PubMed Central

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

    2012-01-01

    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. PMID:23046130

  1. NASA/ESMD Analogue Mission Plans

    NASA Technical Reports Server (NTRS)

    Hoffman, Stephen J.

    2007-01-01

    A viewgraph presentation exploring Earth and its analogues is shown. The topics include: 1) ESMD Goals for the Use of Earth Analogues; 2) Stakeholders Summary; 3) Issues with Current Analogue Situation; 4) Current state of Analogues; 5) External Implementation Plan (Second Step); 6) Recent Progress in Utilizing Analogues; 7) Website Layout Example-Home Page; 8) Website Layout Example-Analogue Site; 9) Website Layout Example-Analogue Mission; 10) Objectives of ARDIG Analog Initiatives; 11) Future Plans; 12) Example: Cold-Trap Sample Return; 13) Example: Site Characterization Matrix; 14) Integrated Analogue Studies-Prerequisites for Human Exploration; and 15) Rating Scale Definitions.

  2. Binding-Induced Fluorescence of Serotonin Transporter Ligands: A Spectroscopic and Structural Study of 4-(4-(Dimethylamino)phenyl)-1-methylpyridinium (APP+) and APP+ Analogues

    PubMed Central

    2014-01-01

    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

  3. Tertiary Lymphoid Structure-Associated B Cells are Key Players in Anti-Tumor Immunity

    PubMed Central

    Germain, Claire; Gnjatic, Sacha; Dieu-Nosjean, Marie-Caroline

    2015-01-01

    It is now admitted that the immune system plays a major role in tumor control. Besides the existence of tumor-specific T cells and B cells, many studies have demonstrated that high numbers of tumor-infiltrating lymphocytes are associated with good clinical outcome. In addition, not only the density but also the organization of tumor-infiltrating immune cells has been shown to determine patient survival. Indeed, more and more studies describe the development within the tumor microenvironment of tertiary lymphoid structures (TLS), whose presence has a positive impact on tumor prognosis. TLS are transient ectopic lymphoid aggregates displaying the same organization and functionality as canonical secondary lymphoid organs, with T-cell-rich and B-cell-rich areas that are sites for the differentiation of effector and memory T cells and B cells. However, factors favoring the emergence of such structures within tumors still need to be fully characterized. In this review, we survey the state of the art of what is known about the general organization, induction, and functionality of TLS during chronic inflammation, and more especially in cancer, with a particular focus on the B-cell compartment. We detail the role played by TLS B cells in anti-tumor immunity, both as antigen-presenting cells and tumor antigen-specific antibody-secreting cells, and raise the question of the capacity of chemotherapeutic and immunotherapeutic agents to induce the development of TLS within tumors. Finally, we explore how to take advantage of our knowledge on TLS B cells to develop new therapeutic tools. PMID:25755654

  4. Design and synthesis of new fluconazole analogues.

    PubMed

    Pore, Vandana S; Agalave, Sandip G; Singh, Pratiksha; Shukla, Praveen K; Kumar, Vikash; Siddiqi, Mohammad I

    2015-06-21

    We have synthesized new fluconazole analogues containing two different 1,2,3-triazole units in the side chain. The synthesis of new amide analogues using a variety of acids is also described. All the compounds showed very good antifungal activity. A hemolysis study of the most active compounds 6e and 13j showed that both compounds did not cause any hemolysis at the dilutions tested. These compounds did not exhibit any toxicity to L929 cells at MIC and lower concentrations. In the docking study, the overall binding mode of 6e and 13j appeared to be reasonable and provided a good insight into the structural basis of inhibition of Candida albicans Cyp51 by these compounds. PMID:25975803

  5. Analogue Missions on Earth, a New Approach to Prepare Future Missions on the Moon

    NASA Astrophysics Data System (ADS)

    Lebeuf, Martin

    Human exploration of the Moon is a target by 2020 with an initial lunar outpost planned in polar regions. Current architectures maintain a capability for sorties to other latitudes for science activities. In the early stages of design of lunar outpost infrastructure and science activity planning, it has been recognized that analogue missions could play a major role in Moon mission design. Analogue missions, as high fidelity simulations of human and robotic surface operations, can help field scientists and engineers develop and test strategies as well as user requirements, as they provide opportunities to groundtruth measurements, and for the team to share understanding of key science needs and key engineering trades. These types of missions also provide direct training in planning science operations, and in team building and communication. The Canadian Space Agency's Exploration Core Program targets the development of technology infrastructure elements in key areas of science, technology and robotics in preparation for its role in the future exploration of the Moon and Mars. Within this Program, Analogue Missions specifically target the operations requirements and lessons learned that will reduce costs and lower the risk of planetary surface missions. Analogue missions are simulations of planetary surface operations that take place at analogue sites on Earth. A terrestrial analogue site resembles in some key way: eg. geomorphologically or geochemically, a surface environment of another planet. An analogue mission can, therefore, be defined as an integrated set of activities that represent (or simulate) entire mission designs or narrowly focus on specific aspects of planned or potential future planetary exploration missions. Within the CSA's Exploration Core Program, Analogue Missions facilitate the maturation of science instruments and mission concepts by integrating ongoing space instrument and technology development programs with science and analogue elements. As well as using analogue missions to meet agency programmatic needs, the Canadian Space Agency encourages scientists and engineers to make use of opportunities presented by analogue missions to further their own research objectives. Specific objectives of Analogue Missions are to (1) foster a multidisciplinary approach to planning, data acquisition, processing and interpretation, calibration of instruments, and telemetry during mission operations; (2) integrate new science with emerging technologies; and (3) develop an expertise on exploration architecture design from projects carried out at terrestrial analogue sites. Within Analogue Missions, teams develop planning tools, use mission-specific software and technology, and communicate results as well as lessons learned during tactical operations. The expertise gained through Analogue Missions will contribute to inform on all aspects of exploration architectures, including planetary mobility requirements and astronaut training.

  6. Population structure of Symbiodinium sp. associated with the common sea fan, Gorgonia ventalina , in the Florida Keys across distance, depth, and time

    Microsoft Academic Search

    Nathan L. Kirk; Jason P. Andras; C. Drew Harvell; Scott R. Santos; Mary Alice Coffroth

    2009-01-01

    Numerous marine invertebrates form endosymbiotic relationships with dinoflagellates in the genus Symbiodinium. However, few studies have examined the fine-scale population structure of these symbionts. Here, we describe the genetic\\u000a structure of Symbiodinium type “B1\\/B184” inhabiting the gorgonian Gorgonia\\u000a ventalina along the Florida Keys. Six polymorphic microsatellite loci were utilized to examine 16 populations along the Upper, Middle,\\u000a and Lower Keys

  7. Crystal structure of vitelline membrane outer layer protein I (VMO-I): a folding motif with homologous Greek key structures related by an internal three-fold symmetry.

    PubMed Central

    Shimizu, T; Vassylyev, D G; Kido, S; Doi, Y; Morikawa, K

    1994-01-01

    The crystal structure of vitelline membrane outer layer protein I (VMO-I), which is isolated from the vitelline membrane outer layer of hen's eggs, has been determined by the multiple isomorphous replacement method and refined to an R-factor of 18.8% at 2.2 A resolution. The main chain folds into an unusual structure that consists of three beta-sheets forming Greek key motifs, which are related by an internal pseudo three-fold symmetry. The internal portion surrounded by these three beta-sheets is filled with hydrophobic side chains. This conformational feature coincides with three internal repeats in the sequence. Although a similar fold exists in the second domain of delta-endotoxin, there are significant structural differences between the two proteins, with the three-fold symmetry being most regular in VMO-I. Images PMID:8131734

  8. Digitoxin Analogues with Improved Anticytomegalovirus Activity

    PubMed Central

    2014-01-01

    Cardiac glycosides are potent inhibitors of cancer cell growth and possess antiviral activities at nanomolar concentrations. In this study we evaluated the anticytomegalovirus (CMV) activity of digitoxin and several of its analogues. We show that sugar type and sugar length attached to the steroid core structure affects its anticytomegalovirus activity. Structure–activity relationship (SAR) studies identified the l-sugar containing cardiac glycosides as having improved anti-CMV activity and may lead to better understanding of how these compounds inhibit CMV replication. PMID:24900847

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

    NASA Astrophysics Data System (ADS)

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

    2012-04-01

    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.

  10. Divergent total synthesis of triptolide, triptonide, tripdiolide, 16-hydroxytriptolide, and their analogues.

    PubMed

    Xu, Hongtao; Tang, Huanyu; Feng, Huijin; Li, Yuanchao

    2014-11-01

    A divergent route was developed for the formal total synthesis of triptolide, triptonide, and tripdiolide, as well as a total synthesis of 16-hydroxytriptolide and their analogues in an enantioselective form. Common advanced intermediate 5 was concisely assembled by employing an indium(III)-catalyzed cationic polycyclization reaction and a palladium-catalyzed carbonylation-lactone formation reaction as key steps. This advanced intermediate was readily converted to the above natural products by using palladium-catalyzed cross-coupling or the Claisen rearrangement reaction as key steps. Additionally, preliminary structure-cytotoxic activity relationship studies of C13 suggested that it might be a new modification site that could still retain the cytotoxicity. PMID:25296383

  11. Preliminary structural design and key technology demonstration of cryogenic assembly in the next-generation infrared space telescope SPICA

    NASA Astrophysics Data System (ADS)

    Mizutani, Tadahito; Yamawaki, Toshihiko; Komatsu, Keiji; Goto, Ken; Takeuchi, Shinsuke; Shinozaki, Keisuke

    2014-08-01

    The infrared space telescope SPICA, Space Infrared Telescope for Cosmology and Astrophysics, is a next-generation astronomical project of the Japanese Aerospace Exploration Agency (JAXA), which features a 3m-class and 6K cryogenically- cooled space telescope. This paper outlines the current status for the preliminary structural design of the SPICA payload module. Dedicated studies were conducted for key technologies to enhance the design accuracy of the SPICA cryogenic assembly and mitigate the development risk. One of the results is described in this paper for the concept of the on-orbit truss separation mechanisms, which aim to both reduce the heat load from the main truss assembly and isolate the micro-vibration by changing the natural frequency of the spacecraft.

  12. En Route to Osmium Analogues of KP1019: Synthesis, Structure, Spectroscopic Properties and Antiproliferative Activity of trans-[OsIVCl4(Hazole)2

    PubMed Central

    2011-01-01

    By controlled Anderson type rearrangement reactions complexes of the general formula trans-[OsIVCl4(Hazole)2], where Hazole = 1H-pyrazole, 2H-indazole, 1H-imidazole, and 1H-benzimidazole, have been synthesized. Note that 2H-indazole tautomer stabilization in trans-[OsIVCl4(2H-indazole)2] is unprecedented in coordination chemistry of indazole. The metal ion in these compounds possesses the same coordination environment as ruthenium(III) in (H2ind)[RuIIICl4(Hind)2], where Hind = 1H-indazole, (KP1019), an investigational anticancer drug in phase I clinical trials. These osmium(IV) complexes are appropriate precursors for the synthesis of osmium(III) analogues of KP1019. In addition the formation of an adduct of trans-[OsIVCl4(Hpz)2] with cucurbit[7]uril is described. The compounds have been comprehensively characterized by elemental analysis, EI and ESI mass spectrometry, spectroscopy (IR, UV–vis, 1D and 2D NMR), cyclic voltammetry, and X-ray crystallography. Their antiproliferative acitivity in the human cancer cell lines CH1 (ovarian carcinoma), A549 (nonsmall cell lung carcinoma), and SW480 (colon carcinoma) is reported. PMID:21739939

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

    PubMed Central

    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.

    2013-01-01

    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. PMID:24035097

  14. Synthesis and Biological Evaluation of Carbocyclic Analogues of Pachastrissamine

    PubMed Central

    Kwon, Yongseok; Song, Jayoung; Bae, Hoon; Kim, Woo-Jung; Lee, Joo-Youn; Han, Geun-Hee; Lee, Sang Kook; Kim, Sanghee

    2015-01-01

    A series of carbocyclic analogues of naturally-occurring marine sphingolipid pachastrissamine were prepared and biologically evaluated. The analogues were efficiently synthesized via a tandem enyne/diene-ene metathesis reaction as a key step. We found that the analogue 4b exhibited comparable cytotoxicity and more potent inhibitory activity against sphingosine kinases, compared to pachastrissamine. Molecular modeling studies were conducted to provide more detailed insight into the binding mode of 4b in sphingosine kinase. In our docking model, pachastrissamine and 4b were able to effectively bind to the binding pocket of sphingosine kinase 1 as co-crystalized sphingosine. However, 4b showed a hydrophobic interaction with Phe192, which suggests that it contributes to its increased inhibitory activity against sphingosine kinase 1. PMID:25654428

  15. The structural parameters for antimicrobial activity, human epithelial cell cytotoxicity and killing mechanism of synthetic monomer and dimer analogues derived from hBD3 C-terminal region.

    PubMed

    Zhou, L; Liu, S P; Chen, L Y; Li, J; Ong, L B; Guo, L; Wohland, T; Tang, C C; Lakshminarayanan, R; Mavinahalli, J; Verma, C; Beuerman, R W

    2011-01-01

    Understanding the molecular mechanisms of antimicrobial peptide-membrane interactions is crucial in predicting the design of useful synthetic antimicrobial peptide analogues. Defensins are small (3-5 kDa) cysteine-rich cationic proteins which constitute the front line of host innate immunity. In this study, a series of eight 10 AA C-terminal analogues of hBD3 [sequence: RGRKXXRRKK, X = W, F, Y, V, L, I, H, C(Acm); net charge = +7, coded as W2, F2, Y2, V2, L2, I2, H2, and C2] and covalent V2-dimer [(RGRKVVRR)(2)KK] (18 AA, net charge = +11) were synthesized using solid phase peptide synthesis (SPPS) in Fmoc chemistry. Wild-type hBD3 was used as a control in all analyses. W2, V2, and especially Y2 showed high activity selectively against Gram-negative bacteria Pseudomonas aeruginosa in the concentration range of 4.3-9.7 microM. The covalent dimeric form of V2-monomer, V2-dimer, showed increased antibacterial killing compared to the monomeric form, V2-monomer. Cytotoxicity assays on a human conjunctival epithelial cell line (IOBA-NHC cells) showed that no change in viable cell number 24 h after constant exposure to all the eight peptide analogues even at concentrations up to 200 microg/ml. Fluorescence correlation spectroscopy (FCS) was used to study the interaction of these peptides against POPC vesicles (neutral; mammalian cell membrane mimic) and POPG vesicles (negatively charged; bacterial cell membrane mimic). Using FCS, significant aggregation and some leakage of Rhodamine dye were observed with POPG with Y2, W2 and V2 at the concentration of 5-10 mmicroM and no significant aggregation or disruption of vesicles was observed for all peptide analogues tested against POPC. V2-dimer induced more leakage and aggregation than the monomeric form. Overall, V2-dimer is the most effective antimicrobial peptide, with aggregation of POPG vesicles observed at concentrations as low as 1 microM. The concentration of 5-10 microM for Y2 from FCS correlated with the concentration of 5 microM (6.25 microg/ml), at which Y2 showed a cooperative increase in the activity. This suggests a structural transition of Y2 in the 2.5-5 microM concentration range resulting in the correlated increased antimicrobial activity. These results and the FCS together with previous NMR and molecular dynamics (MD) suggested that the charge density-based binding affinity, stable covalent dimerization, the ability to dimerize or even oligomerize and adopt a well-defined structure are important physicochemical properties distinguishing more effective cationic antimicrobial peptides. PMID:20397033

  16. Analogue modelling of syntectonic leucosomes in migmatitic schists

    NASA Astrophysics Data System (ADS)

    Druguet, Elena; Carreras, Jordi

    2006-10-01

    Migmatites from the Cap de Creus tectonometamorphic belt display a wide variety of structures, from those formed when the leucosomes were melt-bearing, to those developed during solid-state deformation. The observed field structures have been modelled by means of analogue experiments. The materials used in the models are layered plasticine as a schist analogue, and chocolate as analogue of the crystallizing leucosome. A model for the development of syntectonic migmatites is proposed in which initial melt-bearing patches, preferentially formed within fertile pelitic layers, progressively evolve towards lens-shaped veins. Furthermore, heterogeneous deformation of anisotropic metasediments facilitates formation of extensional sites for further melt accumulation and transport. Melt crystallization implies a rapid increase in effective viscosity of leucosomes producing a reversal in competence contrast with respect to the enclosing schists. During the whole process, deformation localizes around crystallizing veins, giving rise to different and contrasting structures for melt-bearing and for solid-state stages.

  17. Structural Analysis of the R-2,3-Sialyltransferase Cst-I from Campylobacter jejuni in Apo and Substrate-Analogue Bound Forms,

    E-print Network

    Strynadka, Natalie

    roles in a wide variety of essential biological processes. From the Carbohydrate-Active en- ZYmes (CAZy: Sialic acid is an essential sugar in biology that plays key roles in numerous cellular processes) as the universal donor sugar and transfer the Neu5Ac moiety onto a diverse range of complex carbohydrates found

  18. Ring closing metathesis reactions of ?-methylene-?-lactams: application to the synthesis of a simplified phyllostictine analogue with herbicidal activity.

    PubMed

    Coe, Samuel; Pereira, Nicole; Geden, Joanna V; Clarkson, Guy J; Fox, David J; Napier, Richard M; Neve, Paul; Shipman, Michael

    2015-07-01

    Ring closing metathesis (RCM) reactions of ?-methylene-?-lactams are used to construct strained 11- and 12-membered macrocycles that mimic key structural elements of phyllostictine A. The highest yield and stereoselectivity was achieved making 12-membered macrocycle Z- with use of a p-methoxyphenyl group on the lactam nitrogen. Interestingly, substrate concentration had an important influence on the stereochemical course of the reaction. A simplified analogue produced using this approach displays phytotoxic activity against Chlamydomonas reinhardtii suggesting that the ?-methylene-?-lactam subunit is responsible, at least in part, for the herbicidal activity of phyllostictine A. PMID:26081012

  19. Phonon analogue of topological nodal semimetals

    NASA Astrophysics Data System (ADS)

    Po, Hoi Chun; Bahri, Yasaman; Vishwanath, Ashvin

    2015-03-01

    Recently, Kane and Lubensky proposed a mapping between bosonic phonon problems on isostatic lattices to chiral fermion systems based on factorization of the dynamical matrix [Nat. Phys. 10, 39 (2014)]. The existence of topologically protected zero modes in such mechanical problems is related to their presence in the fermionic system and is dictated by a local index theorem. Here we adopt the proposed mapping to construct a two-dimensional mechanical analogue of a fermionic topological nodal semimetal that hosts a robust bulk node in its linearized phonon spectrum. Such topologically protected soft modes with tunable wavevector may be useful in designing mechanical structures with fault-tolerant properties.

  20. Molecular structure differences between the antiviral Nucleoside Analogue 5-iodo-2'-deoxyuridine and the natural nucleoside 2'-deoxythymidine using MP2 and DFT methods: conformational analysis, crystal simulations, DNA pairs and possible behaviour.

    PubMed

    Alcolea Palafox, M

    2014-01-01

    5-iodo-2'-deoxyuridine Nucleoside Analogue (IUdR) was the first selective antiviral nucleoside against herpes simplex virus type 1 and 2, and it was also a meaningful anticancer drug. Within a full study of this drug and its possible behaviour, previously, a comprehensive theoretical conformational analysis by MP2 and B3LYP was carried out, and all the possible stable structures were determined with full relaxation of all geometrical parameters. The search located 45 stable structures, and in all them, the whole conformational parameters ([Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], P, [Formula: see text]max) were analyzed as well as the NBO natural atomic charges. Comparisons of the conformers with those of the natural Nucleoside 2'-deoxythymidine (dT) were carried out, and the main differences between IUdR and dT were analyzed. The accuracy of the methods used was probed with the simulation of the X-ray crystal data by a tetramer form. Watson-Crick (WC) IUdR/dT···2'-deoxyadenosine pairs were analyzed for the first time using quantum chemical calculations, as well as the mispairing IUdR/dT···2'-deoxyguanosine. As result, it is observed that IUdR give rises to a slightly stronger WC pair and weaker mispairing than those with dT, therefore deforming slightly the DNA axis and difficulting the growth of the DNA virus and consequently, killing it. PMID:23731482

  1. Transfer RNA structural change is a key element in the reassignment of the CUG codon in Candida albicans.

    PubMed Central

    Santos, M A; Perreau, V M; Tuite, M F

    1996-01-01

    The human pathogenic yeast Candida albicans and a number of other Candida species translate the standard leucine CUG codon as serine. This is the latest addition to an increasing number of alterations to the standard genetic code which invalidate the theory that the code is frozen and universal. The unexpected finding that some organisms evolved alternative genetic codes raises two important questions: how have these alternative codes evolved and what evolutionary advantages could they create to allow for their selection? To address these questions in the context of serine CUG translation in C.albicans, we have searched for unique structural features in seryl-tRNA(CAG), which translates the leucine CUG codon as serine, and attempted to reconstruct the early stages of this genetic code switch in the closely related yeast species Saccharomyces cerevisiae. We show that a purine at position 33 (G33) in the C.albicans Ser-tRNA(CAG) anticodon loop, which replaces a conserved pyrimidine found in all other tRNAs, is a key structural element in the reassignment of the CUG codon from leucine to serine in that it decreases the decoding efficiency of the tRNA, thereby allowing cells to survive low level serine CUG translation. Expression of this tRNA in S.cerevisiae induces the stress response which allows cells to acquire thermotolerance. We argue that acquisition of thermotolerance may represent a positive selection for this genetic code change by allowing yeasts to adapt to sudden changes in environmental conditions and therefore colonize new ecological niches. Images PMID:8890179

  2. STRUCTURES OF A KEY INTERACTION PROTEIN FROM THE TRYPANOSOMA BRUCEI EDITOSOME IN COMPLEX WITH SINGLE DOMAIN ANTIBODIES

    PubMed Central

    Wu, Meiting; Park, Young-jun; Pardon, Els; Turley, Stewart; Hayhurst, Andrew; Deng, Junpeng; Steyaert, Jan; Hol, Wim G. J.

    2010-01-01

    Several major global diseases are caused by single-cell parasites called trypanosomatids. These organisms exhibit many unusual features including a unique and essential U-insertion-deletion RNA editing process in their single mitochondrion. Many key RNA editing steps occur in ~ 20S editosomes, which have a core of 12 proteins. Among these, the “interaction protein” KREPA6 performs a central role in maintaining the integrity of the editosome core and also binds to ssRNA. The use of llama single domain antibodies (VHH domains) accelerated crystal growth of KREPA6 from Trypanosoma brucei dramatically. All three structures obtained are heterotetramers with a KREPA6 dimer in the center, and one VHH domain bound to each KREPA6 subunit. Two of the resultant heterotetramers use complementarity determining region 2 (CDR2) and framework residues to form a parallel pair of beta strands with KREPA6 – a mode of interaction not seen before in VHH domain-antigen complexes. The third type of VHH domain binds in a totally different manner to KREPA6. Intriguingly, while KREPA6 forms tetramers in solution adding either one of the three VHH domains results in the formation of a heterotetramer in solution, in perfect agreement with the crystal structures. Biochemical solution studies indicate that the C-terminal tail of KREPA6 is involved in the dimerization of KREPA6 dimers to form tetramers. The implications of these crystallographic and solution studies for possible modes of interaction of KREPA6 with its many binding partners in the editosome are discussed. PMID:20969962

  3. Crystal structures and catalytic mechanism of the C-methyltransferase Coq5 provide insights into a key step of the yeast coenzyme Q synthesis pathway.

    PubMed

    Dai, Ya-Nan; Zhou, Kang; Cao, Dong-Dong; Jiang, Yong-Liang; Meng, Fei; Chi, Chang-Biao; Ren, Yan-Min; Chen, Yuxing; Zhou, Cong-Zhao

    2014-08-01

    Saccharomyces cerevisiae Coq5 is an S-adenosyl methionine (SAM)-dependent methyltransferase (SAM-MTase) that catalyzes the only C-methylation step in the coenzyme Q (CoQ) biosynthesis pathway, in which 2-methoxy-6-polyprenyl-1,4-benzoquinone (DDMQH2) is converted to 2-methoxy-5-methyl-6-polyprenyl-1,4-benzoquinone (DMQH2). Crystal structures of Coq5 were determined in the apo form (Coq5-apo) at 2.2?Å resolution and in the SAM-bound form (Coq5-SAM) at 2.4?Å resolution, representing the first pair of structures for the yeast CoQ biosynthetic enzymes. Coq5 displays a typical class I SAM-MTase structure with two minor variations beyond the core domain, both of which are considered to participate in dimerization and/or substrate recognition. Slight conformational changes at the active-site pocket were observed upon binding of SAM. Structure-based computational simulation using an analogue of DDMQH2 enabled us to identify the binding pocket and entrance tunnel of the substrate. Multiple-sequence alignment showed that the residues contributing to the dimeric interface and the SAM- and DDMQH2-binding sites are highly conserved in Coq5 and homologues from diverse species. A putative catalytic mechanism of Coq5 was proposed in which Arg201 acts as a general base to initiate catalysis with the help of a water molecule. PMID:25084328

  4. Alternative administration of camptothecin analogues.

    PubMed

    Glaberman, Ursa; Rabinowitz, Ian; Verschraegen, Claire F

    2005-03-01

    In order to improve the therapeutic index of camptothecin (CPT) analogues, alternative administration of CPT analogues is being evaluated. Topotecan, irinotecan, rubitecan, lurtotecan and 9-aminocamptothecin have been administered orally with response rates equivalent to that seen after intravenous administration, where applicable. Oral availability and administration of some of the newer CPT analogues, including diflomotecan (BN80915) and grimatecan (ST1481), have also shown promising results. Aerosolisation of liposomal 9-nitrocamptothecin has been studied in patients with advanced malignancies involving the lung, demonstrating systemic antitumour activity. Intrathecal administration of topotecan has been studied in children with refractory neoplastic meningitis. It is well tolerated and associated with some antitumour activity. Intraperitoneal administration of topotecan as consolidation therapy in patients with ovarian cancer has shown promising results. Transdermal administration of rubitecan has been studied in mice. So far, no CPT has been approved for an alternative route of administration. PMID:16296757

  5. Dimetallaborane analogues of pentaborane.

    PubMed

    Brânzanic, Adrian M V; Lupan, Alexandru; King, R Bruce

    2015-04-28

    The structures of five-vertex dimetallaboranes Cp2M2B3H7 (Cp = ?(5)-C5H5) of the second and third row transition metals, including the experimentally known Cp*2Rh2B3H7 (Cp* = ?(5)-Me5C5), have been investigated by density functional theory. The predicted low-energy structures for Cp2M2B3H7 (M = Rh, Ir) are tetragonal pyramids similar to Cp*2Rh2B3H7 and pentaborane-9 B5H9 and consistent with their 14 Wadean skeletal electrons. Two Cp*2Rh2B3H7 structures with the same central Rh2B3 tetragonal prism are found with energies within ?1 kcal mol(-1) of each other, consistent with the experimental observation of two isomers in solution. The electron-richer Cp2M2B3H7 (M = Pd, Pt) systems having 16 Wadean skeletal electrons are predicted to exhibit more open structures analogous to the known structure for the valence isoelectronic pentaborane-11 B5H11. Trigonal bipyramids with the metal atoms at equatorial vertices are typically found to be low-energy structures for the hypoelectronic Cp2M2B3H7 systems (M = Ru, Os, Re, Mo, W, Ta). In addition, the low-energy Cp2Re2B3H7 structures of the rhenium derivatives Cp2Re2B3H7 provide examples of structures based on a central Re2B2 tetrahedron with the Re-Re edge bridged by the third boron atom. Such structures can be derived from a trigonal bipyramid by the rupture of one of the axial-equatorial edges. PMID:25797320

  6. Photoprotective activity of resveratrol analogues.

    PubMed

    Polonini, Hudson Caetano; Lima, Larissa Lavorato; Gonçalves, Karla Mara; do Carmo, Antônio Márcio Resende; da Silva, Adilson David; Raposo, Nádia Rezende Barbosa

    2013-02-15

    Resveratrol is a promising agent for protecting human skin from UV radiation and to reduce the occurrence of cutaneous malignancies. We describe the photoprotective activity of six resveratrol analogues using the diffuse transmittance technique to determine the SPF and the protection against UVA radiation. The analogues presented a varied profile of photoprotection, the SPF ranging from 2 to 10 and the UVAPF from 0 to 9. Among the six compounds tested, the protection against UVB sunrays provided by compound B was more significant than the protection provided by resveratrol; compounds C, D, E and F show photoprotection similar to resveratrol. PMID:23321013

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

    PubMed Central

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

    2010-01-01

    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. PMID:20886112

  8. Electromagnetic wave analogue of electronic diode

    E-print Network

    Shadrivov, Ilya V; Kivshar, Yuri S; Fedotov, Vassili A; Zheludev, Nikolay I

    2010-01-01

    An electronic diode is a nonlinear semiconductor circuit component that allows conduction of electrical current in one direction only. A component with similar functionality for electromagnetic waves, an electromagnetic isolator, is based on the Faraday effect of the polarization state rotation and is also a key component of optical and microwave systems. Here we demonstrate a chiral electromagnetic diode, which is a direct analogue of an electronic diode: its functionality is underpinned by an extraordinary strong nonlinear wave propagation effect in the same way as electronic diode function is provided by a nonlinear current characteristic of a semiconductor junction. The effect exploited in this new electromagnetic diode is an intensity-dependent polarization change in an artificial chiral metamolecule. This microwave effect exceeds a similar optical effect previously observed in natural crystals by more than 12 orders of magnitude and a direction-dependent transmission that differing by a factor of 65.

  9. Vertical structure and physical processes of the Madden-Julian oscillation: Exploring key model physics in climate simulations

    NASA Astrophysics Data System (ADS)

    Jiang, Xianan; Waliser, Duane E.; Xavier, Prince K.; Petch, Jon; Klingaman, Nicholas P.; Woolnough, Steven J.; Guan, Bin; Bellon, Gilles; Crueger, Traute; DeMott, Charlotte; Hannay, Cecile; Lin, Hai; Hu, Wenting; Kim, Daehyun; Lappen, Cara-Lyn; Lu, Mong-Ming; Ma, Hsi-Yen; Miyakawa, Tomoki; Ridout, James A.; Schubert, Siegfried D.; Scinocca, John; Seo, Kyong-Hwan; Shindo, Eiki; Song, Xiaoliang; Stan, Cristiana; Tseng, Wan-Ling; Wang, Wanqiu; Wu, Tongwen; Wu, Xiaoqing; Wyser, Klaus; Zhang, Guang J.; Zhu, Hongyan

    2015-05-01

    Aimed at reducing deficiencies in representing the Madden-Julian oscillation (MJO) in general circulation models (GCMs), a global model evaluation project on vertical structure and physical processes of the MJO was coordinated. In this paper, results from the climate simulation component of this project are reported. It is shown that the MJO remains a great challenge in these latest generation GCMs. The systematic eastward propagation of the MJO is only well simulated in about one fourth of the total participating models. The observed vertical westward tilt with altitude of the MJO is well simulated in good MJO models but not in the poor ones. Damped Kelvin wave responses to the east of convection in the lower troposphere could be responsible for the missing MJO preconditioning process in these poor MJO models. Several process-oriented diagnostics were conducted to discriminate key processes for realistic MJO simulations. While large-scale rainfall partition and low-level mean zonal winds over the Indo-Pacific in a model are not found to be closely associated with its MJO skill, two metrics, including the low-level relative humidity difference between high- and low-rain events and seasonal mean gross moist stability, exhibit statistically significant correlations with the MJO performance. It is further indicated that increased cloud-radiative feedback tends to be associated with reduced amplitude of intraseasonal variability, which is incompatible with the radiative instability theory previously proposed for the MJO. Results in this study confirm that inclusion of air-sea interaction can lead to significant improvement in simulating the MJO.

  10. Asymmetric syntheses of (-)-lentiginosine and an original pyrrolizidinic analogue thereof from a versatile epoxyamine intermediate.

    PubMed

    Ayad, Tahar; Génisson, Yves; Baltas, Michel

    2005-07-21

    Ready access to natural (-)-lentiginosine and its pyrrolizidinic analogue from a chiral vinylic epoxyamine in a straightforward five-step sequence is presented. Careful use of the RCM reaction on aminotriols and constitutes the key feature of the synthetic pathway. The alpha-amyloglucosidase inhibitory activities of the target compounds were evaluated and showed that the more easily accessible pyrrolizidinic analogue possesses an inhibitory activity quite similar to that of (-)-lentiginosine. PMID:15999197

  11. Synthesis and bioactivity of analogues of the marine antibiotic tropodithietic acid

    PubMed Central

    Rabe, Patrick; Klapschinski, Tim A; Brock, Nelson L; Citron, Christian A; D’Alvise, Paul; Gram, Lone

    2014-01-01

    Summary Tropodithietic acid (TDA) is a structurally unique sulfur-containing antibiotic from the Roseobacter clade bacterium Phaeobacter inhibens DSM 17395 and a few other related species. We have synthesised several structural analogues of TDA and used them in bioactivity tests against Staphylococcus aureus and Vibrio anguillarum for a structure–activity relationship (SAR) study, revealing that the sulfur-free analogue of TDA, tropone-2-carboxylic acid, has an antibiotic activity that is even stronger than the bioactivity of the natural product. The synthesis of this compound and of several analogues is presented and the bioactivity of the synthetic compounds is discussed. PMID:25161739

  12. 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

    Kataoka, T; Yamada, A; Bando, M; Honma, T; Mizoue, K; Nagai, K

    2000-01-01

    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. PMID:10886392

  13. FUNCTION GENERATOR FOR ANALOGUE COMPUTERS

    Microsoft Academic Search

    H. K. Skramstad; J. H. Wright; L. Taback

    1961-01-01

    An improved analogue computer is designed which can be used to determine ; the final ground position of radioactive fallout particles in an atomic cloud. ; The computer determines the fallout pattern on the basis of known wind velocity ; and direction at various altitudes, and intensity of radioactivity in the ; mushroom cloud as a function of particle size

  14. Naturally occurring crystalline phases: analogues for radioactive waste forms

    SciTech Connect

    Haaker, R.F.; Ewing, R.C.

    1981-01-01

    Naturally occurring mineral analogues to crystalline phases that are constituents of crystalline radioactive waste forms provide a basis for comparison by which the long-term stability of these phases may be estimated. The crystal structures and the crystal chemistry of the following natural analogues are presented: baddeleyite, hematite, nepheline; pollucite, scheelite;sodalite, spinel, apatite, monazite, uraninite, hollandite-priderite, perovskite, and zirconolite. For each phase in geochemistry, occurrence, alteration and radiation effects are described. A selected bibliography for each phase is included.

  15. Synthesis and analgesic activities of endomorphin-2 and its analogues.

    PubMed

    Shi, Zhi-Hao; Wei, Yun-Yang; Wang, Chuan-Jin; Yu, Li

    2007-03-01

    Endomorphin-2 (1; H-Tyr-Pro-Phe-Phe-NH2; EM2) and its novel cyclic asparagine (cycloAsn) analogues, H-Tyr-cAsn(CHPh)-Phe-Phe-NH2 (2) and H-Tyr-cAsn(CHMe2)-Phe-Phe-NH2 (3), were synthesized via liquid-phase synthesis. The structures of the products and intermediates were characterized by IR, 1H-NMR, MS, and HR-MS analyses. The antinociceptive activity of EM2 and its cyclic asparagine analogues were assessed in AcOH-induced abdominal constriction tests in mice with i.p. injection. The results show that the antinociceptive activities of EM2 and its cyclic asparagine analogue 2 were higher than those of aspirine and meperidine. Analogue 2 was observed to be a stronger analgesic with dose-dependence than EM2. The test mice did not show any tendency to be addicted while administrated of analogue 2 repeatedly and regularly. PMID:17372948

  16. Migrastatin Analogues Target Fascin to Block Tumor Metastasis

    PubMed Central

    Chen, Lin; Yang, Shengyu; Jakoncic, Jean; Zhang, J. Jillian; Huang, Xin-Yun

    2010-01-01

    Tumor metastasis is the primary cause of death of cancer patients. Development of new therapeutics preventing tumor metastasis is urgently needed. Migrastatin is a natural product secreted by Streptomyces 1,2, and synthesized migrastatin analogues are potent inhibitors of metastatic tumor cell migration, invasion and tumor metastasis 3–6. Here we show that these migrastatin analogues target the actin-bundling protein fascin to inhibit its activity. X-ray crystal structural studies reveal that migrastatin analogues bind to one of the actin-binding sites on fascin. Our data demonstrate that actin cytoskeletal proteins, such as fascin, can be explored as new molecular targets for cancer treatment, similar to the microtubule protein tubulin. PMID:20393565

  17. Synthesis and antifungal activity of novel streptochlorin analogues.

    PubMed

    Zhang, Ming-Zhi; Chen, Qiong; Xie, Cai-Hong; Mulholland, Nick; Turner, Sarah; Irwin, Dianne; Gu, Yu-Cheng; Yang, Guang-Fu; Clough, John

    2015-03-01

    Streptochlorin, first isolated as a new antibiotic in 1988 from the lipophilic extracts of the mycelium of a Streptomyces sp, is an indole natural products with a variety of biological activities. Based on the methods developed for the synthesis of pimprinine in our laboratory, we have synthesized a series of indole-modified streptochlorin analogues and measured their activities against seven phytopathogenic fungi. Some of the analogues displayed good activity in the primary assays, and the seven compounds 10b, 10c, 11e, 13e, 21, 22c and 22e (shown in Figure 1) were identified as the most promising candidates for further study. Structural optimization is still ongoing with the aim of discovering synthetic analogues with improved antifungal activity. PMID:25633493

  18. Migrastatin analogues target fascin to block tumour metastasis

    SciTech Connect

    Chen, L.; Jakoncic, J.; Yang, S.; Zhang, J.; Huang, X.Y.

    2010-04-15

    Tumour metastasis is the primary cause of death of cancer patients. Development of new therapeutics preventing tumour metastasis is urgently needed. Migrastatin is a natural product secreted by Streptomyces, and synthesized migrastatin analogues such as macroketone are potent inhibitors of metastatic tumour cell migration, invasion and metastasis. Here we show that these migrastatin analogues target the actin-bundling protein fascin to inhibit its activity. X-ray crystal structural studies reveal that migrastatin analogues bind to one of the actin-binding sites on fascin. Our data demonstrate that actin cytoskeletal proteins such as fascin can be explored as new molecular targets for cancer treatment, in a similar manner to the microtubule protein tubulin.

  19. Convergent assembly of highly potent analogues of bryostatin 1 via pyran annulation: bryostatin look-alikes that mimic phorbol ester function.

    PubMed

    Keck, Gary E; Kraft, Matthew B; Truong, Anh P; Li, Wei; Sanchez, Carina C; Kedei, Noemi; Lewin, Nancy E; Blumberg, Peter M

    2008-05-28

    Highly potent bryostatin analogues which contain the complete bryostatin core structure have been synthesized using a pyran annulation approach as a key strategic element. The A ring pyran was assembled using a pyran annulation reaction between a C1-C8 hydroxy allylsilane and an aldehyde comprising C9-C13. This pyran was transformed to a new hydroxy allylsilane and then coupled with a preformed C ring aldehyde subunit in a second pyran annulation, with concomitant formation of the B ring. This tricyclic intermediate was elaborated to bryostatin analogues which displayed nanomolar to subnanomolar affinity for PKC, but displayed properties indistinguishable from a phorbol ester in a proliferation/attachment assay. PMID:18452293

  20. A new class of glucosidase inhibitor: analogues of the naturally occurring glucosidase inhibitor salacinol with different ring heteroatom substituents and acyclic chain extension.

    PubMed

    Liu, Hui; Sim, Lyann; Rose, David R; Pinto, B Mario

    2006-04-14

    Six chain-extended analogues of the naturally occurring glycosidase inhibitor salacinol, with ring-heteroatom variation, were synthesized for structure-activity studies with different glycosidase enzymes. The syntheses involved the reaction of PMB-protected D- and L- seleno-, thio-, and iminoarabinitol with a benzylidene- and isopropylidene-protected 1,3-cyclic sulfate, derived from commercially available D-sorbitol, in 1,1,1,3,3,3-hexafluoro-2-propanol containing potassium carbonate. Deprotection of the products afforded the novel selenonium, sulfonium, and iminium analogues of salacinol containing polyhydroxylated, monosulfated, extended acyclic chains of 6-carbons, differing in stereochemistry at the stereogenic centers and ring-heteroatom constitution. Four of these compounds inhibit recombinant human maltase glucoamylase, one of the key intestinal enzymes involved in the breakdown of glucose oligosaccharides in the small intestine, with Ki values in the micromolar range, thus providing lead candidates for the treatment of Type 2 diabetes. PMID:16599595

  1. Answer Keys

    NSDL National Science Digital Library

    2010-01-01

    Answer keys provide acceptable answers to the questions posed in a case. Since these questions are intended to be answered by students and are often graded, keys are password-protected and access limited to registered instructors affiliated with an educational institution.

  2. Studies on two types of PTP1B inhibitors for the treatment of type 2 diabetes: Hologram QSAR for OBA and BBB analogues

    Microsoft Academic Search

    Yuanhua Cheng; Mei Zhou; Chen-Ho Tung; Mingjuan Ji; Fushi Zhang

    2010-01-01

    Hologram quantitative structure–activity relationships (HQSAR) analysis were conducted on two series of PTP1B inhibitors, 39 2-(oxalylamino) benzoic acid (OBA) analogues and 60 benzofuran and benzothiophene biphenyls (BBB) analogues. The optimal HQSAR model of the OBA analogue has q2=0.592 and r2=0.940, while the optimal HQSAR model for the BBB analogues shows q2=0.667 and r2=0.863. Two models were employed to predict the

  3. Syntheses, structures and redox properties of {Os(PPh 3) 2Cp} 2{?-(C C) x } ( x = 2, 3, 4): Comparisons with the Ru analogues

    Microsoft Academic Search

    Michael I. Bruce; Kathy A. Kramarczuk; Brian W. Skelton; Allan H. White

    2010-01-01

    The syntheses of {Os(PPh3)2Cp}2{?-(CC)x} (x=2, 3, 4) from reactions between OsBr(PPh3)2Cp* and Me3Si(CC)xSiMe3 in the presence of KF\\/NaBPh4 are described. The molecular structure of x=3 has been determined by a single-crystal XRD study. Comparison of the redox properties of {M(PPh3)2Cp}2{?-(CC)x} (M=Ru, Os) shows that the oxidation potentials of the osmium complexes are invariably lower (by between 0.16 and 0.64V) than

  4. Pharmacological comparison of novel synthetic fenamate analogues with econazole and 2-APB on the inhibition of TRPM2 channels

    PubMed Central

    Chen, Gui-Lan; Zeng, Bo; Eastmond, Sarah; Elsenussi, Sandra E; Boa, Andrew N; Xu, Shang-Zhong

    2012-01-01

    BACKGROUND AND PURPOSE Fenamate analogues, econazole and 2-aminoethoxydiphenyl borate (2-APB) are inhibitors of transient receptor potential melastatin 2 (TRPM2) channels and are used as research tools. However, these compounds have different chemical structures and therapeutic applications. Here we have investigated the pharmacological profile of TRPM2 channels by application of newly synthesized fenamate analogues and the existing channel blockers. EXPERIMENTAL APPROACH Human TRPM2 channels in tetracycline-regulated pcDNA4/TO vectors were transfected into HEK293 T-REx cells and the expression was induced by tetracycline. Whole cell currents were recorded by patch-clamp techniques. Ca2+ influx or release was monitored by fluorometry. KEY RESULTS Flufenamic acid (FFA), mefenamic acid (MFA) and niflumic acid (NFA) concentration-dependently inhibited TRPM2 current with potency order FFA > MFA = NFA. Modification of the 2-phenylamino ring by substitution of the trifluoromethyl group in FFA with –CH3, –F, –CF3, –OCH3, –OCH2CH3, –COOH, and –NO2 at various positions, reduced channel blocking potency. The conservative substitution of 3-CF3 in FFA by –CH3 (3-MFA), however, gave the most potent fenamate analogue with an IC50 of 76 µM, comparable to that of FFA, but unlike FFA, had no effect on Ca2+ release. 3-MFA and FFA inhibited the channel intracellularly. Econazole and 2-APB showed non-selectivity by altering cytosolic Ca2+ movement. Econazole also evoked a non-selective current. CONCLUSION AND IMPLICATIONS The fenamate analogue 3-MFA was more selective than other TRPM2 channel blockers. FFA, 2-APB and econazole should be used with caution as TRPM2 channel blockers, as these compounds can interfere with intracellular Ca2+ movement. PMID:22646516

  5. A quantitative structure-activity relationship study of herbicidal analogues of alpha-hydroxy-substituted 3-benzylidenepyrrolidene-2,4-diones.

    PubMed

    Zhu, You-Quan; Liu, Pei; Si, Xue-Kai; Zou, Xiao-Mao; Liu, Bin; Song, Hai-Bin; Yang, Hua-Zheng

    2006-09-20

    A series of pyrrolidine-2,4-dione and piperidine-2,4-dione derivatives were prepared and evaluated for their herbicidal activities where some of these compounds exhibited good bioactivity against Echinochloa crus-galli in comparison with sulcotrione. Quantitative structure-activity relationship studies were performed on these compounds using physicochemical parameters (hydrophobic, electronic, and Taft) as independent parameters and herbicidal activity as a dependent parameter, where herbicidal activity correlated best (r > 0.8) with hydrophobic (pi(o) + pi(p)), steric (Es), STERIMOL (B4), indicator (H(M)), van der Waals volume (V), and electronic parameter (sigma(m) + sigma(p)) in this set of molecules; the optimum van der Waals volume for R(2) is about 41.8 A3; when B4 is equal to 3, the target molecule possessed the lowest herbicidal activity. PMID:16968083

  6. Synthesis and Temperature-Induced Structural Phase and Spin Transitions in Hexadecylboron-Capped Cobalt(II) Hexachloroclathrochelate and Its Diamagnetic Iron(II)-Encapsulating Analogue.

    PubMed

    Vologzhanina, Anna V; Belov, Alexander S; Novikov, Valentin V; Dolganov, Alexander V; Romanenko, Galina V; Ovcharenko, Victor I; Korlyukov, Alexander A; Buzin, Mikhail I; Voloshin, Yan Z

    2015-06-15

    Template condensation of dichloroglyoxime with n-hexadecylboronic acid on the corresponding metal ion as a matrix under vigorous reaction conditions afforded n-hexadecylboron-capped iron and cobalt(II) hexachloroclathrochelates. The complexes obtained were characterized using elemental analysis, MALDI-TOF mass spectrometry, IR, UV-vis, (1)H and (13)C{(1)H} NMR, (57)Fe Mössbauer spectroscopies, SQUID magnetometry, electron paramagnetic resonance, and cyclic voltammetry (CV) and by X-ray crystallography. The multitemperature single-crystal X-ray diffraction, SQUID magnetometry, and differential scanning calorimetry experiments were performed to study the temperature-induced spin-crossover [for the paramagnetic cobalt(II) complex] and the crystal-to-crystal phase transitions (for both of these clathrochelates) in the solid state. Analysis of their crystal packing using the molecular Voronoi polyhedra and the Hirshfeld surfaces reveals the structural rearrangements of the apical long-chain alkyl substituents resulting from such phase transitions being more pronounced for a macrobicyclic cobalt(II) complex. Its fine-crystalline sample undergoes the gradual and fully reversible spin transition centered at approximately 225 K. The density functional theory calculated parameters for an isolated molecule of this cobalt(II) hexachloroclathrochelate in its low- and high-spin states were found to be in excellent agreement with the experimental data and allowed to localize the spin density within a macrobicyclic framework. CV of the cobalt(II) complex in the cathodic range contains one reversible wave assigned to the Co(2+/+) redox couple with the reduced anionic cobalt(I)-containing species stabilized by the electronic effect of six strong electron-withdrawing chlorine substituents. The quasireversible character of the Fe(2+/+) wave suggests that the anionic iron(I)-containing macrobicyclic species undergo substantial structural changes and side chemical reactions after such metal-centered reduction. PMID:26017024

  7. Substrate analogues for isoprenoid enzymes

    SciTech Connect

    Stremler, K.E.

    1987-01-01

    Diphosphonate analogues of geranyl diphosphate, resistant to degradation by phosphatases, were found to be alternate substrates for the reaction with farnesyl diphosphate synthetase isolated from avian liver. The difluoromethane analogue was shown to be the better alternate substrate, in agreement with solvolysis results which indicate that the electronegativity of the difluoromethylene unit more closely approximates that of the normal bridging oxygen. The usefulness of the C/sub 10/ difluoro analogue, for detecting low levels of isoprenoid enzymes in the presence of high levels of phosphatase activity, was demonstrated with a cell-free preparation from lemon peel. A series of C/sub 5/ through C/sub 15/ homoallylic and allylic diphosphonates, as well as two 5'-nucleotide diphosphonates, was prepared in high overall yield using the activation-displacement sequence. Radiolabeled samples of several of the allylic diphosphonates were prepared with tritium located at C1. A series of geraniols, stereospecifically deuterated at C1, was prepared. The enantiomeric purities and absolute configurations were determined by derivatization as the mandelate esters for analysis by /sup 1/H NMR. The stereochemistry of the activation-displacement sequence was examined using C1-deuterated substrates.

  8. Fluorinated retinoic acids and their analogues. 3. Synthesis and biological activity of aromatic 6-fluoro analogues.

    PubMed

    Lovey, A J; Pawson, B A

    1982-01-01

    Several analogues (15a--e) of methyl (E,E,Z,E)-3,7-dimethyl-6-fluoro-9-(4-methoxy-2,3,6-trimethylphenyl)nonatetraenoate (15f), which had been found to cause a marked regression of chemically induced skin papillomas in mice, were prepared. Two synthetically versatile methods leading to these derivatives are described. The key intermediate, ethyl (Z)-2-fluoro-3-methyl-4,4-dimethoxy-2-butenoate (8), was elaborated to the C10 aldehyde ester, methyl (2E,4E,6Z)-3-methyl-6-fluoro-7-formyl-2,4,6-octatrienoate (14a), which upon Wittig condensation with the aryl-phosphonium salts 13a--e gave the (2E,4E,6Z,8E)-3,7-dimethyl-6-fluoro-9-aryl-2,4,6,8-nonatetraenoates 15a--e. Alternatively, Wittig reaction of 8 and [(4-methoxy-2,3,6-trimethylphenyl)methyl]triphenylphosphonium chloride (13f) gave a mixture of (E/Z,E)-2-fluoro-3-methyl-5-(2,3,6-trimethyl-4-methoxyphenyl)-2,4-pentadienoates 17 and 18, which was converted to 15f. The biological activity of these analogues and the 1H and 19F NMR spectral properties of the intermediates and final products are discussed. PMID:7086825

  9. Ultradeep pyrosequencing and molecular modeling identify key structural features of hepatitis B virus RNase H, a putative target for antiviral intervention.

    PubMed

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

    2014-01-01

    Last-generation nucleoside/nucleotide analogues are potent against hepatitis B virus (HBV) and have a high barrier to resistance. However, delayed responses have been observed in patients previously exposed to other drugs of the same class, long-term resistance is possible, and cure of infection cannot be achieved with these therapies, emphasizing the need for alternative therapeutic approaches. The HBV RNase H represents an interesting target because its enzyme activity is essential to the HBV life cycle. The goal of our study was to characterize the structure of the HBV RNase H by computing a 3-dimensional molecular model derived from E. coli RNase H and analyzing 2,326 sequences of all HBV genotypes available in public databases and 958,000 sequences generated by means of ultradeep pyrosequencing of sequences from a homogenous population of 73 treatment-naive patients infected with HBV genotype D. Our data revealed that (i) the putative 4th catalytic residue displays unexpected variability that could be explained by the overlap of the HBx gene and has no apparent impact on HBV replicative capacity and that (ii) the C-helix-containing basic protrusion, which is required to guide the RNA/DNA heteroduplex into the catalytic site, is highly conserved and bears unique structural properties that can be used to target HBV-specific RNase H inhibitors without cross-species activity. The model shows substantial differences from other known RNases H and paves the way for functional and structural studies as a prerequisite to the development of new inhibitors of the HBV cell cycle specifically targeting RNase H activity. PMID:24173223

  10. Macrocyclic analogues of the diuretic insect neuropeptide helicokinin I show strong receptor-binding.

    PubMed

    Tran Van, Chien; Nennstiel, Dirk; Scherkenbeck, Jürgen

    2015-07-01

    Helicokinin I, a diuretic neuropeptide of the relevant cotton pest Helicoverpa zea represents a promising target for the design of insect neuropeptide mimetics. Using a ring-closing metathesis reaction, N-terminal bridged macrocyclic helicokinin I analogues with different rigidity were prepared and tested in a helicokinin receptor assay. A partially peptidomimetic helicokinin analogue, containing two structural modifications provides a deeper insight into the structural-requirements for receptor-binding. PMID:25960326

  11. Metamorphic core complexes vs. synkinematic plutons in continental extension setting: insights from key structures (Shandong Province, eastern China)

    E-print Network

    Paris-Sud XI, Université de

    ) the exhumation of the Late Jurassic-Early Cretaceous Linglong MCC below the SE-dipping Linglong detachment fault by partially-melted lower to middle crust upward into the Linglong MCC should be revised to Late Jurassic-Early Cretaceous period. Key-words: Mesozoic extension, eastern Asia, Metamorphic Core Complex, synkinematic pluton

  12. 28 //Vol. 46, No. 1, pp. 28--34, 2002 Key Words: Tactile sensing, artificial skin, smart structure,

    E-print Network

    Shinoda, Hiroyuki

    ] M. H. Lee and H. R. Nicholls: Tactile Sensing for Mechatronics -- A State of the Art Survey; Mecha |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| * |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 1. [1] 20 ( [2--4]) [5] [5] Key Words: Tactile sensing: Feature De- tection with an Image Based Compliant Tactile Sen- sor; Proc. IEEE/RSJ Int. Conf

  13. Tris(2,2'-azobispyridine) complexes of copper(II): X-ray structures, reactivities, and the radical nonradical bis(ligand) analogues.

    PubMed

    Maity, Suvendu; Kundu, Suman; Weyhermüller, Thomas; Ghosh, Prasanta

    2015-02-16

    Tris(abpy) complexes of types mer-[Cu(II)(abpy)3][PF6]2 (mer-1(2+)[PF6(–)]2) and ctc-[Cu(II)(abpy)2(bpy)][PF6]2 (ctc-2(2+)[PF6(–)]2) were successfully isolated and characterized by spectra and single-crystal X-ray structure determinations (abpy = 2,2?-azobispyridine; bpy = 2,2?-bipyridine). Reactions of mer-1(2+) and ctc-2(2+) ions with catechol, o-aminophenol, p-phenylenediamine, and diphenylamine (Ph–NH–Ph) in 2:1 molar ratio afford [CuI(abpy)2](+) (3(+)) and corresponding quinone derivatives. The similar reactions of [Cu(II)(bpy)3](2+) and [Cu(II)(phen)3](2+) with these substrates yielding [Cu(I)(bpy)2](+) and [Cu(I)(phen)2](+) imply that these complexes undergo reduction-induced ligand dissociation reactions (phen = 1,10-phenanthroline). The average ?N?N– lengths in mer-1(2+)[PF6(–)]2 and ctc-2(2+)[PF6(–)]2 are 1.248(4), while that in 3(+)[PF6(–)]·2CH2Cl2 is relatively longer, 1.275(2) Å, due to dCu ? ?azo* back bonding. In cyclic voltammetry, mer-1(2+) exhibits one quasi-reversible wave at ?0.42 V due to Cu(II)/Cu(I) and abpy/abpy(•–) couples and two reversible waves at ?0.90 and ?1.28 V due to abpy/abpy(•–) couple, while those of ctc-2(2+) ion appear at ?0.44, ?0.86, and ?1.10 V versus Fc(+)/Fc couple. The anodic 3(2+)/3(+) and the cathodic 3(+)/3 redox waves at +0.33 and ?0.40 V are reversible. The electron paramagnetic resonance spectra and density functional theory (DFT) calculations authenticated the existence of abpy anion radical (abpy(•–)) in 3, which is defined as a hybrid state of [Cu(I)(abpy(0.5•–))(abpy(0.5•–))] and [Cu(II)(abpy(•–))(abpy(•–))] states. 3(2+) ion is a neutral abpy complex of copper(II) of type [Cu(II)(abpy)2](2+). 3 exhibits a near-IR absorption band at 2400–3000 nm because of the intervalence ligand-to-ligand charge transfer, elucidated by time-dependent DFT calculations in CH2Cl2. PMID:25650719

  14. Syntheses and biological activities of renin inhibitors containing statine analogues.

    PubMed

    Nishi, T; Saito, F; Nagahori, H; Kataoka, M; Morisawa, Y; Yabe, Y; Sakurai, M; Higashida, S; Shoji, M; Matsushita, Y

    1990-01-01

    Syntheses and biological activities of dipeptide renin inhibitors that contain statine analogues are described. The key steps of the synthetic approach to dipeptide renin inhibitors are the asymmetric synthesis of 2(R)-substituted-3-aminocarbonylpropionic acids and the diastereoselective syntheses of (3S,4S)-statine analogues. These inhibitors (2,14-40) inhibited human renin in the 3-140 nM range. Inhibitor ES 6864 (2) was found to be a highly potent inhibitor of human renin (IC50: 4.6 x 10(-9) M) and showed high enzyme specificity. Oral administration of ES 6864 at 3 mg/kg to conscious, sodium-depleted marmosets inhibited plasma renin activity (PRA) more than 80% after 1 h. PMID:2110866

  15. Synthesis and evaluation of heterocyclic analogues of bromoxynil.

    PubMed

    Cutulle, Matthew A; Armel, Gregory R; Brosnan, James T; Best, Michael D; Kopsell, Dean A; Bruce, Barry D; Bostic, Heidi E; Layton, Donovan S

    2014-01-15

    One attractive strategy to discover more active and/or crop-selective herbicides is to make structural changes to currently registered compounds. This strategy is especially appealing for those compounds with limited herbicide resistance and whose chemistry is accompanied with transgenic tools to enable herbicide tolerance in crop plants. Bromoxynil is a photosystem II (PSII) inhibitor registered for control of broadleaf weeds in several agronomic and specialty crops. Recently at the University of Tennessee-Knoxville several analogues of bromoxynil were synthesized including a previously synthesized pyridine (2,6-dibromo-5-hydroxypyridine-2-carbonitrile sodium salt), a novel pyrimidine (4,6-dibromo-5-hydroxypyrimidine-2-carbonitrile sodium salt), and a novel pyridine N-oxide (2,6-dibromo-1-oxidopyridin-1-ium-4-carbonitrile). These new analogues of bromoxynil were also evaluated for their herbicidal activity on soybean (Glycine max), cotton (Gossypium hirsutum), redroot pigweed (Amaranthus retroflexus), velvetleaf (Abutilon theophrasti), large crabgrass (Digitaria sanguinalis), and pitted morningglory ( Ipomoea lacunose ) when applied at 0.28 kg ha(-1). A second study was conducted on a glyphosate-resistant weed (Amaranthus palmeri) with the compounds being applied at 0.56 kg ha(-1). Although all compounds were believed to inhibit PSII by binding in the quinone binding pocket of D1, the pyridine and pyridine-N-oxide analogues were clearly more potent than bromoxynil on Amaranthus retroflexus. However, application of the pyrimidine herbicide resulted in the least injury to all species tested. These variations in efficacy were investigated using molecular docking simulations, which indicate that the pyridine analogue may form a stronger hydrogen bond in the pocket of the D1 protein than the original bromoxynil. A pyridine analogue was able to control the glyphosate-resistant Amaranthus palmeri with >80% efficacy. The pyridine analogues of bromoxynil showed potential to have a different weed control spectrum compared to bromoxynil. A pyridine analogue of bromoxynil synthesized in this research controlled several weed species greater than bromoxynil itself, potentially due to enhanced binding within the PSII binding pocket. Future research should compare this analogue to bromoxynil using optimized formulations at higher application rates. PMID:24354444

  16. A cyclobutanone analogue mimics penicillin in binding to isopenicillin N synthase.

    PubMed

    Stewart, Amanda C; Clifton, Ian J; Adlington, Robert M; Baldwin, Jack E; Rutledge, Peter J

    2007-11-01

    A carbocyclic analogue of the beta-lactam antibiotic isopenicillin N (IPN) has been synthesised and cocrystallised with isopenicillin N synthase (IPNS), the central enzyme in the biosynthesis of penicillin antibiotics. The crystal structure of the IPNS-cyclobutanone complex reveals an active site environment similar to that seen in the enzyme-product complex generated by turnover of the natural substrate within the crystalline protein. The IPNS-cyclobutanone structure demonstrates that the product analogue is tethered to the protein by hydrogen bonding and salt bridge interactions with its carboxylate groups, as seen previously for the natural substrate and product. Furthermore, the successful cocrystallisation of this analogue with IPNS provides firm structural evidence for the utility of such cyclobutanone derivatives as hydrolytically stable analogues of bicyclic beta-lactams. PMID:17907118

  17. Molecular dynamics study of the conformations of glycosidic linkages in sialic acid modified ganglioside GM3 analogues.

    PubMed

    Jaishree, G; Sharmila, D Jeya Sundara

    2014-07-01

    The objective of the present study is to model the analogues of monosialoganglioside (GM3) by making modifications in its sialic acid residue with different substitutions in aqueous environment and to determine their structural stability based upon computational molecular dynamics. Molecular mechanics and molecular dynamics investigation was carried out to study the conformational preferences of the analogues of GM3. Dynamic simulations were carried out on the analogues of GM3 varying in the substituents at C-1, C-4, C-5, C-8 and C-9 positions of their sialic acid or Neuraminic acid (NeuAc) residue. The analogues are soaked in a periodic box of TIP3P water as solvent and subjected to a 10 ns molecular dynamics (MD) simulation using AMBER ff03 and gaff force fields with 30 ps equilibration. The analogue of GM3 with 9-N-succNeuAc (analogue5, C9 substitution) was observed to have the lowest energy of -6112.5 kcal/mol. Graphical analysis made on the MD trajectory reveals the direct and water mediated hydrogen bonds existing in these sialic acid analogues. The preferable conformations for glycosidic linkages of GM3 analogues found in different minimum energy regions in the conformational maps were identified. This study sheds light on the conformational preferences of GM3 analogues which may be essential for the design of GM3 analogues as inhibitors for different ganglioside specific pathogenic proteins such as bacterial toxins, influenza toxins and neuraminidases. PMID:24909815

  18. Interaction with the hERG channel and cytotoxicity of amiodarone and amiodarone analogues

    PubMed Central

    Waldhauser, K M; Brecht, K; Hebeisen, S; Ha, H R; Konrad, D; Bur, D; Krähenbühl, S

    2008-01-01

    Background and purpose: Amiodarone (2-n-butyl-3-[3,5 diiodo-4-diethylaminoethoxybenzoyl]-benzofuran, B2-O-CH2CH2-N-diethyl) is an effective class III antiarrhythmic drug demonstrating potentially life-threatening organ toxicity. The principal aim of the study was to find amiodarone analogues that retained human ether-a-go-go-related protein (hERG) channel inhibition but with reduced cytotoxicity. Experimental approach: We synthesized amiodarone analogues with or without a positively ionizable nitrogen in the phenolic side chain. The cytotoxic properties of the compounds were evaluated using HepG2 (a hepatocyte cell line) and A549 cells (a pneumocyte line). Interactions of all compounds with the hERG channel were measured using pharmacological and in silico methods. Key results: Compared with amiodarone, which displayed only a weak cytotoxicity, the mono- and bis-desethylated metabolites, the further degraded alcohol (B2-O-CH2-CH2-OH), the corresponding acid (B2-O-CH2-COOH) and, finally, the newly synthesized B2-O-CH2-CH2-N-pyrrolidine were equally or more toxic. Conversely, structural analogues such as the B2-O-CH2-CH2-N-diisopropyl and the B2-O-CH2-CH2-N-piperidine were significantly less toxic than amiodarone. Cytotoxicity was associated with a drop in the mitochondrial membrane potential, suggesting mitochondrial involvement. Pharmacological and in silico investigations concerning the interactions of these compounds with the hERG channel revealed that compounds carrying a basic nitrogen in the side chain display a much higher affinity than those lacking such a group. Specifically, B2-O-CH2-CH2-N-piperidine and B2-O-CH2-CH2-N-pyrrolidine revealed a higher affinity towards hERG channels than amiodarone. Conclusions and implications: Amiodarone analogues with better hERG channel inhibition and cytotoxicity profiles than the parent compound have been identified, demonstrating that cytotoxicity and hERG channel interaction are mechanistically distinct and separable properties of the compounds. PMID:18604229

  19. Experience with insulin analogues in children.

    PubMed

    Danne, Thomas; Deiss, Dorothee; Hopfenmüller, Werner; von Schütz, Wolfgang; Kordonouri, Olga

    2002-01-01

    Current data on rapid and long-acting insulin analogues in the paediatric age group is limited. While several studies indicate a benefit in reducing hypoglycaemia, particularly at night, with rapid or long-acting insulin analogue treatment, the effect on long-term glycaemic control remains controversial. The continuous glucose monitoring system offers a new option for tailoring treatment with insulin analogues to achieve optimal glycaemia. In 29 adolescents with diabetes this approach confirmed the non-inferiority of postprandial rapid-acting analogue administration compared to preprandial regular insulin, but revealed significant mealtime differences, with increased analogue requirement at breakfast and dinner. Although rapid- and long-acting insulin analogues may offer potential benefits for problems frequently encountered in paediatric diabetology, their value for the individual child still has to be tested in long-term observations in daily clinical practice. PMID:11979022

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

    NASA Astrophysics Data System (ADS)

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

    2009-12-01

    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 (http://keckcaves.org). 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.

  1. Trehalose Analogues: Latest Insights in Properties and Biocatalytic Production

    PubMed Central

    Walmagh, Maarten; Zhao, Renfei; Desmet, Tom

    2015-01-01

    Trehalose (?-d-glucopyranosyl ?-d-glucopyranoside) is a non-reducing sugar with unique stabilizing properties due to its symmetrical, low energy structure consisting of two 1,1-anomerically bound glucose moieties. Many applications of this beneficial sugar have been reported in the novel food (nutricals), medical, pharmaceutical and cosmetic industries. Trehalose analogues, like lactotrehalose (?-d-glucopyranosyl ?-d-galactopyranoside) or galactotrehalose (?-d-galactopyranosyl ?-d-galactopyranoside), offer similar benefits as trehalose, but show additional features such as prebiotic or low-calorie sweetener due to their resistance against hydrolysis during digestion. Unfortunately, large-scale chemical production processes for trehalose analogues are not readily available at the moment due to the lack of efficient synthesis methods. Most of the procedures reported in literature suffer from low yields, elevated costs and are far from environmentally friendly. “Greener” alternatives found in the biocatalysis field, including galactosidases, trehalose phosphorylases and TreT-type trehalose synthases are suggested as primary candidates for trehalose analogue production instead. Significant progress has been made in the last decade to turn these into highly efficient biocatalysts and to broaden the variety of useful donor and acceptor sugars. In this review, we aim to provide an overview of the latest insights and future perspectives in trehalose analogue chemistry, applications and production pathways with emphasis on biocatalysis. PMID:26084050

  2. Choline Analogues in Malaria Chemotherapy

    PubMed Central

    Peyrottes, Suzanne; Caldarelli, Sergio; Wein, Sharon; Périgaud, Christian; Pellet, Alain; Vial, Henri

    2012-01-01

    Emerging resistance against well-established anti-malaria drugs warrants the introduction of new therapeutic agents with original mechanisms of action. Inhibition of membrane-based phospholipid biosynthesis, which is crucial for the parasite, has thus been proposed as a novel and promising therapeutic strategy. This review compiles literature concerning the design and study of choline analogues and related cation derivatives as potential anti-malarials. It covers advances achieved over the last two decades and describes: the concept validation, the design and selection of a clinical candidate (Albitiazolium), back-up derivatives while also providing insight into the development of prodrug approaches. PMID:22607139

  3. POLYCHLORINATED BIPHENYLS AS HORMONALLY ACTIVE STRUCTURAL ANALOGUES

    EPA Science Inventory

    Among the environmental chemicals believed to have the potential to disrupt the endocrine systems of animals including humans, the polychlorinated biphenyls are a chemical class of considerable concern. Possible mechanisms by which these chemicals may interfere with endocrine fun...

  4. Polychlorinated biphenyls as hormonally active structural analogues

    Microsoft Academic Search

    J. D. McKinney; C. L. Waller

    1994-01-01

    Among the environmental chemicals that may be able to disrupt the endocrine systems of animals and humans, the polychlorinated biphenyls (PCBs) are a chemical class of considerable concern. One possible mechanism by which PCBs may interfere with endocrine function is their ability to mimic natural hormones. These actions reflect a close relationship between the physicochemical properties encoded in the PCB

  5. The Analogue-I and the Analogue-Me: The Avatars of the Self

    Microsoft Academic Search

    Mark R. Leary; Marie-Joelle Estrada; Ashley Batts Allen

    2009-01-01

    The analogue-I and analogue-me refer to mental self-relevant images that take a first-person vs. third-person perspective, respectively. Mental self-analogues are essential for goal setting, planning, and rehearsal of behavioral strategies, but they often fuel emotional and interpersonal problems when people react to their analogue selves as if they were real. This article examines the beneficial and detrimental consequences of the

  6. Rational design of ?-helix-stabilized exendin-4 analogues.

    PubMed

    Rovó, Petra; Farkas, Viktor; Stráner, Pál; Szabó, Mária; Jermendy, Agnes; Hegyi, Orsolya; Tóth, Gábor K; Perczel, András

    2014-06-10

    Exendin-4 (Ex4) is a potent glucagon-like peptide-1 receptor agonist, a drug regulating the plasma glucose level of patients suffering from type 2 diabetes. The molecule's poor solubility and its readiness to form aggregates increase the likelihood of unwanted side effects. Therefore, we designed Ex4 analogues with improved structural characteristics and better water solubility. Rational design was started from the parent 20-amino acid, well-folded Trp cage (TC) miniprotein and involved the step-by-step N-terminal elongation of the TC head, resulting in the 39-amino acid Ex4 analogue, E19. Helical propensity coupled to tertiary structure compactness was monitored and quantitatively analyzed by electronic circular dichroism and nuclear magnetic resonance (NMR) spectroscopy for the 14 peptides of different lengths. Both (15)N relaxation- and diffusion-ordered NMR measurements were established to investigate the inherent mobility and self-association propensity of Ex4 and E19. Our designed E19 molecule has the same tertiary structure as Ex4 but is more helical than Ex4 under all studied conditions; it is less prone to oligomerization and has preserved biological activity. These conditions make E19 a perfect lead compound for further drug discovery. We believe that this structural study improves our understanding of the relationship between local molecular features and global physicochemical properties such as water solubility and could help in the development of more potent Ex4 analogues with improved pharmacokinetic properties. PMID:24828921

  7. Semisynthetic analogues of the marine cembranoid sarcophine as prostate and breast cancer migration inhibitors.

    PubMed

    Hassan, Hossam M; Sallam, Asmaa A; Mohammed, Rabab; Hifnawy, Mohamed S; Youssef, Diaa T A; El Sayed, Khalid A

    2011-08-15

    Sarcophine (1) is a bioactive cembranoid diterpene isolated from the Red Sea soft coral Sarcophyton glaucum. Previous semisynthesis attempts resulted in decreased or complete loss of 1's anticancer activity. Sarcophine and analogues showed antimigratory activity against breast and prostate cancer cell lines. This encouraged further semisynthestic optimizations to improve its activity and establish a preliminary structure-activity relationship. Eight new and five known semisynthetic analogues were generated. These compounds were evaluated for their ability to inhibit growth, proliferation, and migration of the prostate and breast metastatic cancer cell lines PC-3 and MDA-MB-231, respectively. Most analogues exhibited enhanced antimigratory activity. PMID:21775154

  8. Crystal structure of a substrate complex of myo-inositol oxygenase, a di-iron oxygenase with a key role in inositol metabolism.

    PubMed

    Brown, Peter M; Caradoc-Davies, Tom T; Dickson, James M J; Cooper, Garth J S; Loomes, Kerry M; Baker, Edward N

    2006-10-10

    Altered metabolism of the inositol sugars myo-inositol (MI) and d-chiro-inositol is implicated in diabetic complications. In animals, catabolism of MI and D-chiro-inositol depends on the enzyme MI oxygenase (MIOX), which catalyzes the first committed step of the glucuronate-xylulose pathway, and is found almost exclusively in the kidneys. The crystal structure of MIOX, in complex with MI, has been determined by multiwavelength anomalous diffraction methods and refined at 2.0-A resolution (R=0.206, Rfree=0.253). The structure reveals a monomeric, single-domain protein with a mostly helical fold that is distantly related to the diverse HD domain superfamily. Five helices form the structural core and provide six ligands (four His and two Asp) for the di-iron center, in which the two iron atoms are bridged by a putative hydroxide ion and one of the Asp ligands, Asp-124. A key loop forms a lid over the MI substrate, which is coordinated in bidentate mode to one iron atom. It is proposed that this mode of iron coordination, and interaction with a key Lys residue, activate MI for bond cleavage. The structure also reveals the basis of substrate specificity and suggests routes for the development of specific MIOX inhibitors. PMID:17012379

  9. Stawell gold deposit: a key to unravelling the cambrian to early devonian structural evolution of the western Victorian goldfields

    Microsoft Academic Search

    J. Mc L. Miller; C. J. L. Wilson; L. J. Dugdale

    2006-01-01

    Major 440 Ma orogenic-gold deposits in the western Victorian goldfields formed during east – west shortening but have markedly different structural complexity. These deposits occur in: (i) a Cambrian Delamerian basement block that was substantially reworked and reactivated during the Lachlan Orogeny (Stawell); and (ii) Ordovician turbidites deformed solely by Lachlan-aged deformation (Bendigo, Ballarat, Castlemaine). This produced different structural histories prior to mineralisation,

  10. The Valles natural analogue project

    SciTech Connect

    Stockman, H.; Krumhansl, J.; Ho, C. [Sandia National Labs., Albuquerque, NM (United States); McConnell, V. [Alaska Univ., Fairbanks, AK (United States). Geophysical Inst.

    1994-12-01

    The contact between an obsidian flow and a steep-walled tuff canyon was examined as an analogue for a highlevel waste repository. The analogue site is located in the Valles Caldera in New Mexico, where a massive obsidian flow filled a paleocanyon in the Battleship Rock tuff. The obsidian flow provided a heat source, analogous to waste panels or an igneous intrusion in a repository, and caused evaporation and migration of water. The tuff and obsidian samples were analyzed for major and trace elements and mineralogy by INAA, XRF, X-ray diffraction; and scanning electron microscopy and electron microprobe. Samples were also analyzed for D/H and {sup 39}Ar/{sup 4O} isotopic composition. Overall,the effects of the heating event seem to have been slight and limited to the tuff nearest the contact. There is some evidence of devitrification and migration of volatiles in the tuff within 10 meters of the contact, but variations in major and trace element chemistry are small and difficult to distinguish from the natural (pre-heating) variability of the rocks.

  11. The fluorite related modulated structures of the Gd{sub 2}(Zr{sub 2-x}Ce{sub x})O{sub 7} solid solution: An analogue for Pu disposition

    SciTech Connect

    Reid, D.P. [Immobilisation Science Laboratory, Department of Materials Science and Engineering, University of Sheffield, Mappin Street, Sheffield S1 3JD (United Kingdom); Stennett, M.C., E-mail: m.c.stennett@sheffield.ac.uk [Immobilisation Science Laboratory, Department of Materials Science and Engineering, University of Sheffield, Mappin Street, Sheffield S1 3JD (United Kingdom); Hyatt, N.C., E-mail: n.c.hyatt@sheffield.ac.uk [Immobilisation Science Laboratory, Department of Materials Science and Engineering, University of Sheffield, Mappin Street, Sheffield S1 3JD (United Kingdom)

    2012-07-15

    We present an overview of the Gd{sub 2}(Zr{sub 2-x}Ce{sub x})O{sub 7} phase diagram, of interest as a model system for ceramic disposition of Pu (with Ce as a Pu surrogate). The fluorite related structures of this solid solution were determined using a modulated structure approach, to identify the underlying cation and vacancy ordering mechanisms from analysis of key satellite reflections in selected zone axis electron diffraction patterns. This revealed the formation of four structure types: pyrochlore for x<0.25, defect fluorite for 0.5structure for x=1.00, and a C-type structure for x>1.50. X-ray absorption (XAS) and electron energy loss (EELS) spectra confirmed the presence of Ce{sup 4+} as the dominant species in compositions across this system, remaining analogous to Pu{sup 4+}. - Graphical abstract: Electron diffraction reveals the cation vacancy ordering mechanisms leading to fluorite related superstructures in the Gd{sub 2}(Zr{sub 2-x}Ce{sub x})O{sub 7} solid solution. Highlights: Black-Right-Pointing-Pointer The fluorite related solid solution Gd{sub 2}(Zr{sub 1-x}Ce{sub x})O{sub 7} was prepared by solid state synthesis. Black-Right-Pointing-Pointer Ce L{sub 3} edge XAS and Ce M{sub 4,5} EELS measurements show Ce substitutes as Ce{sup 4+}. Black-Right-Pointing-Pointer Cation and oxygen vacancy ordering results in four fluorite related structures.

  12. On a pragmatic approach optical analogues of gravitational attractors

    E-print Network

    D. P. San-Roman-Alerigi; A. B. Slimane; T. K. Ng; M. Alsunaidi; B. S. Ooi

    2012-12-10

    In our work we theoretically demonstrate a refractive index mapping to enable optical analogues to celestial mechanics, where is possible to achieve light confinement and trapping by means of a static, and planar, refractive index mapping which could be implemented under current technological and [meta]material constraints at optical frequencies. The mathematical and physical background to make possible these effects bring forth an exciting ground to test celestial mechanics in the laboratory, and provides the key to enable miscellany of planar optical system that are of great interest to photonic applications, namely optical time delays, transient optical memories and random resonators.

  13. Antifouling Activity of Bromotyrosine-Derived Sponge Metabolites and Synthetic Analogues

    Microsoft Academic Search

    Sofia Ortlepp; Martin Sjögren; Mia Dahlström; Horst Weber; Rainer Ebel; RuAngelie Edrada; Carsten Thoms; Peter Schupp; Lars Bohlin; Peter Proksch

    2007-01-01

    Eighteen brominated sponge-derived metabolites and synthetic analogues were analyzed for antilarval settlement of Balanus improvisus. Only compounds exhibiting oxime substituents including bastadin-3 (4), ?4 (1), ?9 (2), and ?16 (3), hemibastadin-1 (6), aplysamine-2 (5), and psammaplin A (10) turned out to inhibit larval settling at 1 to 10 ?M. Analogues of hemibastadin-1 (6) were synthesized and tested for structure activity studies.

  14. Synthesis of Chamaecypanone C Analogues from in situ-Generated Cyclopentadienones and their Biological Evaluation

    PubMed Central

    Dong, Suwei; Qin, Tian; Hamel, Ernest; Beutler, John A.; Porco, John A.

    2012-01-01

    A rhodium-catalyzed dehydrogenation protocol has been developed for conversion of 3,5-diarylcyclopentenones to the corresponding 2,4-diarylcyclopentadienones. Using this protocol, analogues of the cytotoxic agent chamaecypanone C have been synthesized via Diels-Alder cycloaddition between the cyclopentadienones and in situ-generated ortho-quinols. Biological evaluation of these analogues revealed a compound with higher activity as a microtubule inhibitor and cytotoxic agent in comparison with the parent structure. PMID:23110297

  15. Discrete analogue computing with rotor-routers

    E-print Network

    Propp, James

    Discrete analogue computing with rotor-routers James Propp August 18, 2010 Abstract: Rotor a certificate that can itself be computed by the rotor-router network. Rotor- router networks can be viewed processes. Rotor-router networks are discrete analogues of continuous linear systems such as electrical

  16. CO2 Capture with Enzyme Synthetic Analogue

    SciTech Connect

    Harry Cordatos

    2010-11-08

    Overview of an ongoing, 2 year research project partially funded by APRA-E to create a novel, synthetic analogue of carbonic anhydrase and incorporate it into a membrane for removal of CO2 from flue gas in coal power plants. Mechanism background, preliminary feasibility study results, molecular modeling of analogue-CO2 interaction, and program timeline are provided.

  17. Synthesis, biological activity, and conformational study of N-methylated allatostatin analogues inhibiting juvenile hormone biosynthesis.

    PubMed

    Xie, Yong; Zhang, Li; Zhang, Chuanliang; Wu, Xiaoqing; Deng, Xile; Yang, Xinling; Tobe, Stephen S

    2015-03-25

    An allatostatin (AST) neuropeptide mimic (H17) is a potential insect growth regulator, which inhibits the production of juvenile hormone (JH) by the corpora allata. To determine the effect of conformation of novel AST analogues and their ability to inhibit JH biosynthesis, eight insect AST analogues were synthesized using H17 as the lead compound by N-methylation scanning, which is a common strategy for improving the biological properties of peptides. A bioassay using JH production by corpora allata of the cockroach Diploptera punctata indicated that single N-methylation mimics (analogues 1-4) showed more activity than double N-methylation mimics (analogues 5-8). Especially, analogues 1 and 4 showed roughly equivalent activity to that of H17, with IC50 values of 5.17 × 10(-8) and 6.44 × 10(-8) M, respectively. Molecular modeling based on nuclear magnetic resonance data showed that the conformation of analogues 1 and 4 seems to be flexible, whereas analogues 2 and 3 showed a type IV ?-turn. This flexible linear conformation was hypothesized to be a new important and indispensable structural element beneficial to the activity of AST mimics. PMID:25751662

  18. Hippocampal Structure and Human Cognition: Key Role of Spatial Processing and Evidence Supporting the Efficiency Hypothesis in Females

    ERIC Educational Resources Information Center

    Colom, Roberto; Stein, Jason L.; Rajagopalan, Priya; Martinez, Kenia; Hermel, David; Wang, Yalin; Alvarez-Linera, Juan; Burgaleta, Miguel; Quiroga, Ma. Angeles; Shih, Pei Chun; Thompson, Paul M.

    2013-01-01

    Here we apply a method for automated segmentation of the hippocampus in 3D high-resolution structural brain MRI scans. One hundred and four healthy young adults completed twenty one tasks measuring abstract, verbal, and spatial intelligence, along with working memory, executive control, attention, and processing speed. After permutation tests…

  19. Ungeremine and Its hemisynthesized analogues as bactericides against Flavobacterium columnare.

    PubMed

    Schrader, Kevin K; Avolio, Fabiana; Andolfi, Anna; Cimmino, Alessio; Evidente, Antonio

    2013-02-13

    The Gram-negative bacterium Flavobacterium columnare is the cause of columnaris disease, which can occur in channel catfish ( Ictalurus punctatus ). In a previous study, the betaine-type alkaloid ungeremine, 1, obtained from Pancratium maritimum L. was found to have strong antibacterial activity against F. columnare. In this study, analogues of 1 were evaluated using a rapid bioassay for activity against F. columnare to determine if the analogues might provide greater antibacterial activity and to determine structure-activity relationships of the test compounds. Several ungeremine analogues were prepared by hydrochlorination of the alkaloid and by selenium dioxide oxidation of both lycorine, 7, and pseudolycorine, 8, which yielded the isomer of ungeremine, 3, and zefbetaine, 4, respectively. The treatment of lycorine with phosphorus oxychloride allowed the synthesis of an anhydrolycorine lactam, 5, showing, with respect to 1, the deoxygenation and oxygenation of C-2 and C-7 of the C and B rings, respectively. The results of the structure-activity relationship studies showed that the aromatization of the C ring and the oxidation to an azomethine group of C-7 of the B ring are structural features important for antibacterial activity. In addition, the position of the oxygenation of the C ring as well as the presence of the 1,3-dioxole ring joined to the A ring of the pyrrolo[de]phenanthridine skeleton also plays a significant role in imparting antibacterial activity. On the basis of 24-h 50% inhibition concentration (IC(50)) results, ungeremine hydrochloride, 2, was similar in toxicity to 1, whereas 5 had the lowest activity. Analogue 2 is soluble in water, which may provide the benefit for use as an effective feed additive or therapeutant compared to ungeremine. PMID:23331165

  20. Analogue black hole in magnetohydrodynamics

    E-print Network

    Felipe A. Asenjo; Nelson Zamorano

    2011-02-13

    We consider an irrotational plasma fluid evolving under the effect of a background magnetic field. The magnetohydrodynamic formalism is used to describe the electromagnetic waves and the dynamics is described by a scalar field that follows a second order differential equation. This equation can also be recovered as the wave equation associated to a field in a curved space-time. Through this analogy we recreate a sonic horizon, equivalent to those found in perfect fluid theories. However, in this case, the magnetic field creates a pressure in the plasma which contributes to the magnetoacoustic speed that builds the horizon. This effect enhances the temperature produced by the Hawking radiation expected from this analogue black hole, and eventually, making its experimental detection worth to consider.

  1. Surface and Moho topography as key constraints for understanding the thermo-rheological structure and longevity of cratons and tectons

    NASA Astrophysics Data System (ADS)

    Burov, E. B.; Francois, T.

    2013-12-01

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

  2. Cup-shaped Intrusions, Morphology and Emplacement Mechanism Investigate Through Analogue Modelling

    NASA Astrophysics Data System (ADS)

    Mathieu, L.; van Wyk de Vries, B.

    2007-12-01

    We investigate the morphology of large-scale shallow-depth magma intrusions and sub-volcanic complexes with analogue models. Intrusions of analogue magma are done in a granular material that can contain a ductile layer. The model surface is flat to model the formation of plutonic intrusions and it is overlain by a cone when modelling late sub-volcanic complexes. For flat-top models, we obtain cup-shaped intrusions fed by dykes. Cup-shaped intrusions are inverted-cone like bodies. They are different from saucer-shaped intrusions as they possess neither a well developed sill-base, nor an outer rim. However, like saucers, cups are shallow depth intrusions that dome the country rocks. They initiate from an advancing dyke and first develop an inverted-cone like morphology. Then, the central thickness increases and thrusts form at the edge of the domed country rocks. At this stage, the intrusions progressively involve toward a lopolith shape. By using analogue magma of various viscosities we have been able to constrain key relationships: higher intrusion viscosity causes deeper initiation and the deeper they initiate, the larger is the intrusion diameter. A natural example of such intrusion might by the circles of volcanoes like the Azufre-Lastaria (Peru) that might be overlain be a large-scale cup-shaped intrusion. When adding a cone at the surface of the model and, sometimes, a thin ductile layer in the substratum, the morphology of cup-shaped intrusions vary. Note that the ductile layer of our models is not thick enough to induce the gravitational spreading of the cone. Generally, cup-shaped intrusions are asymmetric in cross section and elliptical in plan view. Their formation creates extension structures in the cone (croissant-shaped rift, straight rift or normal fault) and thrusts in some sectors below the cone. Both types of structures are bordered by strike-slip faults. Cups and saucers share many similarities, but differ probably in the fact that saucers are partially sills that are guided by stratigraphic horizons. However, the basic formation mechanisms may be the same and saucers could be regarded as a special form of cup.

  3. Keys to Lipid Selection in Fatty Acid Amide Hydrolase Catalysis: Structural Flexibility, Gating Residues and Multiple Binding Pockets.

    PubMed

    Palermo, Giulia; Bauer, Inga; Campomanes, Pablo; Cavalli, Andrea; Armirotti, Andrea; Girotto, Stefania; Rothlisberger, Ursula; De Vivo, Marco

    2015-06-01

    The fatty acid amide hydrolase (FAAH) regulates the endocannabinoid system cleaving primarily the lipid messenger anandamide. FAAH has been well characterized over the years and, importantly, it represents a promising drug target to treat several diseases, including inflammatory-related diseases and cancer. But its enzymatic mechanism for lipid selection to specifically hydrolyze anandamide, rather than similar bioactive lipids, remains elusive. Here, we clarify this mechanism in FAAH, examining the role of the dynamic paddle, which is formed by the gating residues Phe432 and Trp531 at the boundary between two cavities that form the FAAH catalytic site (the "membrane-access" and the "acyl chain-binding" pockets). We integrate microsecond-long MD simulations of wild type and double mutant model systems (Phe432Ala and Trp531Ala) of FAAH, embedded in a realistic membrane/water environment, with mutagenesis and kinetic experiments. We comparatively analyze three fatty acid substrates with different hydrolysis rates (anandamide > oleamide > palmitoylethanolamide). Our findings identify FAAH's mechanism to selectively accommodate anandamide into a multi-pocket binding site, and to properly orient the substrate in pre-reactive conformations for efficient hydrolysis that is interceded by the dynamic paddle. Our findings therefore endorse a structural framework for a lipid selection mechanism mediated by structural flexibility and gating residues between multiple binding cavities, as found in FAAH. Based on the available structural data, this exquisite catalytic strategy for substrate specificity seems to be shared by other lipid-degrading enzymes with similar enzymatic architecture. The mechanistic insights for lipid selection might assist de-novo enzyme design or drug discovery efforts. PMID:26111155

  4. Keys to Lipid Selection in Fatty Acid Amide Hydrolase Catalysis: Structural Flexibility, Gating Residues and Multiple Binding Pockets

    PubMed Central

    Palermo, Giulia; Bauer, Inga; Campomanes, Pablo; Cavalli, Andrea; Armirotti, Andrea; Girotto, Stefania; Rothlisberger, Ursula; De Vivo, Marco

    2015-01-01

    The fatty acid amide hydrolase (FAAH) regulates the endocannabinoid system cleaving primarily the lipid messenger anandamide. FAAH has been well characterized over the years and, importantly, it represents a promising drug target to treat several diseases, including inflammatory-related diseases and cancer. But its enzymatic mechanism for lipid selection to specifically hydrolyze anandamide, rather than similar bioactive lipids, remains elusive. Here, we clarify this mechanism in FAAH, examining the role of the dynamic paddle, which is formed by the gating residues Phe432 and Trp531 at the boundary between two cavities that form the FAAH catalytic site (the “membrane-access” and the “acyl chain-binding” pockets). We integrate microsecond-long MD simulations of wild type and double mutant model systems (Phe432Ala and Trp531Ala) of FAAH, embedded in a realistic membrane/water environment, with mutagenesis and kinetic experiments. We comparatively analyze three fatty acid substrates with different hydrolysis rates (anandamide > oleamide > palmitoylethanolamide). Our findings identify FAAH’s mechanism to selectively accommodate anandamide into a multi-pocket binding site, and to properly orient the substrate in pre-reactive conformations for efficient hydrolysis that is interceded by the dynamic paddle. Our findings therefore endorse a structural framework for a lipid selection mechanism mediated by structural flexibility and gating residues between multiple binding cavities, as found in FAAH. Based on the available structural data, this exquisite catalytic strategy for substrate specificity seems to be shared by other lipid-degrading enzymes with similar enzymatic architecture. The mechanistic insights for lipid selection might assist de-novo enzyme design or drug discovery efforts. PMID:26111155

  5. Natural analogue studies as supplements to biomineralization research

    SciTech Connect

    McNeil, M.B. [Nuclear Regulatory Commission, Washington, DC (United States)

    1995-09-01

    Chemical reactions can alter the chemistry and crystal structure of solid objects over archeological or geological times, while preserving external physical shapes. The reactions resulting in these structures offer natural analogues to laboratory experiments in biomineralization and to biologically influenced alteration of nuclear waste packages, and thus, they offer the only available way of validating models that purport waste package behavior over archaeological or geological times. Potential uses of such analogues in the construction and validation of hypothetical mechanisms of microbiological corrosion and biomineralization are reviewed. Evidence from such analogues suggests that biofilms can control materials alteration in ways usually overlooked. The newly hypothesized mechanisms involve control by biofilms of the cation flow near the solid surface and offer plausible mechanisms for the formation of mixed-cation minerals under conditions that would lead to dealloying in abiotic experiments; they also account for the formation of unusual minerals [such as posnjakite, Cu{sub 4}SO{sub 4}(OH){sub 6{center_dot}}H{sub 2}O] and mineral morphologies unusual in corrosion [malachite, Cu{sub 2}CO{sub 3}(OH){sub 2}, rarely forms botryoidally under corrosion conditions and its occasional presence on archaeological objects that appear to have undergone microbiological corrosion may be related to biofilm phenomena].

  6. Crystal Structure Analysis of Human Glutamine : Fructose 6-Phosphate Amidotransferase, a Key Regulator in Type 2 Diabetes

    NASA Astrophysics Data System (ADS)

    Nakaishi, Yuichiro; Bando, Masahiko

    Glutamine : fructose 6-phosphate amidotransferase (GFAT) is a rate-limiting enzyme in the hexoamine biosythetic pathway and plays an important role in type 2 diabetes. We now report the first structures of the isomerase domain of the human GFAT in the presence of cyclic glucose 6-phosphate and linear glucosamine 6-phosphate. The C-terminal tail including the active site displays a rigid conformation, similar to the corresponding Escherichia coli enzyme. The diversity of the CF helix near the active site suggests the helix is a major target for drug design. Our study provides insights into the development of therapeutic drugs for type 2 diabetes.

  7. The Response of Greek Key Proteins to Changes in Connectivity Depends on the Nature of Their Secondary Structure

    E-print Network

    Kemplen, Katherine R.; De Sancho, David; Clarke, Jane

    2015-04-07

    reductase from Escherichia coli. J Mol Biol 2003;328:273–88. [13] Bulaj G, Koehn RE, Goldenberg DP. Alteration of the disulfide-coupled folding pathway of BPTI by circular permutation. Protein Sci 2004;13:1182–96. [14] Cellitti J, Llinas M, Echols N, Shank... - tivity on the stability and structure of dihydrofolate reductase from E. coli: fragment complementation and circular permu- tation reveal stable, alternatively folded forms. Protein Sci 2000;10:116–28. [16] Mart? ?n-Sierra FM, Candel AM, Casares S...

  8. Analogue Transformations in Physics and their Application to Acoustics

    NASA Astrophysics Data System (ADS)

    García-Meca, C.; Carloni, S.; Barceló, C.; Jannes, G.; Sánchez-Dehesa, J.; Martínez, A.

    2013-06-01

    Transformation optics has shaped up a revolutionary electromagnetic design paradigm, enabling scientists to build astonishing devices such as invisibility cloaks. Unfortunately, the application of transformation techniques to other branches of physics is often constrained by the structure of the field equations. We develop here a complete transformation method using the idea of analogue spacetimes. The method is general and could be considered as a new paradigm for controlling waves in different branches of physics, from acoustics in quantum fluids to graphene electronics. As an application, we derive an ``analogue transformation acoustics'' formalism that naturally allows the use of transformations mixing space and time or involving moving fluids, both of which were impossible with the standard approach. To demonstrate the power of our method, we give explicit designs of a dynamic compressor, a spacetime cloak for acoustic waves and a carpet cloak for a moving aircraft.

  9. Antimalarial activity of abietane ferruginol analogues possessing a phthalimide group.

    PubMed

    González, Miguel A; Clark, Julie; Connelly, Michele; Rivas, Fatima

    2014-11-15

    The abietane-type diterpenoid (+)-ferruginol, a bioactive compound isolated from New Zealand's Miro tree (Podocarpus ferruginea), displays relevant pharmacological properties, including antimicrobial, cardioprotective, anti-oxidative, anti-plasmodial, leishmanicidal, anti-ulcerogenic, anti-inflammatory and anticancer. Herein, we demonstrate that ferruginol (1) and some phthalimide containing analogues 2-12 have potential antimalarial activity. The compounds were evaluated against malaria strains 3D7 and K1, and cytotoxicity was measured against a mammalian cell line panel. A promising lead, compound 3, showed potent activity with an EC50 = 86 nM (3D7 strain), 201 nM (K1 strain) and low cytotoxicity in mammalian cells (SI>290). Some structure-activity relationships have been identified for the antimalarial activity in these abietane analogues. PMID:25316317

  10. Analogue Transformations in Physics and their Application to Acoustic

    E-print Network

    García-Meca, C; Barceló, C; Jannes, G; Sánchez-Dehesa, J; Martínez, A

    2013-01-01

    Transformation optics has shaped up a revolutionary electromagnetic design paradigm, enabling scientists to build astonishing devices such as invisibility cloaks. Unfortunately, the application of transformation techniques to other branches of physics is often constrained by the structure of the field equations. We develop here a complete transformation method using the idea of analogue spacetimes. The method is general and could be considered as a new paradigm for controlling waves in different branches of physics, from acoustics in quantum fluids to graphene electronics. As an application, we derive an "analogue transformation acoustics" formalism that naturally allows the use of transformations mixing space and time or involving moving fluids, both of which were impossible with the standard approach. To demonstrate the power of our method, we give an explicit design of a spacetime compressor for acoustic waves and a carpet cloak for a moving aircraft.

  11. Analogue Transformations in Physics and their Application to Acoustic

    E-print Network

    C. García-Meca; S. Carloni; C. Barceló; G. Jannes; J. Sánchez-Dehesa; A. Martínez

    2013-06-21

    Transformation optics has shaped up a revolutionary electromagnetic design paradigm, enabling scientists to build astonishing devices such as invisibility cloaks. Unfortunately, the application of transformation techniques to other branches of physics is often constrained by the structure of the field equations. We develop here a complete transformation method using the idea of analogue spacetimes. The method is general and could be considered as a new paradigm for controlling waves in different branches of physics, from acoustics in quantum fluids to graphene electronics. As an application, we derive an "analogue transformation acoustics" formalism that naturally allows the use of transformations mixing space and time or involving moving fluids, both of which were impossible with the standard approach. To demonstrate the power of our method, we give an explicit design of a spacetime compressor for acoustic waves and a carpet cloak for a moving aircraft.

  12. Analogue transformations in physics and their application to acoustics.

    PubMed

    García-Meca, C; Carloni, S; Barceló, C; Jannes, G; Sánchez-Dehesa, J; Martínez, A

    2013-01-01

    Transformation optics has shaped up a revolutionary electromagnetic design paradigm, enabling scientists to build astonishing devices such as invisibility cloaks. Unfortunately, the application of transformation techniques to other branches of physics is often constrained by the structure of the field equations. We develop here a complete transformation method using the idea of analogue spacetimes. The method is general and could be considered as a new paradigm for controlling waves in different branches of physics, from acoustics in quantum fluids to graphene electronics. As an application, we derive an "analogue transformation acoustics" formalism that naturally allows the use of transformations mixing space and time or involving moving fluids, both of which were impossible with the standard approach. To demonstrate the power of our method, we give explicit designs of a dynamic compressor, a spacetime cloak for acoustic waves and a carpet cloak for a moving aircraft. PMID:23774575

  13. A first-principles density-functional calculation of the electronic and vibrational structure of the key melanin monomers

    NASA Astrophysics Data System (ADS)

    Powell, B. J.; Baruah, T.; Bernstein, N.; Brake, K.; McKenzie, Ross H.; Meredith, P.; Pederson, M. R.

    2004-05-01

    We report first-principles density-functional calculations for hydroquinone (HQ), indolequinone (IQ), and semiquinone (SQ). These molecules are believed to be the basic building blocks of the eumelanins, a class of biomacromolecules with important biological functions (including photoprotection) and with the potential for certain bioengineering applications. We have used the difference of self-consistent fields method to study the energy gap between the highest occupied molecular orbital and the lowest unoccupied molecular orbital, ?HL. We show that ?HL is similar in IQ and SQ, but approximately twice as large in HQ. This may have important implications for our understanding of the observed broadband optical absorption of the eumelanins. The possibility of using this difference in ?HL to molecularly engineer the electronic properties of eumelanins is discussed. We calculate the infrared and Raman spectra of the three redox forms from first principles. Each of the molecules have significantly different infrared and Raman signatures, and so these spectra could be used in situ to nondestructively identify the monomeric content of macromolecules. It is hoped that this may be a helpful analytical tool in determining the structure of eumelanin macromolecules and hence in helping to determine the structure-property-function relationships that control the behavior of the eumelanins.

  14. High-affinity blockade of voltage-operated skeletal muscle and neuronal sodium channels by halogenated propofol analogues

    PubMed Central

    Haeseler, G; Karst, M; Foadi, N; Gudehus, S; Roeder, A; Hecker, H; Dengler, R; Leuwer, M

    2008-01-01

    Background and purpose: Voltage-operated sodium channels constitute major target sites for local anaesthetic-like action. The clinical use of local anaesthetics is still limited by severe side effects, in particular, arrhythmias and convulsions. These side effects render the search for new local anaesthetics a matter of high interest. Experimental approach: We have investigated the effects of three halogenated structural analogues of propofol on voltage-operated human skeletal muscle sodium channels (NaV1.4) and the effect of one compound (4-chloropropofol) on neuronal sodium channels (NaV1.2) heterologously expressed in human embryonic kidney cell line 293. Key results: 4-Iodo-, 4-bromo- and 4-chloropropofol reversibly suppressed depolarization-induced whole-cell sodium inward currents with high potency. The IC50 for block of resting channels at ?150?mV was 2.3, 3.9 and 11.3??M in NaV1.4, respectively, and 29.2??M for 4-chloropropofol in NaV1.2. Membrane depolarization inducing inactivation strongly increased the blocking potency of all compounds. Estimated affinities for the fast-inactivated channel state were 81?nM, 312?nM and 227?nM for 4-iodopropofol, 4-bromopropofol and 4-chloropropofol in NaV1.4, and 450?nM for 4-chloropropofol in NaV1.2. Recovery from fast inactivation was prolonged in the presence of drug leading to an accumulation of block during repetitive stimulation at high frequencies (100?Hz). Conclusions and implications: Halogenated propofol analogues constitute a novel class of sodium channel-blocking drugs possessing almost 100-fold higher potency compared with the local anaesthetic and anti-arrhythmic drug lidocaine. Preferential drug binding to inactivated channel states suggests that halogenated propofol analogues might be especially effective in suppressing ectopic discharges in a variety of pathological conditions. PMID:18574460

  15. Plant Volatile Analogues Strengthen Attractiveness to Insect

    PubMed Central

    Sun, Yufeng; Yu, Hao; Zhou, Jing-Jiang; Pickett, John A.; Wu, Kongming

    2014-01-01

    Green leaf bug Apolygus lucorum (Meyer-Dür) is one of the major pests in agriculture. Management of A. lucorum was largely achieved by using pesticides. However, the increasing population of A. lucorum since growing Bt cotton widely and the increased awareness of ecoenvironment and agricultural product safety makes their population-control very challenging. Therefore this study was conducted to explore a novel ecological approach, synthetic plant volatile analogues, to manage the pest. Here, plant volatile analogues were first designed and synthesized by combining the bioactive components of ?-ionone and benzaldehyde. The stabilities of ?-ionone, benzaldehyde and analogue 3 g were tested. The electroantennogram (EAG) responses of A. lucorum adult antennae to the analogues were recorded. And the behavior assay and filed experiment were also conducted. In this study, thirteen analogues were acquired. The analogue 3 g was demonstrated to be more stable than ?-ionone and benzaldehyde in the environment. Many of the analogues elicited EAG responses, and the EAG response values to 3 g remained unchanged during seven-day period. 3 g was also demonstrated to be attractive to A. lucorum adults in the laboratory behavior experiment and in the field. Its attractiveness persisted longer than ?-ionone and benzaldehyde. This indicated that 3 g can strengthen attractiveness to insect and has potential as an attractant. Our results suggest that synthetic plant volatile analogues can strengthen attractiveness to insect. This is the first published study about synthetic plant volatile analogues that have the potential to be used in pest control. Our results will support a new ecological approach to pest control and it will be helpful to ecoenvironment and agricultural product safety. PMID:24911460

  16. Key Elements of Cratonic and Pericratonic Lithospheric Structure Revealed by Deep Seismic Reflection Profiling in North America

    NASA Astrophysics Data System (ADS)

    Brown, L. D.

    2008-05-01

    Deep seismic reflection profiling collected both by national programs (COCORP in the US; LITHOPROBE in Canada) and regional programs (e.g. GLIMPCE, CDROM,) have traversed most of the major tectonic elements of the North American craton and its Precambrian periphery. Once argued to be relatively bland in terms of reflection character, the craton has turned out to exhibit a rich diversity of fabrics and features of fundamental tectonic significance. Among the more distinctive characteristics are: 1) crustal penetrating zones of pronounced reflectivity that suggest distributed shear fabrics, a likely fingerprint of past crustal flow. The type example is the Grenville Front at the eastern edge of the Superior Province; 2) A sharp contrast in reflectivity across the Moho, exemplified by seismic reflection profiles in the Abitibi-Grenville, Superior and Slave Provinces; 3) Distinct, dipping reflections that penetrate into the mantle from the lower crust, usually interpret as fossil subduction zones; 4) Prominent reflections that delineate thin, extensive sills in the upper to mid crust; 5) Thick layered sequences that mark extensive buried volcano-sedimentary units in the peripheral platforms of the central U.S.; and 6) Apparent continuity of crustal fabrics across the Moho that argue for preservation of Precambrian tectonic structures in the upper mantle, even in Phanerozoic remobilized terranes, and/or evolution of the Moho as a phase change rather than a lithologic contrast in some areas. For the most part, the structural assemblages revealed by deep seismic reflection profiling in the North American craton support a plate tectonic regime in the Archean. Perhaps the most iconic of the deep reflection transects of cratonic North America is the SNORCLE transect of the LITHOPROBE program, which demonstrates not only the intrinsic heterogeneity of the crust and crust-mantle boundary, but a complex assemblage of mantle discontinuities that preserve tectonic fabrics well into the mantle lithosphere. Finally, these surveys make clear that in spite of the great improvements in lithospheric imaging achieved by various passive seismic techniques (e.g. refraction tomography, receiver functions etc.) only seismic reflection profiling provides the structural resolution necessary to address many fundamental questions of cratonic evolution.

  17. Synthesis and biological evaluation of febrifugine analogues.

    PubMed

    Mai, Huong Doan Thi; Thanh, Giang Vo; Tran, Van Hieu; Vu, Van Nam; Vu, Van Loi; Le, Cong Vinh; Nguyen, Thuy Linh; Phi, Thi Dao; Truong, Bich Ngan; Chau, Van Minh; Pham, Van Cuong

    2014-12-01

    A series of febrifugine analogues were designed and synthesized. Antimalarial activity evaluation of the synthetic compounds indicated that these derivatives had a strong inhibition against both chloroquine-sensitive and -resistant Plasmodium falciparum parasites. Many of them were found to be more active than febrifugine hydrochloride. The tested analogues had also a significant cytotoxicity against four cancer cell lines (KB, MCF7, LU1 and HepG2). Among the synthetic analogues, two compounds 17b and 17h displayed a moderate cytotoxicity while they exhibited a remarkable antimalarial activity. PMID:25632466

  18. Global Government applications of analogues, SAR s and QSAR s to predict aquatic toxicity, chemical or physical properties, environmental fate parameters and health effects of organic chemicals

    Microsoft Academic Search

    J. D. Walker; L. Carlsen; E. Hulzebos; B. Simon-Hettich

    2002-01-01

    Faced with the need to predict physical and chemical properties, environmental fate, ecological effects and health effects of organic chemicals in the absence of experimental data, several Government organizations have been applying analogues, Structure Activity Relationships (SARs) and Quantitative Structure Activity Relationships (QSARs) to develop those predictions. To establish some benchmarks for monitoring future increases in applications of analogues, SARs

  19. Synthesis and Binding Affinity of Homologated Adenosine Analogues as A3 Adenosine Receptor Ligands

    PubMed Central

    Lee, Hyuk Woo; Choi, Won Jun; Jacobson, Kenneth A.; Jeong, Lak Shin

    2015-01-01

    Homologated analogues 3a and 3b of potent and selective A3 adenosine receptor ligands, IB-MECA and dimethyl-IB-MECA were synthesized from commercially available 1-O-acetyl-2,3,5-tri-O-benzoyl-?-d-ribofuranose (4) via Co2(CO)8-catalyzed siloxymethylation as a key step. Unfortunately, homologated analogues 3a and 3b did not show significant binding affinities at three subtypes of adenosine receptors, indicating that free rotation, resulting from homologation, induced unfavorable interactions in the binding site of the receptor maybe due to the presence of many conformations.

  20. Flux Synthesis, Structure, Properties, and Theoretical Magnetic Study of Uranium(IV)-Containing A2USi6O15 (A = K, Rb) with an Intriguing Green-to-Purple, Crystal-to-Crystal Structural Transition in the K Analogue.

    PubMed

    Morrison, Gregory; Ramanantoanina, Harry; Urland, Werner; Smith, Mark D; Zur Loye, Hans-Conrad

    2015-06-01

    The flux growth of uranium(IV) oxides presents several challenges, and to the best of our knowledge, only one example has ever been reported. We succeeded in growing two new reduced uranium silicates A2USi6O15 (A = K, Rb) under flux growth conditions in sealed copper tubes. The compounds crystallize in a new structure type with space group C2/c and lattice parameters a = 24.2554(8) Å, b = 7.0916(2) Å, c = 17.0588(6) Å, ? = 97.0860(6) ° (K) and a = 24.3902(8) Å, b = 7.1650(2) Å, c = 17.2715(6) Å, ? = 96.8600(6) ° (Rb). A2USi6O15 (A = K, Rb) are isocompositional to a previously reported Cs2USi6O15, and the two structures are compared. K2USi6O15 undergoes an interesting crystal-to-crystal structural phase transition at T ? 225 K to a triclinic structure, which is accompanied by an intense color change. The magnetic properties of A2USi6O15 (A = K, Rb, Cs) are reported and differ from the magnetism observed in other U(4+) compounds. Calculations are performed on the (UO6)(-8) clusters of K2USi6O15 to study the cause of these unique magnetic properties. PMID:25978501

  1. Past and present of analogue modelling, and its future trend

    NASA Astrophysics Data System (ADS)

    Koyi, Hemin

    2015-04-01

    Since Hull (1815) published his article on modelling, analogue modelling has expanded to simulate both a wider range of tectonic regimes and target more challenging set-ups, and has become an integrated part of the fields of tectonics and structural geology. Establishment of new laboratories testifies for the increased attention the technique receives. The ties between modellers and field geoscientists have become stronger with the focus being on understanding the parameters that govern the evolution of a tectonic regime and the processes that dominate it. Since the first sand castle was built with damp sand on a beach, sand has proven to be an appropriate material analogue. Even though granular materials is the most widely used analogue material, new materials are also (re)introduced as rock analogues. Emphasis has been on more precise measurements of the mechanical properties of the materials and on minimizing the preparation effects, which have a great impact on scaling, interpretations and benchmarking. The analytical technique used to quantify model results has also seen a great deal of improvement. In addition to X-ray tomography used to visualise internal structures of models, new techniques (e.g. PIV, high-resolution laser scanning, and interferometry) have enabled monitoring kinematics with a higher precision. Benchmarking exercises have given modelling an additional checking tool by outlining, in addition to the rheology of the modelling materials, the impact of different preparation approaches, the effect of boundary conditions, and the human factor on model results. However, despite the different approaches and deformation rigs, results of models of different tectonic laboratories have shown a great deal of similarities. Even with the introduction of more sophisticated numerical codes and usage of more powerful computers which enable the simulation of more challenging material properties and combinations of those, and 3D model set-up, analogue modelling can still play a significant role both as a physical checking tool and a complementary technique. Additional fine-tuning takes enables the technique to take on more challenging tasks. However, the foundation of the technique is in its link to natural prototypes and that model results can only give some hints about a geologic process or structure. Sixty years ago, Ernest Cloos stated that "....Many interpretations would never have been published if the author had only once tried his suggested mechanism of folding or faulting in an experiment". He has also said that "... experimenting is a good deal of fun". Both statements do still hold!

  2. Novel combretastatin analogues endowed with antitumor activity.

    PubMed

    Simoni, Daniele; Romagnoli, Romeo; Baruchello, Riccardo; Rondanin, Riccardo; Rizzi, Michele; Pavani, Maria Giovanna; Alloatti, Domenico; Giannini, Giuseppe; Marcellini, Marcella; Riccioni, Teresa; Castorina, Massimo; Guglielmi, Mario B; Bucci, Federica; Carminati, Paolo; Pisano, Claudio

    2006-06-01

    We studied the anticancer activity of a series of new combretastatin derivatives with B-ring modifications. The structure-activity relationship (SAR) information confirmed the importance of cis-stereochemistry and of a phenolic moiety in B-ring. We selected the benzo[b]thiophene and benzofuran combretastatin analogues 11 (ST2151) and 13 (ST2179) and their phosphate prodrugs (29 and 30) for their high antitumor activity in in vitro and in vivo models. Cell exposure to IC50 of 11, 13, and CA-4 led to the arrest of various cell types in the G2/M phase of the cell cycle and induction of apoptosis. Mainly, 11 and 13 induced the formation of multinucleated cells with abnormal chromatin distribution, with only a minimal effect on the microtubule organization, with respect to CA-4. Interestingly, both the pharmacokinetic profile of 29 and its in vivo antitumor effect and those of 30, active even after oral administration, suggest additional pharmacological differences between these compounds and CA-4P. PMID:16722633

  3. Space analogue studies in Antarctica

    NASA Astrophysics Data System (ADS)

    Lugg, D.; Shepanek, M.

    1999-09-01

    Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mltogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

  4. Space analogue studies in Antarctica

    NASA Technical Reports Server (NTRS)

    Lugg, D.; Shepanek, M.

    1999-01-01

    Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mitogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

  5. The Nisi Fault as a key structure for understanding the active deformation of the NW Peloponnese, Greece

    NASA Astrophysics Data System (ADS)

    Zygouri, V.; Koukouvelas, I. K.; Kokkalas, S.; Xypolias, P.; Papadopoulos, G. A.

    2015-05-01

    The previously unknown Nisi Fault in NW Peloponnese was ruptured during the 2008 Movri Mountain earthquake attaining a maximum offset of 25 cm. The fault is interpreted as a branch of a flower structure above a blind strike-slip fault. We investigate the Nisi Fault seismotectonic evolution using morphotectonic analysis in order to determine whether the landscape is affected by tectonic forcing and paleoseismology to determine earthquake recurrence interval and fault slip rates. We applied several geomorphic indices, such as the asymmetry factor (AF), the stream length-gradient index (SL), the valley floor width to valley height ratio (Vf), the mountain-front sinuosity (Smf), the drainage basin shape (Bs) and the hypsometric curve (Hc), in four large drainage basins of the study area. The results show that fault-related vertical motions and the associated tilting influenced the drainage geometry and the landscape development. Values of stream-gradient indices (SL) are relatively high close to the fault trace. Mountain-front sinuosity (Smf) mean values along the fault zones range from 1.12 to 1.23. Valley floor width to valley height ratios (Vf) mean values along the studied fault range between 0.21 and 2.50. Drainage basin shape (BS) mean values along the fault range from 1.04 to 3.72. Lateral fault growth was likely achieved by propagation primarily towards north-northwestward. The paleoseismic history of the fault, investigated by a trench and 14C dating of seven samples, indicates two morphogenic earthquakes in the last 1 kyr. Therefore, we suggest that the Nisi Fault displays a slip rate on the order of 1 mm/yr and a recurrence interval ranging between 300 and 600 years. From a seismotectonic point of view, the fault is classified as high activity rate, with abundant but discontinuous geomorphic evidence of its activity. Other similar faults affecting the western Peloponnese can be envisaged with a similar procedure. Additionally, the seismic history and surface expression of the Nisi Fault, resembles other faults of similar length in Greece and Italy. Particularly, a crucial issue in terms of seismic risk management is that neotectonic analysis has to be envisaged carefully on short in length faults, since these faults can be possibly related to strong earthquakes.

  6. Analogue Gravity and ultrashort laser pulse filamentation

    E-print Network

    D. Faccio; S. Cacciatori; V. Gorini; V. G. Sala; A. Averchi; A. Lotti; M. Kolesik; J. V. Moloney

    2009-09-18

    Ultrashort laser pulse filaments in dispersive nonlinear Kerr media induce a moving refractive index perturbation which modifies the space-time geometry as seen by co-propagating light rays. We study the analogue geometry induced by the filament and show that one of the most evident features of filamentation, namely conical emission, may be precisely reconstructed from the geodesics. We highlight the existence of favorable conditions for the study of analogue black hole kinematics and Hawking type radiation.

  7. Development of Tyrocidine A Analogues with Improved Antibacterial Activity

    PubMed Central

    Marques, Michael A.; Citron, Diane M.; Wang, Clay C.

    2009-01-01

    The development of new antibacterial therapeutic agents capable of halting microbial resistance is a chief pursuit in clinical medicine. Classes of antibiotics that target and destroy bacterial membranes are attractive due to the decreased likelihood that bacteria will be able to generate resistance to this mechanism. The amphipathic cyclic decapeptide, Tyrocidine A, is a model for this class of antibiotics. Tyrocidine A is composed of a hydrophobic and a hydrophilic face, allowing for insertion into bacterial membranes, creating porous channels and destroying membrane integrity. We have used a combination of molecular modeling and solid phase synthesis to prepare Tyrocidine A and analogues 1–8. The minimum inhibitory concentrations (MIC’s) of these compounds were determined for a host of gram positive species and E. coli as a representative gram negative bacterium. Analogues 2 and 5 demonstrated moderate 2 to 8-fold increases in antibacterial activity over the parent Tyrocidine A for a variety of pathogenic microbes. (Best MIC’s for E. coli 32 ?g/mL and 2 ?g/mL for most gram positives) Examination of the structure activity relationship between the analogues demonstrated a preference for increased amphipathicity but did not show a clear preference for increasing hydrophilicity versus hydrophobicity in improving antibacterial activity. Of note, movement of positively charged lysine residues or neutral pentafluorophenyl residues to different positions within the cyclopeptide ring system demonstrated improvements in antibacterial activity. PMID:17728134

  8. Synthesis and antibacterial evaluation of anziaic acid and analogues as topoisomerase I inhibitors

    PubMed Central

    Lin, Hao; Annamalai, Thirunavukkarasu; Bansod, Priyanka; Tse-Dinh, Yuk-Ching

    2013-01-01

    Naturally occurring anziaic acid was very recently reported as a topoisomerase I inhibitor with antibacterial activity. Herein total synthesis of anziaic acid and structural analogues is described and the preliminary structure-activity relationship (SAR) has been developed based on topoisomerase inhibition and whole cell antibacterial activity. PMID:24363888

  9. OutputInput Analogue Discrete

    E-print Network

    Kraft, Michael

    is founded upon a technique called sigma-delta modulation (E-)-M) or oversampling conversion. Devices of oversampling conversion. The strategy is based upon the determination of the following key factors: 1) closed system which, in the unforced condition, oscillates continuously in one or more limit cycling modes

  10. Chemical Synthesis and Molecular Recognition of Phosphatase-Resistant Analogues of Phosphatidylinositol-3-phosphate

    PubMed Central

    Xu, Yong; Lee, Stephanie A.; Kutateladze, Tatiana G.; Sbrissa, Diego; Shisheva, Assia; Prestwich, Glenn D.

    2008-01-01

    The remodeling of phosphatidylinositol polyphosphates in cellular membranes by phosphatases and kinases orchestrates the signaling by these lipids in space and time. In order to provide chemical tools to study of the changes in cell physiology mediated by these lipids, three new metabolically-stabilized (ms) analogues of phosphatidylinositol-3-phosphate (PtdIns(3)P were synthesized. We describe herein the total asymmetric synthesis of 3-methylphosphonate, 3-monofluoromethylphosphonate and 3-phosphorothioate analogues of PtdIns(3)P. From differentially protected D-myo-inositol key intermediates, a versatile phosphoramidite reagent was employed in the synthesis of PtdIns(3)P analogues with diacylglyceryl moieties containing dioleoyl, dipalmitoyl and dibutyryl chains. In addition, we introduce a new phosphorlyation reagent, monofluoromethylphosphonyl chloride, which has general applications for the preparation of “pKa-matched” monofluorophosphonates. These ms-PtdIns(3)P analogues exhibited reduced binding activities with 15N-labelled FYVE and PX domains, as significant 1H and 15N chemical shift changes in the FYVE domain were induced by titrating ms-PtdIns(3)Ps into membrane-mimetic dodecylphosphocholine (DPC) micelles. In addition, the PtdIns(3)P analogues with dioleyl and dipalmitoyl chains were substrates for the 5-kinase enzyme PIKfyve; the corresponding phosphorylated ms-PI(3,5)P2 products were detected by radio-TLC analysis. PMID:16417379

  11. Discovery of cytotoxic dolastatin 10 analogues with N-terminal modifications.

    PubMed

    Maderna, Andreas; Doroski, Matthew; Subramanyam, Chakrapani; Porte, Alexander; Leverett, Carolyn A; Vetelino, Beth C; Chen, Zecheng; Risley, Hud; Parris, Kevin; Pandit, Jayvardhan; Varghese, Alison H; Shanker, Suman; Song, Cynthia; Sukuru, Sai Chetan K; Farley, Kathleen A; Wagenaar, Melissa M; Shapiro, Michael J; Musto, Sylvia; Lam, My-Hanh; Loganzo, Frank; O'Donnell, Christopher J

    2014-12-26

    Auristatins, synthetic analogues of the antineoplastic natural product Dolastatin 10, are ultrapotent cytotoxic microtubule inhibitors that are clinically used as payloads in antibody-drug conjugates (ADCs). The design and synthesis of several new auristatin analogues with N-terminal modifications that include amino acids with ?,?-disubstituted carbon atoms are described, including the discovery of our lead auristatin, PF-06380101. This modification of the peptide structure is unprecedented and led to analogues with excellent potencies in tumor cell proliferation assays and differential ADME properties when compared to other synthetic auristatin analogues that are used in the preparation of ADCs. In addition, auristatin cocrystal structures with tubulin are being presented that allow for the detailed examination of their binding modes. A surprising finding is that all analyzed analogues have a cis-configuration at the Val-Dil amide bond in their functionally relevant tubulin bound state, whereas in solution this bond is exclusively in the trans-configuration. This remarkable observation shines light onto the preferred binding mode of auristatins and serves as a valuable tool for structure-based drug design. PMID:25431858

  12. Imperial College London EEE 1L1 Autumn 2009 E2.2 Analogue Electronics E2.2 Analogue Electronics

    E-print Network

    Papavassiliou, Christos

    Imperial College London ­ EEE 1L1 Autumn 2009 E2.2 Analogue Electronics E2.2 Analogue Electronics Autumn 2009 E2.2 Analogue Electronics What analogue electronics is · Engineering, i.e. the analysis ­ EEE 3L1 Autumn 2009 E2.2 Analogue Electronics analogue electronics is not only · CMOS integrated

  13. Formulating Fluorogenic Assay to Evaluate S-adenosyl-L-methionine Analogues as Protein Methyltransferase Cofactors

    PubMed Central

    Wang, Rui; Ibáñez, Glorymar; Islam, Kabirul; Zheng, Weihong; Blum, Gil; Sengelaub, Caitlin; Luo, Minkui

    2013-01-01

    Protein methyltransferases (PMTs) catalyze arginine and lysine methylation of diverse histone and nonhistone targets. These posttranslational modifications play essential roles in regulating multiple cellular events in an epigenetic manner. In the recent process of defining PMT targets, S-adenosyl-L-methionine (SAM) analogues have emerged as powerful small molecule probes to label and profile PMT targets. To examine efficiently the reactivity of PMTs and their variants on SAM analogues, we transformed a fluorogenic PMT assay into a ready high throughput screening (HTS) format. The reformulated fluorogenic assay is featured by its uncoupled but more robust character with the first step of accumulation of the commonly-shared reaction byproduct S-adenosyl-L-homocysteine (SAH), followed by SAH-hydrolyase-mediated fluorogenic quantification. The HTS readiness and robustness of the assay were demonstrated by its excellent Z? values of 0.83–0.95 for the so-far-examined 8 human PMTs with SAM as a cofactor (PRMT1, PRMT3, CARM1, SUV39H2, SET7/9, SET8, G9a and GLP1). The fluorogenic assay was further implemented to screen the PMTs against five SAM analogues (allyl-SAM, propargyl-SAM, (E)-pent-2-en-4-ynyl-SAM (EnYn-SAM), (E)-hex-2-en-5-ynyl-SAM (Hey-SAM) and 4-propargyloxy-but-2-enyl-SAM (Pob-SAM)). Among the examined 8×5 pairs of PMTs and SAM analogues, native SUV39H2, G9a and GLP1 showed promiscuous activity on allyl-SAM. In contrast, the bulky SAM analogues, such as EnYn-SAM, Hey-SAM and Pob-SAM are inert toward the panel of human PMTs. These findings therefore provide the useful structure-activity guidance to further evolve PMTs and SAM analogues for substrate labeling. The current assay format is ready to screen methyltransferase variants on structurally-diverse SAM analogues. PMID:21866297

  14. Synthesis, Preliminary Bioevaluation and Computational Analysis of Caffeic Acid Analogues

    PubMed Central

    Liu, Zhiqian; Fu, Jianjun; Shan, Lei; Sun, Qingyan; Zhang, Weidong

    2014-01-01

    A series of caffeic acid amides were designed, synthesized and evaluated for anti-inflammatory activity. Most of them exhibited promising anti-inflammatory activity against nitric oxide (NO) generation in murine macrophage RAW264.7 cells. A 3D pharmacophore model was created based on the biological results for further structural optimization. Moreover, predication of the potential targets was also carried out by the PharmMapper server. These amide analogues represent a promising class of anti-inflammatory scaffold for further exploration and target identification. PMID:24857914

  15. Chalcogen-bonded complexes of some carbon dioxide analogues

    NASA Astrophysics Data System (ADS)

    Ramasami, Ponnadurai; Ford, Thomas A.

    2014-08-01

    Ab initio calculations have been carried out on the sulphur-bonded van der Waals complexes formed between the carbon dioxide analogues carbonyl sulphide, carbon disulphide and thiocarbonyl selenide, and the common electron donors ammonia, water, phosphine and hydrogen sulphide. The structures of these twelve complexes are all similar, and involve an approximately linear XCS⋯Y fragment (X = O, S, Se; Y = N, O, P, S). These structures contrast with those of the oxygen-bound complexes of carbon dioxide, carbonyl sulphide and carbonyl selenide reported earlier which, with the exception of the hydrogen sulphide species, are characterized by four-membered rings with varying orientations involving the C, O, H and Y atoms. The molecular structures, interaction energies and vibrational spectra have been studied, and the variations in these properties have been correlated with the complex structures and with the molecular quadrupole moments of the acid monomers.

  16. Crystal structure of the ternary complex of E. coli purine nucleoside phosphorylase with formycin B, a structural analogue of the substrate inosine, and phosphate (Sulphate) at 2.1 A resolution.

    PubMed

    Koellner, G; Lui?, M; Shugar, D; Saenger, W; Bzowska, A

    1998-07-01

    The ternary complex of purine nucleoside phosphorylase from E. coli with formycin B and a sulphate or phosphate ion crystallized in the hexagonal space group P6122 with unit cell dimensions a=123.11, c=241.22 A and three monomers per asymmetric unit. The biologically active hexamer is formed through 2-fold crystallographic symmetry, constituting a trimer of dimers. High-resolution X-ray diffraction data were collected using synchrotron radiation (Daresbury, England). The crystal structure was determined by molecular replacement and refined at 2.1 A resolution to an R-value of 0.196. There is one active centre per monomer, composed of residues belonging to two subunits of one dimer. The phosphate binding site is strongly positively charged and consists of three arginine residues (Arg24, Arg87 and Arg43 from a neighbouring subunit), Ser90 and Gly20. It is occupied by a sulphate or phosphate anion, each oxygen atom of which accepts at least two hydrogen bonds or salt-bridges. The sulphate or phosphate anion is also in direct contact with the ribose moiety of formycin B. The ribose binding site is composed of Ser90, Met180, Glu181 and His4, the latter belonging to the neighbouring subunit. The base binding site is exposed to solvent, and the base is unspecifically bound through a chain of water molecules and aromatic-aromatic interactions. In all monomers the nucleosides are in the high syn conformation about the glycosidic bonds with chi in the range 100 to 130 degrees. The architecture of the active centre is in line with the known broad specificity and the kinetic properties of E. coli PNP. PMID:9653038

  17. Key-Insulated Public Key Cryptosystems

    Microsoft Academic Search

    Yevgeniy Dodis; Jonathan Katz; Shouhuai Xu; Moti Yung

    2002-01-01

    Cryptographic computations (decryption, signature generation, etc.) are often performed on a relatively insecure device (e.g., a mobile device or an Internet-connected host) which cannot be trusted to maintain secrecy of the pri- vate key. We propose and investigate the notion of key-insulated security whose goal is to minimize the damage caused by secret-key exposures. In our model, the secret key(s)

  18. Theoretical study on absorption and emission spectra of pyrrolo-C analogues

    NASA Astrophysics Data System (ADS)

    Liu, Hongxia; Liu, Jianhua; Yang, Yan; Li, Yan; Wang, Haijun

    2015-01-01

    Fluorescent nucleoside analogues have attracted much attention in studying the structure and dynamics of nucleic acids in recent years. In the present work, we use theoretical calculations to investigate the structural and optical properties of Pyrrolo-C (PyC) and its analogues which are modified via the conjugation or fusion of different aromatic ring to the PyC core. We also consider the effects of aqueous solution and base pairing. The results show that the fluorescent pyrrolo-C analogues can pair with guanosine to form stable H-bonded WC base pairs. The calculated absorption peaks of modified deoxyribonucleosides agree well with the measured data. The absorption and emission maxima of the pyrrolo-C analogues are greatly red shifted compared with nature C. The solvent effects can induce wavelength blue shift and increase the oscillator strengths in both the absorption and emission spectra. With regard to the WC base pairs, the B3LYP functional reveals that the lowest energy transitions of modified GC base pairs are charge transfer excitation while the CAM-B3LYP functional predicts that all the lowest transitions are localised on the pyrrolo-C analogues. The M062X and CAM-B3LYP functionals show good agreement with respect to both the value of the lowest energy transitions as well as the oscillator strengths.

  19. Synthesis and post-coital contraceptive activity of ether and ester analogues of 2,3-diaryl-2H-1-benzopyrans.

    PubMed

    Hajela, K; Kapoor, K K; Kapil, R S

    1995-11-01

    Ether and ester analogues of 2,3-diaryl-2H-1-benzopyrans have been synthesised and tested for their pregnancy inhibiting activity in immature rats. Some of the compounds exhibit potent activity. Structure-activity relationship relative to the hydroxy analogue has been discussed. In general, esters were found to be better inhibitory agents. PMID:8634822

  20. Dynamics of water in prussian blue analogues: Neutron scattering study

    NASA Astrophysics Data System (ADS)

    Sharma, V. K.; Mitra, S.; Thakur, N.; Yusuf, S. M.; Juranyi, Fanni; Mukhopadhyay, R.

    2014-07-01

    Dynamics of crystal water in Prussian blue (PB), Fe(III)4[Fe(II)(CN)6]3.14H2O and its analogue Prussian green (PG), ferriferricynaide, Fe(III)4[Fe(III)(CN)6]4.16H2O have been investigated using Quasielastic Neutron Scattering (QENS) technique. PB and its analogue compounds are important materials for their various interesting multifunctional properties. It is known that crystal water plays a crucial role towards the multifunctional properties of Prussian blue analogue compounds. Three structurally distinguishable water molecules: (i) coordinated water molecules at empty nitrogen sites, (ii) non-coordinated water molecules in the spherical cavities, and (iii) at interstitial sites exist in PB. Here spherical cavities are created due to the vacant sites of Fe(CN)6 units. However, PG does not have any such vacant N or Fe(CN)6 units, and only one kind of water molecules, exists only at interstitial sites. QENS experiments have been carried out on both the compounds in the temperature range of 260-360 K to elucidate the dynamical behavior of different kinds of water molecules. Dynamics is found to be much more pronounced in case of PB, compared to PG. A detailed data analysis showed that localized translational diffusion model could describe the observed data for both PB and PG systems. The average diffusion coefficient is found to be much larger in the PB than PG. The obtained domain of dynamics is found to be consistent with the geometry of the structure of the two systems. Combining the data of the two systems, a quantitative estimate of the dynamics, corresponding to the water molecules at different locations is made.

  1. Transition States, analogues, and drug development.

    PubMed

    Schramm, Vern L

    2013-01-18

    Enzymes achieve their transition states by dynamic conformational searches on the femtosecond to picosecond time scale. Mimics of reactants at enzymatic transition states bind tightly to enzymes by stabilizing the conformation optimized through evolution for transition state formation. Instead of forming the transient transition state geometry, transition state analogues convert the short-lived transition state to a stable thermodynamic state. Enzymatic transition states are understood by combining kinetic isotope effects and computational chemistry. Analogues of the transition state can bind millions of times more tightly than substrates and show promise for drug development for several targets. PMID:23259601

  2. Synthesis of Ruthenium Boryl Analogues of the Shvo Metal–Ligand Bifunctional Catalyst

    PubMed Central

    Koren-Selfridge, Liza; Query, Ian P.; Hanson, Joel A.; Isley, Nicholas A.; Guzei, Ilia A.; Clark, Timothy B.

    2010-01-01

    Metal boryl complexes have received significant attention in the literature in recent years due to their role as key intermediates in a number of metal-catalyzed borylation reactions. The ligand scaffold is known to have a significant impact on the observed reactivity of these metal boryl complexes. A synthetic strategy to access ruthenium boryl analogues of the Shvo metal–ligand catalysts is described. Heating a precursor to Shvo’s catalyst (1) with bis(catecholato)diboron at 50 °C provided ruthenium boryl complex 3 [2,5-Ph2-3,4-Tol2(?5-C4COBcat)Ru(CO)2Bcat] (Bcat = catecholatoboryl). Addition of bis(catecholato)diboron to complex 1 in the presence of a phenol results in ruthenium boryl complex5 [2,5-Ph2-3,4-Tol2(?5-C4COH)Ru(CO)2Bcat] at 22 °C in 30% isolated yield. A single crystal X-ray analysis of complex 5 confirmed the assigned structure. An improved synthesis of ruthenium boryl complex 5 was developed by the in situ formation of complex 3 [2,5-Ph2-3,4-Tol2(?5-C4COBcat)Ru(CO)2Bcat] followed by addition of the phenol, resulting in a 51% yield. PMID:20835402

  3. Cooperative Binding of Cyclodextrin Dimers to Isoflavone Analogues Elucidated by Free Energy Calculations

    PubMed Central

    2014-01-01

    Dimerization of cyclodextrin (CD) molecules is an elementary step in the construction of CD-based nanostructured materials. Cooperative binding of CD cavities to guest molecules facilitates the dimerization process and, consequently, the overall stability and assembly of CD nanostructures. In the present study, all three dimerization modes (head-to-head, head-to-tail, and tail-to-tail) of ?-CD molecules and their binding to three isoflavone drug analogues (puerarin, daidzin, and daidzein) were investigated in explicit water surrounding using molecular dynamics simulations. Total and individual contributions from the binding partners and solvent environment to the thermodynamics of these binding reactions are quantified in detail using free energy calculations. Cooperative drug binding to two CD cavities gives an enhanced binding strength for daidzin and daidzein, whereas for puerarin no obvious enhancement is observed. Head-to-head dimerization yields the most stable complexes for inclusion of the tested isoflavones (templates) and may be a promising building block for construction of template-stabilized CD nanostructures. Compared to the case of CD monomers, the desolvation of CD dimers and entropy changes upon complexation prove to be influential factors of cooperative binding. Our results shed light on key points of the design of CD-based supramolecular assemblies. We also show that structure-based calculation of binding thermodynamics can quantify stabilization caused by cooperative effects in building blocks of nanostructured materials. PMID:24719673

  4. Stereoselective fluorination alters the geometry of a cyclic peptide: exploration of backbone-fluorinated analogues of unguisin A.

    PubMed

    Hu, Xiang-Guo; Thomas, Donald S; Griffith, Renate; Hunter, Luke

    2014-06-10

    New methods for enhancing the efficiency of peptide cyclization, and for fine-tuning the conformations of cyclic peptides, are valuable from a drug development perspective. Herein stereoselective fluorination is investigated as a new strategy for achieving these goals. Four vicinal difluorinated analogues of the natural cyclic heptapeptide unguisin?A have been efficiently synthesized. The analogues are found to adopt dramatically different secondary structures, controlled by the fluorine stereochemistry. PMID:24848423

  5. Blocking effects of promethazine, triprolidine and their analogues on the excitation caused by the peptide, achatin-I

    Microsoft Academic Search

    Thucydides L. Salunga; Xiao Yan Han; Shu Min Wong; Hiroshi Takeuchi; Ken-ichi Matsunami; Christopher Upton; Amanda D. Mercer

    1996-01-01

    An Achatina endogenous tetrapeptide, achatin-I (Gly-d-Phe-Ala-Asp), applied by brief pressure, produced an inward current (Iin) on an Achatina giant neurone type, PON (periodically oscillating neurone). Promethazine, triprolidine and their analogues tested, applied by perfusion, showed a tendency to inhibit the Iin, suggesting that the effective structures vary to a wide extent. With respect to promethazine and its analogues, the presence

  6. Review of Current State of the Art and Key Design Issues With Potential Solutions for Liquid Hydrogen Cryogenic Storage Tank Structures for Aircraft Applications

    NASA Technical Reports Server (NTRS)

    Mital, Subodh K.; Gyekenyesi, John Z.; Arnold, Steven M.; Sullivan, Roy M.; Manderscheid, Jane M.; Murthy, Pappu L. N.

    2006-01-01

    Due to its high specific energy content, liquid hydrogen (LH2) is emerging as an alternative fuel for future aircraft. As a result, there is a need for hydrogen tank storage systems, for these aircraft applications, that are expected to provide sufficient capacity for flight durations ranging from a few minutes to several days. It is understood that the development of a large, lightweight, reusable cryogenic liquid storage tank is crucial to meet the goals of and supply power to hydrogen-fueled aircraft, especially for long flight durations. This report provides an annotated review (including the results of an extensive literature review) of the current state of the art of cryogenic tank materials, structural designs, and insulation systems along with the identification of key challenges with the intent of developing a lightweight and long-term storage system for LH2. The broad classes of insulation systems reviewed include foams (including advanced aerogels) and multilayer insulation (MLI) systems with vacuum. The MLI systems show promise for long-term applications. Structural configurations evaluated include single- and double-wall constructions, including sandwich construction. Potential wall material candidates are monolithic metals as well as polymer matrix composites and discontinuously reinforced metal matrix composites. For short-duration flight applications, simple tank designs may suffice. Alternatively, for longer duration flight applications, a double-wall construction with a vacuum-based insulation system appears to be the most optimum design. The current trends in liner material development are reviewed in the case that a liner is required to minimize or eliminate the loss of hydrogen fuel through permeation.

  7. The Need for Analogue Missions in Scientific Human and Robotic Planetary Exploration

    NASA Technical Reports Server (NTRS)

    Snook, K. J.; Mendell, W. W.

    2004-01-01

    With the increasing challenges of planetary missions, and especially with the prospect of human exploration of the moon and Mars, the need for earth-based mission simulations has never been greater. The current focus on science as a major driver for planetary exploration introduces new constraints in mission design, planning, operations, and technology development. Analogue missions can be designed to address critical new integration issues arising from the new science-driven exploration paradigm. This next step builds on existing field studies and technology development at analogue sites, providing engineering, programmatic, and scientific lessons-learned in relatively low-cost and low-risk environments. One of the most important outstanding questions in planetary exploration is how to optimize the human and robotic interaction to achieve maximum science return with minimum cost and risk. To answer this question, researchers are faced with the task of defining scientific return and devising ways of measuring the benefit of scientific planetary exploration to humanity. Earth-based and spacebased analogue missions are uniquely suited to answer this question. Moreover, they represent the only means for integrating science operations, mission operations, crew training, technology development, psychology and human factors, and all other mission elements prior to final mission design and launch. Eventually, success in future planetary exploration will depend on our ability to prepare adequately for missions, requiring improved quality and quantity of analogue activities. This effort demands more than simply developing new technologies needed for future missions and increasing our scientific understanding of our destinations. It requires a systematic approach to the identification and evaluation of the categories of analogue activities. This paper presents one possible approach to the classification and design of analogue missions based on their degree of fidelity in ten key areas. Various case studies are discussed to illustrate the approach.

  8. Stereoselective preparation of the ABCD tetracycle of the 20-methyl analogue of aspidospermidine and related alkaloids

    Microsoft Academic Search

    Anahi Urrutia; J. Gonzalo Rodríguez

    1998-01-01

    The natural cis[ABCD] tetracycle of the 20-methyl analogue of aspidospermidine has been synthesised, starting from the 4,4-ethylenedioxy-1-cyclohexanone. This, was transformed into 3-methyl-3-(3?-nitropropyl)-1,2,3,4-tetrahydrocarbazol-4-one. Two key synthetic steps permits the construction of the D ring: i) the one pot nickel boride catalyst to the imine tetracycle in excellent yield; and ii) the stereoselective reduction of this imine to the natural cis D

  9. Spectral Characterization of Phobos Analogues Under Simulated Environmental Conditions

    NASA Astrophysics Data System (ADS)

    Donaldson Hanna, K. L.; Bowles, N. E.; Edwards, C. S.; Glotch, T. D.; Greenhagen, B. T.; Pieters, C. M.; Thomas, I.

    2014-12-01

    The surface of Phobos holds many keys for understanding its formation and evolution as well as the history and dynamics of the Mars-Phobos system. Visible to near infrared (VNIR) observations suggests that Phobos' surface is compositionally heterogeneous with 'redder' and 'bluer' units that both appear to be anhydrous in nature. Lunar highland spectra have been identified as spectral analogues for the 'redder' and 'bluer' units while thermally metamorphosed CI/CM chondrites, lab-heated carbonaceous chondrites and highly space weathered mafic mineral assemblages have been identified as the best analogues for the 'bluer' surface units. Additionally, thermal infrared emissivity spectra indicate that if Phobos' surface is optically mature it may be rich in feldspar, which is consistent with VNIR observations of Phobos' surface being spectrally similar to lunar highland spectra. While remote observations provide key insights into the composition and evolution of planetary surfaces, a fundamentally important component to any remote compositional analysis of planetary surfaces is laboratory measurements of well-characterized samples measured under the appropriate environmental conditions. The vacuum environment of airless bodies creates a steep thermal gradient in the upper hundreds of microns of regolith. Lab studies of particulate rocks and minerals as well as selected lunar soils under vacuum and lunar-like conditions have identified significant effects of this thermal gradient on thermal infrared (TIR) spectral measurements. However recent lab measurements of carbonaceous chondrites demonstrated that simulated asteroid conditions do not affect the resulting emissivity spectra to the degree observed in lunar soils and is highly dependent on composition. Such lab studies demonstrate the high sensitivity of TIR emissivity spectra to environmental conditions under which they are measured and indicate that the near surface environment of all airless bodies do not spectrally behave in similar ways. An initial set of TIR emissivity measurements of Phobos analogue materials will be made in the Simulated Lunar Environment chamber at the University of Oxford. These lab measurements will be characterized in an effort better understand how to interpret current and future TIR observations of Phobos.

  10. Rebeccamycin analogues bearing amine substituents or other groups on the sugar moiety

    Microsoft Academic Search

    Fabrice Anizon; Pascale Moreau; Martine Sancelme; William Laine; Christian Bailly; Michelle Prudhomme

    2003-01-01

    In the course of structure–activity relationship studies on rebeccamycin analogues, a series of compounds bearing an amino function on the sugar moiety were synthesized with the aim of improving the solubility and interaction with the macromolecular target(s). The syntheses of amino derivatives and the corresponding chloro, iodo and azido intermediates are described. Their interaction with DNA and effects on human

  11. Semisynthetic analogues of the marine cembranoid sarcophine as prostate and breast cancer migration inhibitors

    Microsoft Academic Search

    Hossam M. Hassan; Asmaa A. Sallam; Rabab Mohammed; Mohamed S. Hifnawy; Diaa T. A. Youssef; Khalid A. El Sayed

    2011-01-01

    Sarcophine (1) is a bioactive cembranoid diterpene isolated from the Red Sea soft coral Sarcophyton glaucum. Previous semisynthesis attempts resulted in decreased or complete loss of 1’s anticancer activity. Sarcophine and analogues showed antimigratory activity against breast and prostate cancer cell lines. This encouraged further semisynthestic optimizations to improve its activity and establish a preliminary structure–activity relationship. Eight new and

  12. Synthetic Analogues of Cysteinate-Ligated Non-Heme Iron and Non-Corrinoid Cobalt Enzymes

    E-print Network

    Kovacs, Julie

    Synthetic Analogues of Cysteinate-Ligated Non-Heme Iron and Non-Corrinoid Cobalt Enzymes Julie A June 24, 2003 Contents 1. Introduction to Non-Heme Iron Enzymes 825 2. Nitrile Hydratase (NHase) 826 2.1. Enzyme Function 826 2.2. Enzyme Active Site Structure 826 2.3. Spectroscopic Properties 827 2

  13. Synthesis and insecticidal activity of chromanone and chromone analogues of diacylhydrazines

    Microsoft Academic Search

    Pei-Liang Zhao; Jing Li; Guang-Fu Yang

    2007-01-01

    Diacylhydrazine derivatives have been identified as one of the most important insect growth regulators. A variety of diacylhydrazine derivatives were designed and synthesized in recent years due to their unique action mechanism, simple structure, and environmental benign character. This paper describes the molecular design, synthesis, and insecticidal activities of a series of chromanone and chromone analogues of diacylhydrazine derivatives. The

  14. Dynamical (e,2e) investigations of tetrahydrofuran and tetrahydrofurfuryl alcohol as DNA analogues

    E-print Network

    Wang, Yayu

    Dynamical (e,2e) investigations of tetrahydrofuran and tetrahydrofurfuryl alcohol as DNA analogues previ- ous measurements on THF and tetrahydrofurfuryl alcohol to further understand the role-molecules is to be accurately simulated, we need to identify and understand the role of isolated chemical structures within them

  15. The antitumour effect of the somatostatin analogue TT232 depends on the treatment regimen

    Microsoft Academic Search

    Miguel Tejeda; Dezsõ Gaál; Orsolya Csuka; Axel Ullrich; Richárd Schwab; Ákos Pap; Anikó Horváth; György Kéri

    2003-01-01

    The somatostatin analogue TT-232, containing a five residue ring structure, has a strong antitumour activity both in vitro and in vivo. This peptide has no effect on growth hormone (GH) release, but exhibits a remarkable tyrosine kinase inhibitory effect and induced apoptosis. We studied the effect of TT-232 in different routes of administration and treatment schedules on various types of

  16. Escape configuration lattice near the nematic-isotropic transition: Tilt analogue of blue phases

    E-print Network

    Buddhapriya Chakrabarti; Yashodhan Hatwalne; N. V. Madhusudana

    2006-04-28

    We predict the possible existence of a new phase of liquid crystals near the nematic-isotropic ($ NI $) transition. This phase is an achiral, tilt-analogue of the blue phase and is composed of a lattice of {\\em double-tilt}, escape-configuration cylinders. We discuss the structure and the stability of this phase and provide an estimate of the lattice parameter.

  17. Remarkable metal-complexed phosphorus analogues of the cyclopropenylcarbene-cyclobutadiene rearrangement.

    PubMed

    Lyaskovskyy, Volodymyr; Elders, Niels; Ehlers, Andreas W; Lutz, Martin; Slootweg, J Chris; Lammertsma, Koop

    2011-06-29

    In situ-generated metal carbonyl-complexed cyclopropenylphosphinidenes undergo a sequence of structural changes leading to phosphorus analogues of Pettit's seminal (?(4)-cyclobutadiene)iron tricarbonyl complex via multiple valence isomers along the reaction pathway and the elimination of one molecule of carbon monoxide. PMID:21627326

  18. Using a GCM analogue model to investigate the potential for Amazonian forest dieback

    Microsoft Academic Search

    C. Huntingford; P. P. Harris; N. Gedney; P. M. Cox; R. A. Betts; J. A. Marengo; J. H. C. Gash

    2004-01-01

    Summary A combined GCM analogue model and GCM land surface representation is used to investigate the influences of climatology and land surface parameterisation on modelled Amazonian vegetation change. This modelling structure (called IMOGEN) captures the main features of the changes in surface climate as estimated by a GCM with enhanced atmospheric greenhouse gas concentrations. Advantage is taken of IMOGEN’s computational

  19. Analogues of stealth: Submarines and aircraft

    Microsoft Academic Search

    Robert P. Haffa JR; James H. Patton JR

    1991-01-01

    Analogues of Stealth “ questions whether stealth technologies (measures designed to reduce the observable signature of a weapons platform) now being applied to aircraft will prove as successful as low?observable technologies and tactics employed by the submarine. To address that question, the article briefly explores the history of antisubmarine warfare, notes the failures of various technologies designed to counter the

  20. An analogue study for flame flickering

    Microsoft Academic Search

    T. Yuan; D. Durox; E. Villermaux

    1994-01-01

    An analogue experiment is proposed to simulate flame flickering comprising a free ascending column fed on its side with a light gas (helium) emerging from a vertical slot in ambient air. The convective motion of the helium jet is considered to represent the motion of burnt gases of buoyant jet flames. The helium jet is accelerated by buoyancy effects and

  1. On an elliptic analogue of Zagier's conjecture.

    E-print Network

    On an elliptic analogue of Zagier's conjecture@math.uni-muenster.de Introduction This article is the elliptic version of "Interpr'etation motivique de la conjec* *ture de are homologically mean- ingful, i.e., yield elements in certain K-groups of symmetric powers of elliptic curves

  2. Dumb holes: analogues for black holes.

    PubMed

    Unruh, W G

    2008-08-28

    The use of sonic analogues to black and white holes, called dumb or deaf holes, to understand the particle production by black holes is reviewed. The results suggest that the black hole particle production is a low-frequency and low-wavenumber process. PMID:18534934

  3. Analogue gravity from field theory normal modes?

    Microsoft Academic Search

    Carlos Barceló; Stefano Liberati; Matt Visser

    2001-01-01

    We demonstrate that the emergence of a curved spacetime `effective Lorentzian geometry' is a common and generic result of linearizing a classical scalar field theory around some non-trivial background configuration. This investigation is motivated by considering the large number of `analogue models' of general relativity that have recently been developed based on condensed matter physics, and asking whether there is

  4. Analogue model for quantum gravity phenomenology

    E-print Network

    Silke Weinfurtner; Stefano Liberati; Matt Visser

    2005-11-18

    So called "analogue models" use condensed matter systems (typically hydrodynamic) to set up an "effective metric" and to model curved-space quantum field theory in a physical system where all the microscopic degrees of freedom are well understood. Known analogue models typically lead to massless minimally coupled scalar fields. We present an extended "analogue space-time" programme by investigating a condensed-matter system - in and beyond the hydrodynamic limit - that is in principle capable of simulating the massive Klein-Gordon equation in curved spacetime. Since many elementary particles have mass, this is an essential step in building realistic analogue models, and an essential first step towards simulating quantum gravity phenomenology. Specifically, we consider the class of two-component BECs subject to laser-induced transitions between the components, and we show that this model is an example for Lorentz invariance violation due to ultraviolet physics. Furthermore our model suggests constraints on quantum gravity phenomenology in terms of the "naturalness problem" and "universality issue".

  5. UNSTRUCTURED MARINE FOOD WEBS AND "POLLUTANT ANALOGUES"

    E-print Network

    envi- ronments. The concentration factor found in the known and describable food chain of the Salton in the simple linear food chain ex- isting in that isolated marine environment and that the cesium/potassium (CsUNSTRUCTURED MARINE FOOD WEBS AND "POLLUTANT ANALOGUES" JOHN D. ISAACS' ABSTRACT The several

  6. Effect of Ginger Constituents and Synthetic Analogues on Cyclooxygenase2 Enzyme in Intact Cells

    Microsoft Academic Search

    Effie Tjendraputra; Van H. Tran; Damien Liu-Brennan; Basil D. Roufogalis; Colin C. Duke

    2001-01-01

    Seventeen pungent oleoresin principles of ginger (Zingiber officinale, Roscoe) and synthetic analogues were evaluated for inhibition of cyclooxygenase-2 (COX-2) enzyme activity in the intact cell. These compounds exhibited a concentration and structure dependent inhibition of the enzyme, with IC50 values in the range of 1–25 ?M. Ginger constituents, [8]-paradol and [8]-shogaol, as well as two synthetic analogues, 3-hydroxy-1-(4-hydroxy-3-methoxyphenyl)decane and 5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)dodecane,

  7. Crystallographic analysis of transition-state mimics bound to penicillopepsin: phosphorus-containing peptide analogues.

    PubMed

    Fraser, M E; Strynadka, N C; Bartlett, P A; Hanson, J E; James, M N

    1992-06-01

    The molecular structures of three phosphorus-based peptide inhibitors of aspartyl proteinases complexed with penicillopepsin [1, Iva-L-Val-L-Val-StaPOEt [Iva = isovaleryl, StaP = the phosphinic acid analogue of statine [(S)-4-amino-(S)-3-hydroxy-6-methylheptanoic acid] (IvaVVStaPOEt)]; 2, Iva-L-Val-L-Val-L-LeuP-(O)Phe-OMe [LeuP = the phosphinic acid analogue of L-leucine; (O)Phe = L-3-phenyllactic acid; OMe = methyl ester] [Iva VVLP(O)FOMe]; and 3, Cbz-L-Ala-L-Ala-L-LeuP-(O)-Phe-OMe (Cbz = benzyloxycarbonyl) [CbzAALP(O)FOMe

  8. Efficient synthesis of dichlorodenafil, an unapproved sildenafil analogue appearing in non-prescription supplements.

    PubMed

    Kim, Jong Yup; Hwang, In Gyun; Oh, Jae Ho; Kang, Il Hyun; Kwon, Sung Won; Kim, Deukjoon

    2013-01-01

    We have developed an efficient synthesis of dichlorodenafil (4), an unapproved sildenafil analogue isolated from dietary supplements. Our sequence employs POCl(3)-mediated chlorination of readily available chloroacetyl compound 7 followed by selective hydrolysis of the chloro-heterocycle function. Our synthesis confirms the structure of the illegal additive, and will provide regulatory agencies with ready access to authentic standard samples of dichlorodenafil (4) to aid in their mission to protect the public from unapproved and potentially harmful erectile dysfunction (ED) drug analogues that are added to herbal and dietary supplements without providing users with appropriate toxicological or pharmacological information. PMID:23649199

  9. Tetrahydrofuran amino acid-containing gramicidin S analogues with improved biological profiles.

    PubMed

    Pal, Sudip; Singh, Gajendra; Singh, Shyam; Tripathi, Jitendra Kumar; Ghosh, Jimut Kanti; Sinha, Sudhir; Ampapathi, Ravi Sankar; Chakraborty, Tushar Kanti

    2015-06-10

    Gramicidin S (GS) is a cyclic cationic antimicrobial peptide (CAP) with a wide spectrum of antibiotic activities whose usage has been limited to topical applications owing to its cytotoxic side effects. We have synthesized tetrahydrofuran amino acid (Taa)-containing GS analogues, and we have carried out conformational analysis and explored their structure activity relationships by evaluating their antitubercular, antibacterial and cytotoxic properties. Two of these analogues showed impressive as well as selective activity against Mycobacterium tuberculosis (MTB) without toxicity towards mammalian Vero cells or human RBCs, and are promising as potential leads. PMID:26008215

  10. Delayed seizure-like activity following analytically confirmed use of previously unreported synthetic cannabinoid analogues.

    PubMed

    Schep, L J; Slaughter, R J; Hudson, S; Place, R; Watts, M

    2015-05-01

    Synthetic cannabinoid use has become widespread, leading to increased burdens on health care providers. Symptoms range from agitation and psychosis to seizures and acute kidney injury. We report a case where a patient was assessed and treated twice within 12 h for seizures following synthetic cannabinoid intoxication. Blood sample determinations showed low concentrations of analogues not previously reported, some of which are legal. Clinicians should be aware that synthetic cannabinoids may cause an array of severe health consequences. Given the ever evolving structure of available analogues, clinicians must also be prepared for other unexpected adverse effects. PMID:25233895

  11. Morphological evidence for an apparent lysosomotropic activity by unsaturated putrescine analogues.

    PubMed

    Porter, C W; Stanek, J; Black, J; Vaughan, M; Ganis, B; Pleshkewych, A

    1990-03-15

    Treatment of cultured L1210 cells with the putrescine analogue, 2,5-diamino-3-hexyne, at 0.5 nM resulted in the rapid (1-2 h) appearance of numerous cytoplasmic vacuoles which were highly visible by light microscopy. Ultrastructural examination revealed that the vacuoles contained numerous membrane vesicles and electron-dense structures resembling endosomal elements. Other cellular organelles were unaffected by the drug. The overall morphological effect by 2,5-diamino-3-hexyne was nearly identical to that produced in the same cells by the known lysosomotropic agent, chloroquine. Since the putrescine analogue, 1,4-diamino-2-butyne at 1.2 mM, also produced comparable cytoplasmic vacuolation, and putrescine itself failed to do so at concentrations as high as 5 mM, it was concluded that the apparent lysosomotropic activity of the putrescine analogues was probably due to their weaker basicity related to the presence of an internal triple bond. Although it is uncertain whether the effect of the analogues on the endosomal system is related to the natural function of polyamines, the finding points out the previously unrecognized potential for certain polyamine analogues to act in this manner. PMID:1689613

  12. Analogue modelling of slope deformation patterns prior to failure

    NASA Astrophysics Data System (ADS)

    Rosser, N. J.

    2009-12-01

    Results are presented from scaled analogue modelling of the temporal and spatial evolution of pre-failure strain states on slopes of increasing geometrical complexity. The aim is to explore experimentally the conditions in which final failure time can be predicted by extrapolating strain-rate accelerations. Strain-rate based failure prediction, often referred to as the ‘Saito method’, has been validated at the micro-scale using stress path tests, where the influence of brittle fracturing on material deformation rate has been shown. In addition a limited number of field examples have been successful in retroactive predictions of failure in real slopes, but few have been successful a priori. The research seeks to establish when and where these approaches can, and crucially cannot, be applied. The degree to which surface strain is an expression of sub-surface deformation in real slopes remains poorly understood. Fundamentally, in real slopes the rate of deformation and the timing of slope failure are complex, being controlled by, for example slope geometry, in addition to material deformation. The paper will, with the use of scaled analogue models, demonstrate the influence of slope geometry on the spatial and temporal evolution of failure, and thus of surface strain, on failing slopes establishing a set of spatio-temporal models to explain the variation in strain accumulation from real slope monitoring data. Deformations are modelled using various slope configurations formed from an elasto-brittle-plastic analogue material, Slope1, placed under stress on a newly developed vertical gravity acceleration table. The table offers significant advantages over conventional centrifuge modelling, permitting control over incremental loading and the rapid cessation of the experiment at points of interest during deformation. Progressive surface deformation is monitored during the experiment using a 3D structured light scanner at 0.05 mm resolution to derive sequential surface DEMs and deformation maps. The research will ultimately allow the validation of using the Saito method for failure prediction in real slopes.

  13. Heteroatom Analogues of Hydrocodone: Synthesis and Biological Activity

    PubMed Central

    Giacometti, Robert D.; Duchek, Jan; Werner, Lukas; Husni, Afeef S.; McCurdy, Christopher R.; Cutler, Stephen J.; Cox, D. Phillip; Hudlicky, Tomas

    2013-01-01

    Heteroatom analogues of hydrocodone, in which the N-methyl functionality was replaced with oxygen, sulfur, sulfoxide, and sulfone, were prepared by a short sequence from the ethylene glycol ketal of hydrocodone; a carbocyclic analogue of bisnorhydrocodone was also prepared. The compounds were tested for receptor binding and revealed moderate levels of activity for the sulfone analogue of hydrocodone. PMID:23397939

  14. Synthesis and Biochemical Evaluation of Thiochromanone Thiosemicarbazone Analogues as Inhibitors of Cathepsin L

    PubMed Central

    2012-01-01

    A series of 36 thiosemicarbazone analogues containing the thiochromanone molecular scaffold functionalized primarily at the C-6 position were prepared by chemical synthesis and evaluated as inhibitors of cathepsins L and B. The most promising inhibitors from this group are selective for cathepsin L and demonstrate IC50 values in the low nanomolar range. In nearly all cases, the thiochromanone sulfide analogues show superior inhibition of cathepsin L as compared to their corresponding thiochromanone sulfone derivatives. Without exception, the compounds evaluated were inactive (IC50 > 10000 nM) against cathepsin B. The most potent inhibitor (IC50 = 46 nM) of cathepsin L proved to be the 6,7-difluoro analogue 4. This small library of compounds significantly expands the structure–activity relationship known for small molecule, nonpeptidic inhibitors of cathepsin L. PMID:24900494

  15. Exploiting Enzymatic Promiscuity to Engineer a Focused Library of Highly Selective Antifungal and Antiproliferative Aureothin Analogues

    PubMed Central

    Werneburg, Martina; Busch, Benjamin; He, Jing; Richter, Martin E.A.; Xiang, Longkuan; Moore, Bradley S.; Roth, Martin; Dahse, Hans-Martin

    2010-01-01

    Aureothin is a shikimate-polyketide hybrid metabolite from Streptomyces thioluteus with a rare nitroaryl moiety, a chiral tetrahydrofuran ring and an O-methylated pyrone ring. The antimicrobial and antitumor activities of aureothin have caught our interest in modulating its structure as well as its bioactivity profile. In an integrated approach using mutasynthesis, biotransformation and combinatorial biosynthesis, a defined library of aureothin analogues was generated. The promiscuity of the polyketide synthase assembly line towards different starter units and the plasticity of the pyrone and tetrahydrofuran ring formation were exploited. A selection of fifteen new aureothin analogues with modifications at the aryl residue, the pyrone ring, and the oxygenated backbone was produced on a preparative scale and fully characterized. Remarkably, various new aureothin derivatives are less cytotoxic than aureothin but have improved antiproliferative activities. Furthermore, we found that the THF ring is crucial for the remarkably selective activity of aureothin analogues against certain pathogenic fungi. PMID:20662518

  16. Identification and screening of a tadalafil analogue found in adulterated herbal products.

    PubMed

    Lee, Ji Hyun; Kim, Hyung Joo; Noh, Eunyoung; Kim, Jung Yeon; Cho, So Hyun; Do, Jung-Ah; Yoon, Chang-Yong; Cho, Sooyeul; Kim, Woo Seong

    2014-11-13

    A tadalafil analogue was detected in an herbal product by high performance liquid chromatography-diode array detector (HPLC-DAD) with a similar chromatographic retention time to tadalafil. The compounds were separated using semi-preparative HPLC. The structure of the detected tadalafil analogue was elucidated by LC-quadrupole time-of-flight mass spectrometry (LC-Q-TOF/MS) and nuclear magnetic resonance (NMR) spectroscopy. A positive ion at m/z 404.1644 was detected by LC-Q-TOF/MS, corresponding to a molecular formula of C23H22N3O4. This unknown compound was identified as an analogue of tadalafil containing an additional methylene group and named homotadalafil. Homotadalafil was detected in 10 of 91 herbal products at concentrations of 0.058mgg(-1) to 8.735mgg(-1). PMID:25462124

  17. Secret Public Key Protocols Revisited

    NASA Astrophysics Data System (ADS)

    Lim, Hoon Wei; Paterson, Kenneth G.

    Password-based protocols are important and popular means of providing human-to-machine authentication. The concept of secret public keys was proposed more than a decade ago as a means of securing password-based authentication protocols against off-line password guessing attacks, but was later found vulnerable to various attacks. In this paper, we revisit the concept and introduce the notion of identity-based secret public keys. Our new identity-based approach allows secret public keys to be constructed in a very natural way using arbitrary random strings, eliminating the structure found in, for example, RSA or ElGamal keys. We examine identity-based secret public key protocols and give informal security analyses, indicating that they are secure against off-line password guessing and other attacks.

  18. Structural Basis for the Enzymatic Formation of the Key Strawberry Flavor Compound 4-Hydroxy-2,5-dimethyl-3(2H)-furanone

    PubMed Central

    Schiefner, André; Sinz, Quirin; Neumaier, Irmgard; Schwab, Wilfried; Skerra, Arne

    2013-01-01

    The last step in the biosynthetic route to the key strawberry flavor compound 4-hydroxy-2,5-dimethyl-3(2H)-furanone (HDMF) is catalyzed by Fragaria x ananassa enone oxidoreductase (FaEO), earlier putatively assigned as quinone oxidoreductase (FaQR). The ripening-induced enzyme catalyzes the reduction of the exocyclic double bond of the highly reactive precursor 4-hydroxy-5-methyl-2-methylene-3(2H)-furanone (HMMF) in a NAD(P)H-dependent manner. To elucidate the molecular mechanism of this peculiar reaction, we determined the crystal structure of FaEO in six different states or complexes at resolutions of ?1.6 ?, including those with HDMF as well as three distinct substrate analogs. Our crystallographic analysis revealed a monomeric enzyme whose active site is largely determined by the bound NAD(P)H cofactor, which is embedded in a Rossmann-fold. Considering that the quasi-symmetric enolic reaction product HDMF is prone to extensive tautomerization, whereas its precursor HMMF is chemically labile in aqueous solution, we used the asymmetric and more stable surrogate product 2-ethyl-4-hydroxy-5-methyl-3(2H)-furanone (EHMF) and the corresponding substrate (2E)-ethylidene-4-hydroxy-5-methyl-3(2H)-furanone (EDHMF) to study their enzyme complexes as well. Together with deuterium-labeling experiments of EDHMF reduction by [4R-2H]NADH and chiral-phase analysis of the reaction product EHMF, our data show that the 4R-hydride of NAD(P)H is transferred to the unsaturated exocyclic C6 carbon of HMMF, resulting in a cyclic achiral enolate intermediate that subsequently becomes protonated, eventually leading to HDMF. Apart from elucidating this important reaction of the plant secondary metabolism our study provides a foundation for protein engineering of enone oxidoreductases and their application in biocatalytic processes. PMID:23589283

  19. Renin inhibitors. Syntheses of subnanomolar, competitive, transition-state analogue inhibitors containing a novel analogue of statine.

    PubMed

    Boger, J; Payne, L S; Perlow, D S; Lohr, N S; Poe, M; Blaine, E H; Ulm, E H; Schorn, T W; LaMont, B I; Lin, T Y

    1985-12-01

    Analogues of the renin octapeptide substrate were synthesized in which replacement of the scissile dipeptide with (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid (statine, Sta) transformed the substrate sequence into potent, transition-state analogue, competitive inhibitors of renin. Synthesis and incorporation of the cyclohexylalanyl analogue of Sta, (3S,4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA), gave the most potent inhibitors of renin yet reported, including N-isovaleryl-L-histidyl-L-prolyl-L-phenylalanyl-L-histidyl-ACHPA-L -leucyl-L- phenylalanyl amide [Iva-His-Pro-Phe-His-ACHPA-Leu-Phe-NH2,3], with renin inhibitions of Ki = 1.6 X 10(-10) M (human kidney renin), IC50 = 1.7 X 10(-10)M (human plasma renin), IC50 = 1.9 X 10(-9)M (dog plasma renin), and IC50 = 2.1 X 10(-8) M (rat plasma renin). This inhibitor 3, containing ACHPA, was 55-76 times more potent vs. human renin than the comparable Sta-containing inhibitor 1 and 17 times more potent vs. dog renin than 1. Inhibitor 3 lowered blood pressure in sodium-deficient dogs, with in vivo potency 19 times that shown by 1, in close agreement with the relative in vitro potencies. Structure-activity results are presented that show the minimal N-terminus for these inhibitors. An ACHPA-containing pentapeptide, N-[(ethyloxy)carbonyl]-L-phenylalanyl-L- histidyl-ACHPA-L-leucyl-L-phenylalanyl amide [Etoc-Phe-His-ACHPA-Leu-Phe-NH2,8], retained subnanomolar inhibitory potency. Molecular modelling studies are described that suggested the design of ACHPA. PMID:3906131

  20. Extrapolating subsurface geometry by surface expressions in transpressional strike slip fault, deduced from analogue experiments with settings of rheology and convergence angle

    NASA Astrophysics Data System (ADS)

    Hsieh, Shang Yu; Neubauer, Franz

    2015-04-01

    The internal structure of major strike-slip faults is still poorly understood, particularly how to extrapolate subsurface structures by surface expressions. Series of brittle analogue experiments by Leever et al., 2011 resulted the convergence angle is the most influential factor for surface structures. Further analogue models with different ductile settings allow a better understanding in extrapolating surface structures to the subsurface geometry of strike-slip faults. Fifteen analogue experiments were constructed to represent strike-slip faults in nature in different geological settings. As key parameters 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 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 transpressional 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.

  1. Design, synthesis and evaluation of antimicrobial activity of N-terminal modified Leucocin A analogues.

    PubMed

    Bodapati, Krishna Chaitanya; Soudy, Rania; Etayash, Hashem; Stiles, Michael; Kaur, Kamaljit

    2013-07-01

    Class IIa bacteriocins are potent antimicrobial peptides produced by lactic acid bacteria to destroy competing microorganisms. The N-terminal domain of these peptides consists of a conserved YGNGV sequence and a disulphide bond. The YGNGV motif is essential for activity, whereas, the two cysteines involved in the disulphide bond can be replaced with hydrophobic residues. The C-terminal region has variable sequences, and folds into a conserved amphipathic ?-helical structure. To elucidate the structure-activity relationship in the N-terminal domain of these peptides, three analogues (1-3) of a class IIa bacteriocin, Leucocin A (LeuA), were designed and synthesized by replacing the N-terminal ?-sheet residues of the native peptide with shorter ?-turn motifs. Such replacement abolished the antibacterial activity in the analogues, however, analogue 1 was able to competitively inhibit the activity of native LeuA. Native LeuA (37-mer) was synthesized using native chemical ligation method in high yield. Solution conformation study using circular dichroism spectroscopy and molecular dynamics simulations suggested that the C-terminal region of analogue 1 adopts helical folding as found in LeuA, while the N-terminal region did not fold into ?-sheet conformation. These structure-activity studies highlight the role of proper folding and complete sequence in the activity of class IIa bacteriocins. PMID:23673216

  2. The Earliest Phases of Star Formation (EPoS): a Herschel key project. The thermal structure of low-mass molecular cloud cores

    NASA Astrophysics Data System (ADS)

    Launhardt, R.; Stutz, A. M.; Schmiedeke, A.; Henning, Th.; Krause, O.; Balog, Z.; Beuther, H.; Birkmann, S.; Hennemann, M.; Kainulainen, J.; Khanzadyan, T.; Linz, H.; Lippok, N.; Nielbock, M.; Pitann, J.; Ragan, S.; Risacher, C.; Schmalzl, M.; Shirley, Y. L.; Stecklum, B.; Steinacker, J.; Tackenberg, J.

    2013-03-01

    Context. The temperature and density structure of molecular cloud cores are the most important physical quantities that determine the course of the protostellar collapse and the properties of the stars they form. Nevertheless, density profiles often rely either on the simplifying assumption of isothermality or on observationally poorly constrained model temperature profiles. The instruments of the Herschel satellite provide us for the first time with both the spectral coverage and the spatial resolution that is needed to directly measure the dust temperature structure of nearby molecular cloud cores. Aims: With the aim of better constraining the initial physical conditions in molecular cloud cores at the onset of protostellar collapse, in particular of measuring their temperature structure, we initiated the guaranteed time key project (GTKP) "The Earliest Phases of Star Formation" (EPoS) with the Herschel satellite. This paper gives an overview of the low-mass sources in the EPoS project, the Herschel and complementary ground-based observations, our analysis method, and the initial results of the survey. Methods: We study the thermal dust emission of 12 previously well-characterized, isolated, nearby globules using FIR and submm continuum maps at up to eight wavelengths between 100 ?m and 1.2 mm. Our sample contains both globules with starless cores and embedded protostars at different early evolutionary stages. The dust emission maps are used to extract spatially resolved SEDs, which are then fit independently with modified blackbody curves to obtain line-of-sight-averaged dust temperature and column density maps. Results: We find that the thermal structure of all globules (mean mass 7 M?) is dominated by external heating from the interstellar radiation field and moderate shielding by thin extended halos. All globules have warm outer envelopes (14-20 K) and colder dense interiors (8-12 K) with column densities of a few 1022 cm-2. The protostars embedded in some of the globules raise the local temperature of the dense cores only within radii out to about 5000 AU, but do not significantly affect the overall thermal balance of the globules. Five out of the six starless cores in the sample are gravitationally bound and approximately thermally stabilized. The starless core in CB 244 is found to be supercritical and is speculated to be on the verge of collapse. For the first time, we can now also include externally heated starless cores in the Lsmm/Lbol vs. Tbol diagram and find that Tbol < 25 K seems to be a robust criterion to distinguish starless from protostellar cores, including those that only have an embedded very low-luminosity object. Herschel is an ESA space observatory with science instruments provided by European-led Principal Investigator consortia and with important participation from NASA.Partially based on observations carried out with the IRAM 30 m Telescope, with the Atacama Pathfinder Experiment (APEX), and with the James Clerk Maxwell Telescope (JCMT). IRAM is supported by INSU/CNRS (France), MPG (Germany) and IGN (Spain). APEX is a collaboration between Max Planck Institut für Radioastronomie (MPIfR), Onsala Space Observatory (OSO), and the European Southern Observatory (ESO). The JCMT is operated by the Joint Astronomy Centre on behalf of the Particle Physics and Astronomy Research Council of the United Kingdom, the Netherlands Association for Scientific Research, and the National Research Council of Canada.Appendices A, B and C are available in electronic form at http://www.aanda.org

  3. Synthesis of Piperlongumine Analogues and Discovery of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activators as Potential Neuroprotective Agents.

    PubMed

    Peng, Shoujiao; Zhang, Baoxin; Meng, Xianke; Yao, Juan; Fang, Jianguo

    2015-07-01

    The cellular antioxidant system plays key roles in blocking or retarding the pathogenesis of adult neurodegenerative disorders as elevated oxidative stress has been implicated in the pathophysiology of such diseases. Molecules with the ability in enhancing the antioxidant defense thus are promising candidates as neuroprotective agents. We reported herein the synthesis of piperlongumine analogues and evaluation of their cytoprotection against hydrogen peroxide- and 6-hydroxydopamine-induced neuronal cell oxidative damage in the neuron-like PC12 cells. The structure-activity relationship was delineated after the cytotoxicity and protection screening. Two compounds (4 and 5) displayed low cytotoxicity and confer potent protection of PC12 cells from the oxidative injury via upregulation of a panel of cellular antioxidant molecules. Genetically silencing the transcription factor Nrf2, a master regulator of the cellular stress responses, suppresses the cytoprotection, indicating the critical involvement of Nrf2 for the cellular action of compounds 4 and 5 in PC12 cells. PMID:26079183

  4. Holographic Fluids with Vorticity and Analogue Gravity

    E-print Network

    Robert G. Leigh; Anastasios C. Petkou; P. Marios Petropoulos

    2012-05-28

    We study holographic three-dimensional fluids with vorticity in local equilibrium and discuss their relevance to analogue gravity systems. The Fefferman-Graham expansion leads to the fluid's description in terms of a comoving and rotating Papapetrou-Randers frame. A suitable Lorentz transformation brings the fluid to the non-inertial Zermelo frame, which clarifies its interpretation as moving media for light/sound propagation. We apply our general results to the Lorentzian Kerr-AdS_4 and Taub-NUT-AdS_4 geometries that describe fluids in cyclonic and vortex flows respectively. In the latter case we associate the appearance of closed timelike curves to analogue optical horizons. In addition, we derive the classical rotational Hall viscosity of three-dimensional fluids with vorticity. Our formula remarkably resembles the corresponding result in magnetized plasmas.

  5. The Brookhaven electron analogue, 1953--1957

    SciTech Connect

    Plotkin, M.

    1991-12-18

    The following topics are discussed on the Brookhaven electron analogue: L.J. Haworth and E.L. VanHorn letters; Original G.K. Green outline for report; General description; Parameter list; Mechanical Assembly; Alignment; Degaussing; Vacuum System; Injection System; The pulsed inflector; RF System; Ferrite Cavity; Pick-up electrodes and preamplifiers; Radio Frequency power amplifier; Lens supply; Controls and Power; and RF acceleration summary.

  6. h-analogue of Fibonacci Numbers

    E-print Network

    H. B. Benaoum

    2009-09-30

    In this paper, we introduce the h-analogue of Fibonacci numbers for non-commutative h-plane. For h h'= 1 and h = 0, these are just the usual Fibonacci numbers as it should be. We also derive a collection of identities for these numbers. Furthermore, h-Binet's formula for the h-Fibonacci numbers is found and the generating function that generates these numbers is obtained.

  7. Identification of a renal receptor for parathyroid hormone by photoaffinity radiolabeling using a synthetic analogue

    SciTech Connect

    Coltera, M.D.; Potts, J.T.; Rosenblatt, M.

    1981-10-01

    To identify a parathyroid hormone-binding component in renal membranes, a biologically active photoaffinity radioligand of parathyroid hormone was designed using chemical strategies based on the experience of earlier structure-activity studies. The sulfur-free, oxidation-resistant, synthetic analogue of bovine parathyroid hormone (bPTH), (Nle-8,Nle-18,Tyr-34) bPTH-(1-34) amide, was radiolabeled with /sup 125/iodine. Two photolabile moieties, 4-fluoro-3-nitrophenyl azide and N-succinimidyl-6(4' -azido-2' -nitrophenyl amino)-hexanoate, were separately conjugated to iodinated peptide under conditions favoring coupling through lysine side chains rather than the NH/sub 2/-terminal amino group. Concurrent studies established that a photolabile analogue was fully active in the renal adenylate cyclase assay. After incubation of both photolabile analogues in darkness with renal membranes in the presence or absence of competing hormone, exposure to light covalently linked the analogues to membrane components. Membranes were then solubilized, reduced, and fractionated on sodium dodecyl sulfate poly- acrylamide gels. Radioautographs of the gels showed four to six labeled membrane components for each analogue in the absence of competing hormone, but only one band failed to label in the presence of competing hormone. This band labeled in the presence of inactive synthetic fragments of parathyroid hormone, and was not identified in membrane preparations derived from a renal cell line that is not parathyroid hormone-responsive. The migration of the band (M/sub r/ approx. = 70,000) was identical regardless of the photolabile analogue employed. These studies provide a technique useful for further study of the interactions of parathyroid hormone and receptor in various target tissues and for receptor purification and characterization.

  8. Cis-Trans Isomerizations of Proline Residues Are Key to Bradykinin Conformations

    E-print Network

    Clemmer, David E.

    of the structureidentification of a -turn involving the Ser6 -Pro7 -Phe8 -Arg9 residues. No definitive structural information and may aid in the design of more effective receptor agonist and antagonist analogues. This study focuses

  9. Synthesis of mixed opioid affinity cyclic endomorphin-2 analogues with fluorinated phenylalanines.

    PubMed

    Piekielna, Justyna; Perlikowska, Renata; do-Rego, Jean Claude; do-Rego, Jean-Luc; Cerlesi, Maria Camilla; Calo, Girolamo; Kluczyk, Alicja; ?api?ski, Krzysztof; Tömböly, Csaba; Janecka, Anna

    2015-05-14

    As part of our continuing studies on the structure-activity relationships of cyclic pentapeptides based on the structure of endomorphin-2 (EM-2), we report here the synthesis and biological activities of a new series of analogues of a general sequence Tyr/Dmt-c[d-Lys-Phe-Phe-Asp]NH2 (where Dmt = 2',6'-dimethyltyrosine), incorporating fluorinated amino acids: 4-fluorophenylalanine (4-F-Phe), 2,4-difluorophenylalanine (2,4-F-Phe), or 4-trifluoromethylphenylalanine (4-CF3-Phe) instead of the Phe residue in position 3 or 4. Depending on the fluorinated amino acid residue and its position in the sequence, analogues were mixed, high affinity MOP/KOP receptor agonists, MOP/DOP/KOP agonists, or selective KOP agonists. The in vitro potencies and efficacies of all novel analogues were assessed in calcium mobilization assay. The most potent analogues, Dmt-c[d-Lys-Phe-4-F-Phe-Asp]NH2 and Dmt-c[d-Lys-Phe-2,4-F-Phe-Asp]NH2, were tested in vivo in the mouse hot-plate test. They produced strong antinociceptive effect not only after intracerebroventricular but also after intraperitoneal injection, indicating that they were able to cross the blood-brain barrier. PMID:26005537

  10. Synthesis and biological evaluation of Esaprazole analogues showing ?1 binding and neuroprotective properties in vitro.

    PubMed

    Kelly, Nicholas M; Wellejus, Anja; Elbrønd-Bek, Heidi; Weidner, Morten Sloth; Jørgensen, Signe Humle

    2013-06-01

    Esaprazole, a molecule previously acknowledged to protect against stomach and intestinal ulcers was surprisingly discovered to have neuroprotective activities and ?1 binding in vitro. A highly diverse set of Esaprazole analogues 2-5 was prepared in order to increase blood-brain barrier penetration. The analogues showed a structure-activity relationship at the ?1 receptor closely matching already published pharmacophores. Many of the analogues were shown to have neuroprotective properties in two assays using primary cultures of cortical neurons exposed to glutamate and hydrogen peroxide. However, no apparent SAR for these two assays could be developed. Metabolic stability of the analogues were also investigated and the structure of R(1) had a significant bearing on the ADME properties of the compound resulting in two series of compounds. Compounds in which R(1) was a H or acyl group had good metabolic stability in RLM but poor BBB penetration, whereas compounds where R(1) was a cyclo- or bicyclo-alkyl group had poor metabolic stability but good BBB penetration. PMID:23601816

  11. The crystal and molecular structure of a valinomycin analogue cyclo[(D-Val-L-Lac-L-Ala-D-Hyi)2(D-Val-L-Lac-L-Val-D-Hyi)]. H2O(C50H82N6 O18.H2O).

    PubMed

    Pletnev, V Z; Ruzeinikov, S N; Tsigannik, I N; Ivanov, V T; Pletnev, S V; Langs, D A; Duax, W L

    1997-11-01

    The crystal and molecular structure of the valinomycin analogue, cyclo[(D-Val-L-Lac-L-Ala-D-Hyi)2(D-Val-L-Lac-L-Val-D-Hyi)] has been solved by x-ray direct methods using the "Shake and Bake" procedure. The crystals, grown from a mixture of octane/CH2Cl2, belong to space group P2(1) (Z = 4) with cell parameters a = 10.29, b = 32.08, c = 18.73 A, beta = 97.05 degrees, and contain two molecules per asymmetric unit. After anisotropic refinement the standard reliability factor was Rl = 0.058. The conformations of both independent molecules is similar to that observed for isoleucinomycin, cyclo[-(D-Ile-L-Lac-L-Ile-D-Hyi)3] [V. Z. Pletnev et al. (1980) Biopolymers, Vol. 19, pp. 1517-1534]. The structure has an asymmetric conformation stabilized by six intramolecular H bonds, five bonds being of the 4-->1 type and one bond being of the 5-->1 type. One water molecule is caged in the internal cavity of each cyclodepsipeptide. This conformation could represent an intermediate state between free and complexed forms of valinomycin. PMID:9358731

  12. Structure and Properties of fac-[Re(I)(CO)3(NTA)](2-) (NTA(3-) = Trianion of Nitrilotriacetic Acid) and fac-[Re(I)(CO)3(L)](n-) Analogues Useful for Assessing the Excellent Renal Clearance of the fac-[(99m)Tc(I)(CO)3(NTA)](2-) Diagnostic Renal Agent.

    PubMed

    Klenc, Jeffrey; Lipowska, Malgorzata; Abhayawardhana, Pramuditha L; Taylor, Andrew T; Marzilli, Luigi G

    2015-07-01

    We previously identified two new agents based on the [(99m)Tc(V)O](3+) core with renal clearances in human volunteers 30% higher than that of the widely used clinical tracer (99m)Tc-MAG3 (MAG3(5-) = penta-anion of mercaptoacetyltriglycine). However, renal agents with even higher clearances are needed. More recently, we changed our focus from the [(99m)Tc(V)O](3+) core to the discovery of superior tracers based on the fac-[(99m)Tc(I)(CO)3](+) core. Compared to (99m)Tc-MAG3, fac-[(99m)Tc(I)(CO)3(NTA)](2-) (NTA(3-) = trianion of nitrilotriacetic acid) holds great promise by virtue of its efficient renal clearance via tubular secretion and the absence of hepatobiliary elimination, even in patients with severely reduced renal function. We report here NMR, molecular (X-ray) structure, and solution data on fac-[Re(I)(CO)3(NTA)](2-) with a -CH2CO2(-) dangling monoanionic chain and on two fac-[Re(I)(CO)3(L)](-) analogues with either a -CH2CONH2 or a -CH2CH2OH dangling neutral chain. In these three fac-[Re(I)(CO)3(L)](n-) complexes, the fac-[Re(I)(CO)3(N(CH2CO2)2)](-) moiety is structurally similar and has similar electronic properties (as assessed by NMR data). In reported and ongoing studies, the two fac-[(99m)Tc(I)(CO)3(L)](-) analogues with these neutral dangling chains were found to have pharmacokinetic properties very similar to those of fac-[(99m)Tc(I)(CO)3(NTA)](2-). Therefore, we reach the unexpected conclusion that in fac-[(99m)Tc(I)(CO)3(L)](n-) agents, renal clearance is affected much more than anticipated by features of the core plus the chelate rings (the [(99m)Tc(I)(CO)3(N(CH2CO2)2)](-) moiety) than by the presence of a negatively charged dangling carboxylate chain. PMID:26068141

  13. Synthesis of azole nucleoside analogues of D-pinitol as potential antitumor agents.

    PubMed

    Zhan, Tianrong; Lou, Hongxiang

    2007-05-01

    A convenient strategy is reported for the synthesis of azole nucleoside analogues of D-pinitol (=3-O-methyl-D-chiro-inositol). The key intermediate 3-O-methyl-4,5-epoxy-D-chiro-inositol was obtained in excellent yield via an epoxidation from mono-methanesulfonate of D-pinitol. The process of opening of the epoxy ring by azole-bases appeared strongly regioselective in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene. All newly synthesized carbocyclic azole nucleosides were assayed against lung and bladder cancer in vitro. Only the triazole and benzotriazole nucleoside analogues inhibited the growth of human lung cancer cell lines (PG) with EC(50) of 11.3 and 22.6 microM, respectively, and showed much less inhibitory activity against human bladder cell lines (T(24)). PMID:17258696

  14. An IMS-IMS Analogue of MS-MS

    SciTech Connect

    Koeniger, Stormy L.; Merenbloom, Samuel I.; Valentine, Stephen J.; Jarrold, Martin F.; Udseth, Harold R.; Smith, Richard D.; Clemmer, David E.

    2006-06-15

    The development of a new ion mobility/mass spectrometry instrument that incorporates a multifield drift tube/ion funnel design is described. In this instrument, individual components from a mixture of ions can be resolved and selected on the basis of mobility differences prior to collisional activation inside the drift tube. The fragment ions that are produced can be dispersed again in a second ion mobility spectrometry (IMS) region prior to additional collisional activation and MS analysis. The result is an IMS-IMS analogue of MS-MS. Here, we describe the preliminary instrumental design and experimental approach. We illustrate the approach by examining the highly characterized bradykinin and ubiquitin systems. Mobility-resolved fragment ions of bradykinin show that b-type ions are readily discernible fragments, because they exist as two easily resolvable structural types. Current limitations and future directions are briefly discussed.

  15. Magnetic neutron scattering of a Prussian blue analogue photomagnet

    NASA Astrophysics Data System (ADS)

    Pajerowski, D. M.; Knowles, E. S.; Calm, Y. M.; Meisel, M. W.; Andrus, M. J.; Gardner, J. E.; Talham, D. R.; Garlea, V. O.; Nagler, S. E.

    2011-03-01

    Since the discovery of photoinduced magnetism in cobalt hexacyanoferrate (CoFe) Prussian blue analogues (PBAs) in 1996,1 there have been many, multifarious studies that elucidated the nature of the photoeffect. However, the magnetization in CoFe has proven difficult to model quantitatively using macroscopic data due to the presence of multiple magnetic species, magnetic bistability, superexchange, and unquenched orbital angular momentum. To investigate the ordered magnetization directly, we have studied dueterated powders of CoFe using unpolarized and polarized neutron diffraction, and observed magnetic neutron scattering for the first time in this compound. A model for the magnetic structure based upon neutron diffraction, elemental analysis, infrared spectroscopy, and macroscopic magnetization will be presented. Supported, in part, by NSF DMR-0701400 (MWM), DMR-1005581 (DRT), and DMR-0654118 (NHMFL). Research at ORNL was sponsored by the Scientific User Facilities Division, BES, DOE.

  16. Inhibition of cytokine release by mycobacterium tuberculosis phenolic glycolipid analogues.

    PubMed

    Elsaidi, Hassan R H; Lowary, Todd L

    2014-05-26

    Infection by Mycobacterium tuberculosis causes tuberculosis, a disease characterized by alteration of host innate and adaptive immunity. These processes are mediated by a series of bacterial biomolecules, among which phenolic glycolipids (PGLs) and the related p-hydroxybenzoic acid derivatives have been suggested to play important roles. To probe the importance of structural features of these glycans on cytokine modulation, we synthesized three M. tuberculosis PGL analogues (1-3), which differ from the native glycoconjugates by possessing a simplified lipid algycone. The ability of 1-3 to modulate the release of proinflammatory cytokines (TNF-?, IL-1?, IL-6, MCP-1) and nitric oxide (NO) was evaluated. None of the compounds stimulated the secretion of these signalling molecules. However, all showed a Toll-like Receptor 2-mediated, concentration-dependent inhibition profile that was related to the methylation pattern on the glycan. PMID:24797221

  17. Pushing Up Lithium Storage through Nanostructured Polyazaacene Analogues as Anode.

    PubMed

    Wu, Jiansheng; Rui, Xianhong; Long, Guankui; Chen, Wangqiao; Yan, Qingyu; Zhang, Qichun

    2015-06-15

    According to the evidence from both theoretical calculations and experimental findings, conjugated ladder polymers containing large ?-conjugated structure, a high number of nitrogen heteroatoms, and a multiring aromatic system, could be an ideal organic anode candidate for lithium-ion batteries (LIBs). In this report, we demonstrated that the nanostructured polyazaacene analogue poly(1,6-dihydropyrazino[2,3g]quinoxaline-2,3,8-triyl-7-(2H)-ylidene-7,8-dimethylidene) (PQL) shows high performance as anode materials in LIBs: high capacity (1750?mAh?g(-1) , 0.05C), good rate performance (303?mAh?g(-1) , 5C), and excellent cycle life (1000 cycles), especially at high temperature of 50?°C. Our results suggest nanostructured conjugated ladder polymers could be alternative electrode materials for the practical application of LIBs. PMID:25960289

  18. Salt diapirism driven by differential loading — Some insights from analogue modelling

    NASA Astrophysics Data System (ADS)

    Warsitzka, Michael; Kley, Jonas; Kukowski, Nina

    2013-04-01

    We applied scaled physical analogue experiments to investigate the early development of salt diapirs induced by differential sedimentary loading in an intra-continental basin realm (e.g. the North German Basin). During the experiments, deformation in a salt-analogue viscous layer was initiated by variations in the thickness of an overlying brittle material and subsequent accumulation of the brittle material further sustained deformation. A 2D optical image correlation system was used to monitor the strain evolution in the salt analogue material. Our models indicate that the formation of salt pillow structures can be achieved by minimum variations in the overburden loading. The increase of differential loading by adding synkinematic layers in the subsided areas causes not only an active piercing of the viscous layer through the brittle overburden but also an additional uplift in the adjacent areas. These elevations, named "secondary structures", act as origins for a successive generation of diapirs. Consequently, an initial perturbation of the salt-sediment-interface can lead to a lateral propagation temporally shifted diapirs. The linkage between primary and secondary structures is reflected in the synkinematic overburden layers such as overlapping peripheral sinks in the transition zone between two diapirs. These sinks, in turn, are a frequently observable phenomenon around salt structures of the North German basin indicating that "secondary diapirism" is an underestimated process - besides regional tectonic stresses - influencing the evolution of salt structures.

  19. S100A13-C2A binary complex structure—a key component in the acidic fibroblast growth factor for the non-classical pathway

    Microsoft Academic Search

    Sepuru K. Mohan; Sandhya G. Rani; Sriramoju M. Kumar; Chin Yu

    2009-01-01

    Fibroblast growth factors (FGFs) are key regulators of cell proliferation, differentiation, tumor-induced angiogenesis and migration. FGFs are essential for early embryonic development, organ formation and angiogenesis. They play important roles in tumor formation, inflammation, wound healing and restenosis. The biological effects of FGFs are mediated through the activation of the four transmembrane phosphotyrosine kinase receptors (FGFRs) in the presence of

  20. The structure of Pyrococcus furiosus glutamate dehydrogenase reveals a key role for ion-pair networks in maintaining enzyme stability at extreme temperatures

    Microsoft Academic Search

    KSP Yip; TJ Stillman; KL Britton; PJ Artymiuk; PJ Baker; SE Sedelnikova; PC Engel; A Pasquo; R Chiaraluce; V Consalvi; R Scandurra; DW Rice

    1995-01-01

    Background: The hyperthermophile Pyrococcus furiosus is one of the most thermostable organisms known, with an optimum growth temperature of 100°C. The proteins from this organism display extreme thermostability. We have undertaken the structure determination of glutamate dehydrogenase from P. furiosus in order to gain further insights into the relationship between molecular structure and thermal stability.Results The structure of P. furiosus

  1. Modular Connector Keying Concept

    NASA Technical Reports Server (NTRS)

    Ishman, Scott; Dukes, Scott; Warnica, Gary; Conrad, Guy; Senigla, Steven

    2013-01-01

    For panel-mount-type connectors, keying is usually "built-in" to the connector body, necessitating different part numbers for each key arrangement. This is costly for jobs that require small quantities. This invention was driven to provide a cost savings and to reduce documentation of individual parts. The keys are removable and configurable in up to 16 combinations. Since the key parts are separate from the connector body, a common design can be used for the plug, receptacle, and key parts. The keying can then be set at the next higher assembly.

  2. Group key management

    SciTech Connect

    Dunigan, T.; Cao, C.

    1997-08-01

    This report describes an architecture and implementation for doing group key management over a data communications network. The architecture describes a protocol for establishing a shared encryption key among an authenticated and authorized collection of network entities. Group access requires one or more authorization certificates. The implementation includes a simple public key and certificate infrastructure. Multicast is used for some of the key management messages. An application programming interface multiplexes key management and user application messages. An implementation using the new IP security protocols is postulated. The architecture is compared with other group key management proposals, and the performance and the limitations of the implementation are described.

  3. Four generations of transition-state analogues for human purine nucleoside phosphorylase

    PubMed Central

    Ho, Meng-Chiao; Shi, Wuxian; Rinaldo-Matthis, Agnes; Tyler, Peter C.; Evans, Gary B.; Clinch, Keith; Almo, Steven C.; Schramm, Vern L.

    2010-01-01

    Inhibition of human purine nucleoside phosphorylase (PNP) stops growth of activated T-cells and the formation of 6-oxypurine bases, making it a target for leukemia, autoimmune disorders, and gout. Four generations of ribocation transition-state mimics bound to PNP are structurally characterized. Immucillin-H (, first-generation) contains an iminoribitol cation with four asymmetric carbons. DADMe-Immucillin-H (, second-generation), uses a methylene-bridged dihydroxypyrrolidine cation with two asymmetric centers. DATMe-Immucillin-H (, third-generation) contains an open-chain amino alcohol cation with two asymmetric carbons. SerMe-ImmH (, fourth-generation) uses achiral dihydroxyaminoalcohol seramide as the ribocation mimic. Crystal structures of PNPs establish features of tight binding to be; 1) ion-pair formation between bound phosphate (or its mimic) and inhibitor cation, 2) leaving-group interactions to N1, O6, and N7 of 9-deazahypoxanthine, 3) interaction between phosphate and inhibitor hydroxyl groups, and 4) His257 interacting with the 5?-hydroxyl group. The first generation analogue is an imperfect fit to the catalytic site with a long ion pair distance between the iminoribitol and bound phosphate and weaker interactions to the leaving group. Increasing the ribocation to leaving-group distance in the second- to fourth-generation analogues provides powerful binding interactions and a facile synthetic route to powerful inhibitors. Despite chemical diversity in the four generations of transition-state analogues, the catalytic site geometry is almost the same for all analogues. Multiple solutions in transition-state analogue design are available to convert the energy of catalytic rate enhancement to binding energy in human PNP. PMID:20212140

  4. Four Generations of Transition State Analogues for Human Purine Nucleoside Phosphorylase

    SciTech Connect

    Ho, M.; Shi, W; Rinaldo-Mathis, A; Tyler, P; Evans, G; Almo, S; Schramm, V

    2010-01-01

    Inhibition of human purine nucleoside phosphorylase (PNP) stops growth of activated T-cells and the formation of 6-oxypurine bases, making it a target for leukemia, autoimmune disorders, and gout. Four generations of ribocation transition-state mimics bound to PNP are structurally characterized. Immucillin-H (K*{sub i} = 58 pM, first-generation) contains an iminoribitol cation with four asymmetric carbons. DADMe-Immucillin-H (K*{sub i} = 9 pM, second-generation), uses a methylene-bridged dihydroxypyrrolidine cation with two asymmetric centers. DATMe-Immucillin-H (K*{sub i} = 9 pM, third-generation) contains an open-chain amino alcohol cation with two asymmetric carbons. SerMe-ImmH (K*{sub i} = 5 pM, fourth-generation) uses achiral dihydroxyaminoalcohol seramide as the ribocation mimic. Crystal structures of PNPs establish features of tight binding to be; (1) ion-pair formation between bound phosphate (or its mimic) and inhibitor cation, (2) leaving-group interactions to N1, O6, and N7 of 9-deazahypoxanthine, (3) interaction between phosphate and inhibitor hydroxyl groups, and (4) His257 interacting with the 5{prime}-hydroxyl group. The first generation analogue is an imperfect fit to the catalytic site with a long ion pair distance between the iminoribitol and bound phosphate and weaker interactions to the leaving group. Increasing the ribocation to leaving-group distance in the second- to fourth-generation analogues provides powerful binding interactions and a facile synthetic route to powerful inhibitors. Despite chemical diversity in the four generations of transition-state analogues, the catalytic site geometry is almost the same for all analogues. Multiple solutions in transition-state analogue design are available to convert the energy of catalytic rate enhancement to binding energy in human PNP.

  5. CARBOCYCLIC THYMIDINE ANALOGUES FOR USE AS POTENTIAL THERAPEUTIC AGENTS

    PubMed Central

    Seley-Radtke, Katherine L.; Sunkara, Naresh K.

    2013-01-01

    The discovery of azidothymidine’s (AZT) activity against human immunodeficiency virus (HIV) provided strong rationale for the design of additional thymidine analogues. One drawback of many nucleoside analogues is the toxicity that often arises due to phosphorylation by cellular kinases. In order to overcome this problem, a number of truncated nucleosides lacking the 4 ?-hydroxymethyl group have been synthesized. In that regard, the synthesis and preliminary biological results for two truncated carbocyclic thymidine analogues are presented herein. PMID:20183606

  6. CO2 Removal using a Synthetic Analogue of Carbonic Anhydrase

    SciTech Connect

    Harry Cordatos

    2010-09-14

    Project attempts to develop a synthetic analogue for carbonic anhydrase and incorporate it in a membrane for separation of CO2 from coal power plant flue gas. Conference poster presents result of first 9 months of project progress including concept, basic system architecture and membrane properties target, results of molecular modeling for analogue - CO2 interaction, and next steps of testing analogue resistance to flue gas contaminants.

  7. Synthesis and antiparasitic activity of albendazole and mebendazole analogues.

    PubMed

    Navarrete-Vázquez, Gabriel; Yépez, Lilián; Hernández-Campos, Alicia; Tapia, Amparo; Hernández-Luis, Francisco; Cedillo, Roberto; González, José; Martínez-Fernández, Antonio; Martínez-Grueiro, Mercedes; Castillo, Rafael

    2003-10-15

    Albendazole (Abz) and Mebendazole (Mbz) analogues have been synthesized and in vitro tested against the protozoa Giardia lamblia, Trichomonas vaginalis and the helminths Trichinella spiralis and Caenorhabditis elegans. Results indicate that compounds 4a, 4b (Abz analogues), 12b and 20 (Mbz analogues) are as active as antiprotozoal agents as Metronidazole against G. lamblia. Compound 9 was 58 times more active than Abz against T. vaginalis. Compounds 8 and 4a also shown high activity against this protozoan. Compounds 4b and 5a were as active as Abz. None of the Mbz analogues showed activity against T. vaginalis. The anthelmintic activity presented by these compounds was poor. PMID:14527558

  8. Analogue holographic correspondence in optical metamaterials

    NASA Astrophysics Data System (ADS)

    Khveshchenko, D. V.

    2015-03-01

    We assess the prospects of using metamaterials for simulating various aspects of analogue gravity and holographic correspondence. Albeit requiring a careful engineering of the dielectric media, some hallmark features reminiscent of the hypothetical “generalized holographic conjecture” can be detected by measuring non-local optical field correlations. The possibility of such simulated behavior might also shed light on the true origin of those ostensibly holographic phenomena in the condensed-matter systems with emergent effective metrics which may not, in fact, require any reference to the string-theoretical holography.

  9. Spectroscopic study of solar twins and analogues

    NASA Astrophysics Data System (ADS)

    Datson, Juliet; Flynn, Chris; Portinari, Laura

    2015-02-01

    Context. Many large stellar surveys have been and are still being carried out, providing huge amounts of data, for which stellar physical parameters will be derived. Solar twins and analogues provide a means to test the calibration of these stellar catalogues because the Sun is the best-studied star and provides precise fundamental parameters. Solar twins should be centred on the solar values. Aims: This spectroscopic study of solar analogues selected from the Geneva-Copenhagen Survey (GCS) at a resolution of 48 000 provides effective temperatures and metallicities for these stars. We test whether our spectroscopic parameters, as well as the previous photometric calibrations, are properly centred on the Sun. In addition, we search for more solar twins in our sample. Methods: The methods used in this work are based on literature methods for solar twin searches and on methods we developed in previous work to distinguish the metallicity-temperature degeneracies in the differential comparison of spectra of solar analogues versus a reference solar reflection spectrum. Results: We derive spectroscopic parameters for 148 solar analogues (about 70 are new entries to the literature) and verify with a-posteriori differential tests that our values are well-centred on the solar values. We use our dataset to assess the two alternative calibrations of the GCS parameters; our methods favour the latest revision. We show that the choice of spectral line list or the choice of asteroid or time of observation does not affect the results. We also identify seven solar twins in our sample, three of which are published here for the first time. Conclusions: Our methods provide an independent means to differentially test the calibration of stellar catalogues around the values of a well-known benchmark star, which makes our work interesting for calibration tests of upcoming Galactic surveys. Based on observations made with ESO Telescopes at the La Silla Observatory under programme ID 077.D-0525 and 090.D-0133.Table 1 is also available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/574/A124Full Table 5 is only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/574/A124

  10. Public Key Cryptography.

    ERIC Educational Resources Information Center

    Tapson, Frank

    1996-01-01

    Describes public key cryptography, also known as RSA, which is a system using two keys, one used to put a message into cipher and another used to decipher the message. Presents examples using small prime numbers. (MKR)

  11. Synthesis of a-factor peptide from Saccharomyces cerevisiae and photoactive analogues via Fmoc solid phase methodology

    PubMed Central

    Mullen, Daniel G.; Kyro, Kelly; Hauser, Melinda; Gustavsson, Martin; Veglia, Gianluigi; Becker, Jeffery M.; Naider, Fred; Distefano, Mark D.

    2010-01-01

    a-Factor from S. cerevisiae is a farnesylated dodecapeptide involved in mating. The molecule binds to a G-protein coupled receptor and hence serves as a simple system for studying the interactions between prenylated molecules and their cognate receptors. Here, we describe the preparation of a-factor and two photoactive analogues via Fmoc solid-phase peptide synthesis using hydrazinobenzoyl AM NovaGel™ resin; the structure of the synthetic a-factor was confirmed by MS-MS analysis and NMR; the structures of the analogues were confirmed by MS-MS analysis. Using a yeast growth arrest assay, the analogues were found to have activity comparable to a-factor itself. PMID:21134758

  12. Certificateless Public Key Cryptography

    Microsoft Academic Search

    Sattam S. Al-riyami; Kenneth G. Paterson

    2003-01-01

    This paper introduces and makes concrete the concept of certiflcateless public key cryptography (CL-PKC), a model for the use of public key cryp- tography which avoids the inherent escrow of identity-based cryptography and yet which does not require certiflcates to guarantee the authenticity of public keys. The lack of certiflcates and the presence of an adversary who has access to

  13. Effect of ginger constituents and synthetic analogues on cyclooxygenase-2 enzyme in intact cells.

    PubMed

    Tjendraputra, E; Tran, V H; Liu-Brennan, D; Roufogalis, B D; Duke, C C

    2001-06-01

    Seventeen pungent oleoresin principles of ginger (Zingiber officinale, Roscoe) and synthetic analogues were evaluated for inhibition of cyclooxygenase-2 (COX-2) enzyme activity in the intact cell. These compounds exhibited a concentration and structure dependent inhibition of the enzyme, with IC(50) values in the range of 1-25 microM. Ginger constituents, [8]-paradol and [8]-shogaol, as well as two synthetic analogues, 3-hydroxy-1-(4-hydroxy-3-methoxyphenyl)decane and 5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)dodecane, showed strong inhibitory effects on COX-2 enzyme activity. The SAR analysis of these phenolic compounds revealed three important structural features that affect COX-2 inhibition: (i) lipophilicity of the alkyl side chain, (ii) substitution pattern of hydroxy and carbonyl groups on the side chain, and (iii) substitution pattern of hydroxy and methoxy groups on the aromatic moiety. PMID:11437391

  14. Potent antimalarial febrifugine analogues against the plasmodium malaria parasite.

    PubMed

    Kikuchi, Haruhisa; Tasaka, Hidehisa; Hirai, Shingo; Takaya, Yoshiaki; Iwabuchi, Yoshiharu; Ooi, Hidenori; Hatakeyama, Susumi; Kim, Hye-Sook; Wataya, Yusuke; Oshima, Yoshiteru

    2002-06-01

    Although febrifugine (1) and isofebrifugine (2), alkaloids isolated from roots of the Dichroa febrifuga plant, show powerful antimalarial activity against Plasmodium falciparum, strong side effects such as the emetic effect have precluded their clinical use against malaria. However, their antimalarial potency makes them attractive substances as leads for developing new types of chemotherapeutic antimalarial drugs. Thus, we have evaluated the in vitro antimalarial activity of the analogues of febrifugine (1) and isofebrifugine (2). The activities of the analogues derived from Df-1 (3) and Df-2 (4), condensation products of 1 and 2 with acetone, respectively, were also obtained. The 3' '-keto derivative (7, EC(50) = 2.0 x 10(-8) M) of 1 was found to exhibit potential antimalarial activity with high selectivity against P. falciparum in vitro. The in vitro activities of the reduction product (8, EC(50) = 2.0 x 10(-8) M) of 1 at C-2' and its cyclic derivatives 9 and 10 (EC(50) = 3.7 x 10(-9) and 8.6 x 10(-9) M, respectively) were found to be strongly active and selective. Additionally, the Dess-Martin oxidation product of 3 was found to be strongly active with high selectivity against P. falciparum. A structure-activity relationship study (SAR) demonstrates that the essential role played by the 4-quinazolinone ring in the appearance of activity and the presence of a 1' '-amino group and C-2', C-3' ' O-functionalities are crucial in the activity of 1. For 7, 8, and 9, prepared as racemic forms, an in vivo study has also been conducted. PMID:12036365

  15. Pepstatin analogues as novel renin inhibitors.

    PubMed

    Guégan, R; Diaz, J; Cazaubon, C; Beaumont, M; Carlet, C; Clément, J; Demarne, H; Mellet, M; Richaud, J P; Segondy, D

    1986-07-01

    Pepstatin analogues corresponding to the general formula A-X-Y-Sta-Ala-Sta-R were synthesized in solution phase. Various changes in the nature of the A, X, and Y groups were made to improve the inhibitory potency against human plasma renin activity. The results were interpreted by use of the active-site model based on the sequence of human angiotensinogen. The tert-butyloxycarbonyl group and the isovaleryl group were found to be the most effective acyl groups (A). The analogues having a Phe residue in place of Val1 (X) and His or amino acid with an aliphatic side chain such as norleucine or norvaline in the Y position showed the highest inhibition of human plasma renin activity with IC50 values of about 10(-8)M. Esterification or amidification of the carboxyl group of the C-terminal statine did not change the inhibitory potency. The selectivity for rat, dog, pig, and monkey plasma renin of the most interesting compounds was studied. PMID:3543358

  16. Charged Analogue of Finch-Skea Stars

    NASA Astrophysics Data System (ADS)

    Hansraj, S.; Maharaj, S. D.

    We present solutions to the Einstein-Maxwell system of equations in spherically symmetric gravitational fields for static interior space-times with a specified form of the electric field intensity. The condition of pressure isotropy yields three category of solutions. The first category is expressible in terms of elementary functions and does not have an uncharged limit. The second category is given in terms of Bessel functions of half-integer order. These charged solutions satisfy a barotropic equation of state and contain Finch-Skea uncharged stars. The third category is obtained in terms of modified Bessel functions of half-integer order and does not have an uncharged limit. The physical features of the charged analogue of the Finch-Skea stars are studied in detail. In particular, the condition of causality is satisfied and the speed of sound does not exceed the speed of light. The physical analysis indicates that this analogue is a realistic model for static charged relativistic perfect fluid spheres.

  17. Detecting Pyrolysis Products from Bacteria in a Mars Soil Analogue

    NASA Technical Reports Server (NTRS)

    Glavin, D. P.; Cleaves, H. J.; Schubert, M.; Aubrey, A.; Buch, A.; Mahaffy, P. R.; Bada, J. L.

    2004-01-01

    One of the primary objectives of the 1976 Viking missions was to determine whether organic compounds, possibly of biological origin, were present in the Martian surface soils. The Viking gas chromatography mass spectrometry (GCMS) instruments found no evidence for any organic compounds of Martian origin above a few parts per billion in the upper 10 cm of surface soil, suggesting the absence of a widely distributed Martian biota. However, it is now known that key organic compounds important to biology, such as amino acids, carboxylic acids and nucleobases, would likely have been missed by the Viking GCMS instruments. In this study, a Mars soil analogue that was inoculated with approx. 10 billion Escherichia coli cells was heated at 500 C under Martian ambient pressure to release volatile organic compounds from the sample. The pyrolysis products were then analyzed for amino acids and nucleobases using high performance liquid chromatography (HPLC) and GCMS. Our experimental results indicate that at the part per billion level, the degradation products generated from several million bacterial cells per gram of Martian soil would not have been detected by the Viking GCMS instruments. Upcoming strategies for Mars exploration will require in-situ analyses by instruments that can assess whether any organic compounds, especially those that might be associated with life, are present in Martian surface samples.

  18. Analogue models of the effect of long-term basement fault movement on volcanic edifices

    Microsoft Academic Search

    Luke Wooller; Benjamin van Wyk de Vries; Emmanuelle Cecchi; Hazel Rymer

    2009-01-01

    Long-term fault movement under volcanoes can control the edifice structure and can generate collapse events. To study faulting\\u000a effects, we explore a wide range of fault geometries and motions, from normal, through vertical to reverse and dip-slip to\\u000a strike-slip, using simple analogue models. We explore the effect of cumulative sub-volcanic fault motions and find that there\\u000a is a strong influence

  19. 1,2,4-triazolo[1,5-a]quinoxaline derivatives and their simplified analogues as adenosine A? receptor antagonists. Synthesis, structure-affinity relationships and molecular modeling studies.

    PubMed

    Catarzi, Daniela; Varano, Flavia; Poli, Daniela; Squarcialupi, Lucia; Betti, Marco; Trincavelli, Letizia; Martini, Claudia; Dal Ben, Diego; Thomas, Ajiroghene; Volpini, Rosaria; Colotta, Vittoria

    2015-01-01

    The 1,2,4-triazolo[1,5-a]quinoxaline (TQX) scaffold was extensively investigated in our previously reported studies and recently, our attention was focused at position 5 of the tricyclic nucleus where different acyl and carboxylate moieties were introduced (compounds 2-15). This study produced some interesting compounds endowed with good hA3 receptor affinity and selectivity. In addition, to find new insights about the structural requirements for hA3 receptor-ligand interaction, the tricyclic TQX ring was destroyed yielding some 1,2,4-triazole derivatives (compounds 16-23). These simplified compounds, though maintaining the crucial structural requirements for adenosine receptor-ligand interaction, have a very low hA3 adenosine receptor affinity, the only exception being compound 23 (1-[3-(4-methoxyphenyl)-1-phenyl-1H-1,2,4-triazol-5-yl]-3-phenylurea) endowed with a Ki value in the micro-molar range and high hA3 selectivity versus both hA1 and hA2A AR subtypes. Evaluation of the side products obtained in the herein reported synthetic pathways led to the identification of some new triazolo[1,5-a]quinoxalines as hA3AR antagonists (compounds 24-27). These derivatives, though lacking the classical structural requirements for the anchoring at the hA3 receptor site, show high hA3 affinity and in some case selectivity versus hA1 and hA2A subtypes. Molecular docking of the herein reported tricyclic and simplified derivatives was carried out to depict their hypothetical binding mode to our model of hA3 receptor. PMID:25497490

  20. Geopyxins A – E, ent-Kaurane Diterpenoids from Endolichenic Fungal Strains, Geopyxis aff. majalis and Geopyxis sp. AZ0066: Structure-Activity Relationships of Geopyxins and their Analogues1

    PubMed Central

    Kithsiri Wijeratne, E. M.; Bashyal, Bharat P.; Liu, Manping X.; Rocha, Danilo D.; Gunaherath, G. M. Kamal B.; U’Ren, Jana M.; Gunatilaka, Malkanthi K.; Arnold, A. Elizabeth; Whitesell, Luke; Gunatilaka, A. A. Leslie

    2012-01-01

    Four new ent-kaurane diterpenoids, geopyxins A–D (1–4) were isolated from Geopyxis aff. majalis, a fungus occurring in the lichen Pseudevernia intensa, whereas Geopyxis sp. AZ0066 inhabiting the same host afforded two new ent-kaurane diterpenoids, geopyxins E and F (5 and 6) together with 1 and 3. The structures of 1–6 were established on the basis of their spectroscopic data while the absolute configurations were assigned using modified Mosher’s ester method. Methylation of 1–3, 5, and 6 gave their corresponding methyl esters 7–11. On acetylation, 1 and 7 yielded their corresponding monoacetates 12 and 14, and diacetates 13 and 15. All compounds were evaluated for their cytotoxic and heat-shock induction activities. Compounds 2, 7–10, 12, 14, and 15 showed cytotoxic activity in the low micromolar range against all five cancer cell lines tested, but only compounds 7–9, 14, and 15 were found to activate the heat-shock response at similar concentrations. From a preliminary structure-activity perspective, the electrophilic ?,?-unsaturated ketone carbonyl motif present in all compounds except 6 and 11 was found to be necessary but not sufficient for both cytotoxicity and heat-shock activation. PMID:22264149

  1. Photoionization spectroscopy of nucleobases and analogues in the gas phase using synchrotron radiation as excitation light source.

    PubMed

    Schwell, Martin; Hochlaf, Majdi

    2015-01-01

    We review here the photoionization and photoelectron spectroscopy of the gas phase nucleic acid bases adenine, thymine, uracil, cytosine, and guanine, as well as the three base analogues 2-hydroxyisoquinoline, 2-pyridone, and ?-valerolactam in the vacuum ultraviolet (VUV) spectral regime. The chapter focuses on experimental work performed with VUV synchrotron radiation and related ab initio quantum chemical calculations of higher excited states beyond the ionization energy. After a general part, where experimental and theoretical techniques are described in detail, key results are presented by order of growing complexity in the spectra of the molecules. Here we concentrate on (1) the accurate determination of ionization energies of isolated gas phase NABs and investigation of the vibrational structure of involved ionic states, including their mutual vibronic couplings, (2) the treatment of tautomerism after photoionization, in competition with other intramolecular processes, (3) the study of fragmentation of these molecular systems at low and high internal energies, and (4) the study of the evolution of the covalent character of hydrogen bonding upon substitution, i.e., examination of electronic effects (acceptor, donor, etc.). PMID:25238717

  2. The multicomponent approach to N-methyl peptides: total synthesis of antibacterial (–)-viridic acid and analogues

    PubMed Central

    Neves Filho, Ricardo A W; Stark, Sebastian; Westermann, Bernhard

    2012-01-01

    Summary Two syntheses of natural viridic acid, an unusual triply N-methylated peptide with two anthranilate units, are presented. The first one is based on peptide-coupling strategies and affords the optically active natural product in 20% overall yield over six steps. A more economical approach with only four steps leads to the similarly active racemate by utilizing a Ugi four-component reaction (Ugi-4CR) as the key transformation. A small library of viridic acid analogues is readily available to provide first SAR insight. The biological activities of the natural product and its derivatives against the Gram-negative bacterium Aliivibrio fischeri were evaluated. PMID:23209543

  3. Experimental study of the formation of molecular hydrogen and carbon dioxide on dust grain analogues

    NASA Astrophysics Data System (ADS)

    Vidali, G.; Roser, J. E.; Manicò, G.; Pirronello, V.

    In the past five years, we have conducted laboratory studies of the formation of key molecules on dust grain analogues in astrophysically relevant conditions. After a description of the apparatus and of the experimental methods, we report on the application of such methods to the resolution of two astrophysical problems that have been left unsolved: (1) The determination of the efficiency and mechanism of formation of molecular hydrogen on different types of interstellar dust grains (silicates, carbonaceous material and ices) and (2) The elucidation of the mechanisms of formation of CO2 in dense, quiescent clouds.

  4. Multicomponent synthesis of 4,4-dimethyl sterol analogues and their effect on eukaryotic cells.

    PubMed

    Alonso, Fernando; Cirigliano, Adriana M; Dávola, María Eugenia; Cabrera, Gabriela M; García Liñares, Guadalupe E; Labriola, Carlos; Barquero, Andrea A; Ramírez, Javier A

    2014-06-01

    Most sterols, such as cholesterol and ergosterol, become functional only after the removal of the two methyl groups at C-4 from their biosynthetic precursors. Nevertheless, some findings suggest that 4,4-dimethyl sterols might be involved in specific physiological processes. In this paper we present the synthesis of a collection of analogues of 4,4-dimethyl sterols with a diamide side chain and a preliminary analysis of their in vitro activity on selected biological systems. The key step for the synthesis involves an Ugi condensation, a versatile multicomponent reaction. Some of the new compounds showed antifungal and cytotoxic activity. PMID:24632026

  5. Treatment of Neuroendocrine GEP Tumours with Somatostatin Analogues

    Microsoft Academic Search

    R. Arnold; B. Simon; M. Wied

    2000-01-01

    Background: Somatostatin and its long-acting analogues are effective in symptom control in patients with functionally active neuroendocrine GEP tumours. Several in vitro and in vivo reports suggest that they are also able to control tumour growth. Methods: Critical review of published data on the effect of long-acting somatostatin analogues on symptom and growth control in patients with metastatic neuroendocrine GEP

  6. Carbocyclic Thymidine Analogues for Use as Potential Therapeutic Agents

    Microsoft Academic Search

    Katherine L. Seley-Radtke; Naresh K. Sunkara

    2009-01-01

    The discovery of azidothymidine's (AZT) activity against human immunodeficiency virus (HIV) provided strong rationale for the design of additional thymidine analogues. One drawback of many nucleoside analogues is the toxicity that often arises due to phosphorylation by cellular kinases. In order to overcome this problem, a number of truncated nucleosides lacking the 4?-hydroxymethyl group have been synthesized. In that regard,

  7. Biological evaluation of analogues of an insect neuropeptide proctolin.

    PubMed

    Wo?nica, Iwona; Szeszel-Fedorowicz, Wioletta; Rosi?skiand, Grzegorz; Konopi?ska, Danuta

    2004-01-01

    Continuing our studies on proctolin (Arg-Tyr-Leu-Pro-Thr) we performed the synthesis and biological evaluation of 52 analogues substituted in position 2, 3, 4, and 5 of the peptide chain. The peptides were bioassayed for cardiotropic activity in vitro on Tenebrio molitor and myotropic activity on foregut of Schistocerca gregaria. Twenty analogues retained 20-80% of proctolin activity. PMID:15094831

  8. Hydrolysis of hydroxybenzoate saxitoxin analogues originating from Gymnodinium catenatum

    Microsoft Academic Search

    Paulo Vale

    2011-01-01

    The paralytic shellfish poisoning (PSP) toxin producer Gymnodinium catenatum produces several hydrophobic analogues of saxitoxin (STX). These are poorly studied due to their recent discovery and lack of standards. It was previously observed these hydrophobic analogues could be partially hydrolysed, loosing its benzoate moiety during alkaline oxidation to obtain fluorescent products measurable by HPLC analysis. The hydrolysis reaction was further

  9. Hashish: synthesis and central nervous system activity of some novel analogues of cannabidiol and oxepin derivatives of delta 9-tetrahydrocannabinol.

    PubMed

    Jorapur, V S; Khalil, Z H; Duffley, R P; Razdan, R K; Martin, B R; Harris, L S; Dewey, W L

    1985-06-01

    Several C-10 substituted cannabidiol (CBD) derivatives and novel oxepin derivatives of delta 9-tetrahydrocannabinol (delta 9-THC) were synthesized and evaluated for biological activity in mice and dogs. Treatment of 10-bromocannabidiol diacetate (3) with various amines in Me2SO gave the corresponding 10-aminocannabidiol derivatives 4-6. Similarly, treatment of 3 with NaN3 gave the azido compound 7, which with LiA1H4 afforded the 10-aminocannabidiol 9. However, reduction of 7 with CrCl2 formed the amide 8, which on further reduction with LiA1H4 gave the N-ethyl analogue 10. Coupling of 9 with 11 in the presence of dicyclohexylcarbodiimide formed 12, which was then deprotected with HCl to give the analogue 13. The oxepin analogue 14a was synthesized from 3 by treatment with Na2CO3 in CH3OH/H2O at room temperature. The dimethylheptyl analogue 14b was similarly prepared. Incorporation of N-ethyl (10), N-methyl-N-propargyl (6), and morpholino (4) groups in CBD at position 10 resulted in analogues that were more potent than CBD in producing hypoactivity in mice. These analogues had relatively little effect on rectal temperature. Selected substitutions at C-10 also resulted in analogues that were partially effective in blocking delta 9-THC antinociceptive activity. This blockade was observed particularly in compound 10, which also showed unusually toxic properties. Incorporation of a seven-membered oxepin in the delta 9-THC structure eliminated cannabinoid activity although substitution of the pentyl side chain with a 1,2-dimethylheptyl in the oxepin 14b resulted in CNS depression in mice. PMID:2989518

  10. Dehydration of planetary ices at high pressure; the role of analogue materials (Invited)

    NASA Astrophysics Data System (ADS)

    Fortes, A. D.

    2013-12-01

    Many planet-forming compounds become unstable with respect to their components under conditions of high pressure. In the Earth, for example, Mg2SiO4 breaks down to MgSiO3 + MgO at ~ 25 GPa, a pressure corresponding to the 670 km seismic discontinuity, with significance for the dynamics of convective flow in the mantle. A similar phenomenon occurs with many hydrate compounds thought to be major ';rock forming minerals' inside outer Solar System bodies, undoubtedly with important consequences for the structure and dynamics of icy worlds. It is well known that clathrates tend to form denser polymorphs with an incrementally greater concentration of the guest molecule, exsolving high-pressure phases of water ice in the process, or else (in the case of CO2), break down to entirely to their component molecular solids. My own recent work using high-pressure neutron powder diffraction has explored not only the behaviour of methane clathrates but also the exsolution of water from ammonia dihydrate and monohydrate, both of which break down eventually to ammonia hemihydrate + ice. In some cases, understanding the sequence of changes in both crystal structure and composition at high pressure is challenging, particularly when the starting materials have a complex crystal structure. Some years ago, I identified a high-pressure phase boundary where MgSO4.11H2O (meridianiite) appeared to break down to another hydrate and high-pressure ice VI. However, the powder diffraction pattern of the hydrate formed under these conditions resembled nothing encountered previously in my high-pressure studies of the next lowest hydrate, MgSO4.7H2O (epsomite). This led me to search for hydration states between 7 and 11 which might have escaped detection over several centuries of study of simple divalent metal sulfates. A wide-ranging systematic study of M2+X6+O4.nH2O compounds at low temperatures uncovered two new hydrates, an 8-hydrate and a 9-hydrate, the former occurring only in NiSO4 solutions, and the latter being found in Ni-, Zn-, Cu-, and Fe-doped MgSO4 solutions. Indeed, I determined that small quantities of pure MgSO4.9H2O can co-crystallise at ambient pressure with meridianiite. However, these all appear to be metastable states, and further work was necessary to try and discover stable forms of these hydrates for further study. In experiments carried out earlier this year, evidence has emerged not only that MgMoO4 can form a (possibly) stable 8-hydrate but also that MgSeO4 can form a 9-hydrate that exists in equilibrium with liquid near the eutectic. These apparently esoteric compounds (from a planetary perspective) may yet hold the key to understanding the high-pressure behaviour of true planetary materials. Just as the search for analogue materials over many decades has substantially advanced our knowledge of Earth materials, similar analogue studies are poised to unlock the mysteries of these planetary ices.

  11. Design of potent linear alpha-melanotropin 4-10 analogues modified in positions 5 and 10.

    PubMed

    Al-Obeidi, F; Hruby, V J; Castrucci, A M; Hadley, M E

    1989-01-01

    alpha-Melanocyte stimulating hormone (alpha-MSH) is a linear tridecapeptide (Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2) that has diverse physiological functions in addition to its reversible darkening of amphibian skins by stimulating melanosome dispersion within melanophores. On the basis of theoretical and experimental results from our laboratory and others, we have designed a group of 1-13, 4-13, and especially 4-10 analogues related to the superpotent analogue [Nle4,D-Phe7]alpha-MSH in which the Glu5 has been replaced with Asp5, and the Gly10 has been replaced with Lys10 and other basic amino acid residues in the 4-10 analogues, and in which Gly10 and Lys11 were interchanged in the longer peptide analogues. In the 1-13 and 4-13 series the Lys10, Gly11 analogues generally retained superpotency for the D-Phe7-containing analogues. Most interestingly, synthesis of Ac-[Nle4,Xxx5,Yyy7,Zzz10]alpha-MSH4-10-NH2 analogues where Xxx = Asp or Glu, Yyy = Phe or D-Phe, and Zzz = basic amino acids (Lys, Orn, alpha,gamma-diaminobutyric acid (Dab), and alpha,beta-diaminopropionic acid (Dpr] provided melanotropins with potencies up to 10 times that of the native hormone in stimulating frog (Rana pipiens) skin darkening and 8-50 times more potent than alpha-MSH in stimulating lizard (Anolis carolinensis) skin melanophores in vitro. To our knowledge, Ac-[Nle4,Asp5,D-Phe7,Dab10]alpha-MSH4-10-NH2, the most potent analogue, is the most potent melanotropin obtained thus far for the Anolis assay system. These results provide new insights into the structural and conformational requirements for biological potency of alpha-MSH and the differential structural and conformational requirements of alpha-MSH and its analogues at two different types of pigment cell receptors. PMID:2535874

  12. Gold-catalyzed asymmetric allylic substitution of free alcohols: an enantioselective approach to chiral chromans with quaternary stereocenters for the synthesis of vitamin E and analogues.

    PubMed

    Uria, Uxue; Vila, Carlos; Lin, Ming-Yuan; Rueping, Magnus

    2014-10-20

    The enantioselective synthesis of ?- and ?-tocopherol (the most biologically active members of vitamin?E family) and analogues has been accomplished employing a new enantioselective gold catalyzed intramolecular allylic alkylation reaction followed by an olefin cross-metathesis as key steps. The methodology proved to be applicable to different olefins highlighting its potential for the synthesis of diverse libraries. PMID:25201099

  13. Therapeutic Efficacy of Stable Analogues of Vasoactive Intestinal Peptide against Pathogens*

    PubMed Central

    Campos-Salinas, Jenny; Cavazzuti, Antonio; O'Valle, Francisco; Forte-Lago, Irene; Caro, Marta; Beverley, Stephen M.; Delgado, Mario; Gonzalez-Rey, Elena

    2014-01-01

    Vasoactive intestinal peptide (VIP) is an anti-inflammatory neuropeptide recently identified as a potential antimicrobial peptide. To overcome the metabolic limitations of VIP, we modified the native peptide sequence and generated two stable synthetic analogues (VIP51 and VIP51(6–30)) with better antimicrobial profiles. Herein we investigate the effects of both VIP analogues on cell viability, membrane integrity, and ultrastructure of various bacterial strains and Leishmania species. We found that the two VIP derivatives kill various non-pathogenic and pathogenic Gram-positive and Gram-negative bacteria as well as the parasite Leishmania major through a mechanism that depends on the interaction with certain components of the microbial surface, the formation of pores, and the disruption of the surface membrane. The cytotoxicity of the VIP derivatives is specific for pathogens, because they do not affect the viability of mammalian cells. Docking simulations indicate that the chemical changes made in the analogues are critical to increase their antimicrobial activities. Consequently, we found that the native VIP is less potent as an antibacterial and fails as a leishmanicidal. Noteworthy from a therapeutic point of view is that treatment with both derivatives increases the survival and reduces bacterial load and inflammation in mice with polymicrobial sepsis. Moreover, treatment with VIP51(6–30) is very effective at reducing lesion size and parasite burden in a model of cutaneous leishmaniasis. These results indicate that the VIP analogues emerge as attractive alternatives for treating drug-resistant infectious diseases and provide key insights into a rational design of novel agents against these pathogens. PMID:24706753

  14. A hypnotic analogue of clinical confabulation.

    PubMed

    Cox, Rochelle E; Barnier, Amanda J

    2015-01-01

    Confabulation-fabricated or distorted memories about oneself-occurs in many disorders, but there is no reliable technique for investigating it in the laboratory. The authors used hypnosis to model clinical confabulation by giving subjects a suggestion for either (a) amnesia for everything that had happened since they started university, (b) amnesia for university plus an instruction to fill in memory gaps, or (c) confusion about the temporal order of university events. They then indexed different types of memory on a confabulation battery. The amnesia suggestion produced the most confabulation, especially for personal semantic information. Notably, subjects confabulated by making temporal confusions. The authors discuss the theoretical implications of this first attempt to model clinical confabulation and the potential utility of such analogues. PMID:25978080

  15. Febrifugine analogue compounds: synthesis and antimalarial evaluation.

    PubMed

    Zhu, Shuren; Chandrashekar, Gudise; Meng, Li; Robinson, Katie; Chatterji, Dipsanker

    2012-01-15

    Febrifugine is an alkaloid isolated from Dichroa febrifuga Lour as the active component against Plasmodium falciparum, but exhibits toxic side effects. In this study novel febrifugine analogues were designed and efficiently synthesized. New compounds underwent efficacy and toxicity evaluation. Some compounds are much less toxic than the natural product febrifugine and existing antimalarial drugs and are expected to possess wide therapeutic windows. In Aotus monkeys infected with the chloroquine resistant FVO strain of P. falciparum, one interesting compound possesses a 50% curative dose of 2mg/kg/day and a 100% curative dose of 8 mg/kg/day. These compounds, as well as the underlying design rationale, may find usefulness in the discovery and development of new antimalarial drugs. PMID:22182577

  16. The inorganic analogues of carbo-benzene

    NASA Astrophysics Data System (ADS)

    Jalife, Said; Audiffred, Martha; Islas, Rafael; Escalante, Sigfrido; Pan, Sudip; Chattaraj, Pratim K.; Merino, Gabriel

    2014-08-01

    Inspired by carbo-benzene, we have analyzed in silico the stability of carbo-borazine (C12B3N3H6) and the iminobora-mer of borazine (B9N9H6). Both systems may be regarded as the inorganic analogues of carbo-benzene, being B9N9H6 the perfect case. Unlike aromatic carbo-benzene, C12B3N3H6 and B9N9H6 can be classified as almost nonaromatic systems as indicated by the computed induced magnetic field. All these systems undergo dimerization very readily; therefore, they cannot be synthesized as such. However, akin to substituted carbo-benzene, the substitution of the hydrogen atom of C12B3N3H6 and B9N9H6 by other groups could stabilize them.

  17. Design, synthesis, and quantitative structure-activity relationship study of herbicidal analogues of pyrazolo[5,1-d][1,2,3,5]tetrazin-4(3H)ones.

    PubMed

    Zhu, You-quan; Wu, Chao; Li, Hua-bin; Zou, Xiao-mao; Si, Xue-kai; Hu, Fang-zhong; Yang, Hua-zheng

    2007-02-21

    A series of pyrazolo[5,1-d][1,2,3,5]tetrazin-4(3H)one derivatives were designed, synthesized, and evaluated for their herbicidal activities where some of these compounds provided >80% control of Brassica campestris at 10 microg/mL. Quantitative structure-activity relationship studies were performed on these compounds using physicochemical parameters (electronic, Verloop, or hydrophobic) as independent parameters and herbicidal activity as a dependent parameter, where herbicidal activity correlated best (r > 0.8) with physicochemical parameters in this set of molecules. The herbicidal activity against B. campestris was mainly affected by the molar refractivity (MR) for R1, Taft (Eso) for R2 or R6, Verloop (Lm) for R3 or R5, and electronic parameters (Hammett's constants) for R4. The optimal MR for herbicidal activity is 0.95. The herbicidal activity against Echinochloa crus-galli was mainly related with the substituents' hydrophobic parameter. The optimal pi parameters for R1 and R4 for herbicidal activity are 0.72 and 0.68, respectively. In general, these compounds showed greater herbicidal activity toward B. campestris than E. crus-galli. PMID:17300154

  18. Series of edge-sharing bi-triangle Ln4 clusters with a ?4-NO3- bridge: syntheses, structures, luminescence, and the SMM behavior of the Dy4 analogue.

    PubMed

    Zou, Hua-Hong; Wang, Rong; Chen, Zi-Lu; Liu, Dong-Cheng; Liang, Fu-Pei

    2014-02-14

    A series of Ln4 clusters, [Ln4L2(?3-OH)2(?4-NO3)(NO3)4(OCH3)(H2O)]·xMeCN·yMeOH (Ln = Gd (1), Tb (2), Dy (3), Ho (4), Er (5), Yb (6), L = 2-{[2-(2-hydroxy-ethoxy)-ethylimino]-methyl}-6-methoxyphenol), have been synthesized by the reaction of Ln(NO)3 and a Schiff-base ligand formed in situ. The six complexes display similar structures, with an overall metal core comprising two edge-sharing triangular Ln3 units linked by a ?4-NO3(-) bridge. The luminescence spectrum of complex 2 shows the characteristic emission of the Tb(III) ions. The magnetic susceptibility studies reveal that the Ln(III) ions are very weakly interacting in all six compounds. Frequency dependence of the ac-susceptibility was found for 3, suggesting a typical single-molecule magnet (SMM) behavior with an anisotropic barrier of 28 K. PMID:24316728

  19. Synthesis and characterization of fac-Re(CO)3-aspartic-N-monoacetic acid, a structural analogue of a potential new renal tracer, fac-(99m)Tc(CO)3(ASMA).

    PubMed

    Klenc, Jeffrey; Lipowska, Malgorzata; Taylor, Andrew T; Marzilli, Luigi G

    2012-09-01

    The reaction of an aminopolycarboxylate ligand, aspartic-N-monoacetic acid (ASMA), with [Re(CO)3(H2O)3](+) was examined. The tridentate coordination of ASMA to this Re(I) tricarbonyl precursor yielded fac-Re(CO)3(ASMA) as a mixture of diastereomers. The chemistry is analogous to that of the Tc(I) tricarbonyl complex, which yields fac-(99m)Tc(CO)3(ASMA) under similar conditions. The formation, structure, and isomerization of fac-Re(CO)3(ASMA) products were characterized by HPLC, (1)H NMR spectroscopy, and X-ray crystallography. The two major fac-Re(CO)3(ASMA) diastereomeric products each have a linear ONO coordination mode with two adjacent five-membered chelate rings, but they differ in the endo or exo orientation of the uncoordinated acetate group, in agreement with expectations based on previous studies. Conditions have been identified for the expedient isomerization of fac-Re(CO)3(ASMA) to a mixture consisting primarily of one major product. Because different isomeric species typically have different pharmacokinetic characteristics, these conditions may provide for the practical isolation of a single (99m)Tc(CO)3(ASMA) species, thus allowing the isolation of the isomer that has optimal imaging and pharmacokinetic characteristics. This information will aid in the design of future (99m)Tc radiopharmaceuticals. PMID:24273448

  20. Synthesis and characterization of fac-Re(CO)3-aspartic-N-monoacetic acid, a structural analogue of a potential new renal tracer, fac-99mTc(CO)3(ASMA)

    PubMed Central

    Klenc, Jeffrey; Lipowska, Malgorzata; Taylor, Andrew T.; Marzilli, Luigi G.

    2013-01-01

    The reaction of an aminopolycarboxylate ligand, aspartic-N-monoacetic acid (ASMA), with [Re(CO)3(H2O)3]+ was examined. The tridentate coordination of ASMA to this ReI tricarbonyl precursor yielded fac-Re(CO)3(ASMA) as a mixture of diastereomers. The chemistry is analogous to that of the TcI tricarbonyl complex, which yields fac-99mTc(CO)3(ASMA) under similar conditions. The formation, structure, and isomerization of fac-Re(CO)3(ASMA) products were characterized by HPLC, 1H NMR spectroscopy, and X-ray crystallography. The two major fac-Re(CO)3(ASMA) diastereomeric products each have a linear ONO coordination mode with two adjacent five-membered chelate rings, but they differ in the endo or exo orientation of the uncoordinated acetate group, in agreement with expectations based on previous studies. Conditions have been identified for the expedient isomerization of fac-Re(CO)3(ASMA) to a mixture consisting primarily of one major product. Because different isomeric species typically have different pharmacokinetic characteristics, these conditions may provide for the practical isolation of a single 99mTc(CO)3(ASMA) species, thus allowing the isolation of the isomer that has optimal imaging and pharmacokinetic characteristics. This information will aid in the design of future 99mTc radiopharmaceuticals. PMID:24273448

  1. Differential inhibition of class I and class II 5-enolpyruvylshikimate-3-phosphate synthases by tetrahedral reaction intermediate analogues.

    PubMed

    Funke, Todd; Healy-Fried, Martha L; Han, Huijong; Alberg, David G; Bartlett, Paul A; Schönbrunn, Ernst

    2007-11-20

    The shikimate pathway enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSP synthase or EPSPS) is best known as the target of the herbicide glyphosate. EPSPS is also considered an attractive target for the development of novel antibiotics since the pathogenicity of many microorganisms depends on the functionality of the shikimate pathway. Here, we have investigated the inhibitory potency of stable fluorinated or phosphonate-based analogues of the tetrahedral reaction intermediate (TI) in a parallel study utilizing class I (glyphosate-sensitive) and class II (glyphosate-tolerant) EPSPS. The (R)-difluoromethyl and (R)-phosphonate analogues of the TI are the most potent inhibitors of EPSPS described to date. However, we found that class II EPSPS are up to 400 times less sensitive to inhibition by these TI analogues. X-ray crystallographic data revealed that the conformational changes of active site residues observed upon inhibitor binding to the representative class I EPSPS from Escherichia coli do not occur in the prototypical class II enzyme from Agrobacterium sp. strain CP4. It appears that because the active sites of class II EPSPS do not possess the flexibility to accommodate these TI analogues, the analogues themselves undergo conformational changes, resulting in less favorable inhibitory properties. Since pathogenic microorganisms such as Staphylococcus aureus utilize class II EPSPS, we conclude that the rational design of novel EPSPS inhibitors with potential as broad-spectrum antibiotics should be based on the active site structures of class II EPSP synthases. PMID:17958399

  2. Chasing An Analogue For The Holocene : The Astronomical Forcing

    NASA Astrophysics Data System (ADS)

    Loutre, M.; Crucifix, M.; Berger, A.

    2008-12-01

    Astronomical theories of paleoclimate, e.g. the Milankovitch theory, explain the long-term variations of climate by the changes in the Earth orbit and position against the Sun, and consequently by the change in the distribution of the solar energy reaching the Earth. On the other hand, anthropogenic activities from early agricultural practices to more recent fossil fuel burning also impact climate change. Models, from conceptual ones to the most sophisticated general circulation models can be used to try to disentangle the contribution from human activity and the natural contribution in the record of climate change. Alternatively, a comparison of the climate records during past interglacials similar to the one we are living in can give some insight into the natural behaviour of the climate system during an interglacial. As far as the long-term climate change is mostly orbitally driven, we will search orbital and insolation time series for past analogues of the non-human perturbed Holocene. When doing so, some key questions must be answered. The first one is related to the time interval to be used as target. A previous study (Loutre and Berger, 2000) focused on the interglacial itself, assuming that the preceding deglaciation had a negligible impact on the interglacial. Rather we decided here to choose a target time interval that includes the deglaciation. Another question is related to the choice of the variable that will be used for correlation. It can be the orbital parameters themselves. It is also possible to use top-of-the-atmosphere insolation. If daily insolation is chosen, the latitude and time in the year for which it is computed are crucial; if a more time- integrated insolation is used (e.g. seasonal insolation), the time interval for the integration is an essential feature. Loutre and Berger (2000) used mid-June insolation at 65N and identified MIS11 as the most recent potential analogue for the future climate. A higher correlation of the insolation was even obtained between the future and MIS19. Here, we focus on the Holocene, starting from the last glacial maximum up to the next millennia (21 ka BP to 9 ka AP). There is a good correlation between the insolation changes during most of the recent interglacials and this target time interval, but the correlation can be poor for the orbital parameters taken separately, due to different leads and lags between the orbital parameters among the different interglacials. Namely, the maximum of eccentricity of the Holocene (14 ka BP) leads the minimum in climatic precession by 2 ka and the maximum of obliquity by 5 ka. At MIS5, the maximum of obliquity occurs 4 ka before the minimum in climatic precession and several thousands of years before the maximum of eccentricity. This rapid comparison underlines that certain interglacials are very poor analogues for the Holocene by reference to the astronomical parameters. A more systematic investigation confirms that no interglacial is displaying high correlations with the Holocene for all the astronomical parameters. For example, MIS11 shows as strong correlation with the present and future insolation (Loutre and Berger, 2000) but the correlation is much smaller for the orbital parameters. On the point of view of the orbital parameters, MIS15 might be the best compromise of the Late Quaternary. Loutre M.F. and Berger A. 2000. Future climatic changes: are we entering an exceptionally long interglacial? Climatic Change 46: 61-90.

  3. Synthesis and Analysis of Oligonucleotides Containing Abasic Site Analogues

    PubMed Central

    Huang, Haidong; Greenberg, Marc M.

    2008-01-01

    DNA damage results in the formation of abasic sites from the formal hydrolysis of the glycosidic bond (AP) and several oxidized abasic lesions. Previous studies on AP sites revealed that DNA polymerases preferentially incorporated dA opposite them in ~80% of the replication events in Escherichia coli. These results were consistent with the hypothesis that the AP sites are noninstructive lesions due to the absence of a Watson–Crick base whose bypass adheres to the “A-rule.” Recent replication studies of the oxidized abasic lesion, 2-deoxyribonolactone (L), revealed that DNA polymerase(s) does not apply the A-rule when bypassing it and incorporates large amounts of dG opposite L. These studies suggested that abasic sites such as L do direct polymerases to selectively incorporate nucleotides opposite them. However, it was not possible to determine the structural basis for this molecular recognition from these experiments. A group of oligonucleotides containing analogues of the AP and L lesions were synthesized and characterized as probes to gain insight into the structural basis for the distinct effect of 2-deoxyribonolactone on replication. These molecules will be useful tools for studying replication in cells and in vitro. PMID:18324835

  4. A search for young solar system analogues with the VLT

    NASA Astrophysics Data System (ADS)

    Zinnecker, Hans; Krabbe, Alfred; McCaughrean, Mark J.; Stanke, Thomas; Stecklum, Bringfried; Brandner, Wolfgang; Padgett, Deborah L.; Stapelfeldt, Karl R.; Yorke, Harold W.

    1999-12-01

    The VLT/UT1 telescope has been used with its facility near-IR camera ISAAC to obtain 1-2.5 {mu m} wavelength images at 0\\farcs4 spatial resolution of six southern young low luminosity sources associated with extended reflection nebulosity. Two are in the Chamaeleon I dark cloud (Cha IR nebula, Cederblad 110 IRS4), and the other four in the Gum Nebula (HH 46/47, CG 30, Re 4, Re 5). Complex structure is seen, including in most cases bipolar blue and red scattering lobes likely due to the illumination of outflow cavities by the central star(s), hidden by a flattened circumstellar disk or envelope. In one object (Re 4), a double jet appears to be emanating from the central source, suggestive of a binary system with nearly aligned disks. These images, when supplemented by polarimetry maps, will help determine the structure and geometry of the young stellar objects, and will also be compared to 3D radiative transfer models to match both the surface brightness distribution of the extended emission and the spectral energy distribution of the central source. Applied to a series of such objects, these analyses will lead to an improved evolutionary sequence for the formation of solar system analogues. Based on observations obtained at the European Southern Observatory, Paranal (ESO proposal 63.I-0691)

  5. Research Advances: Less Expensive and More Convenient Gaucher's Disease Treatment; Structural Loop Regions: Key to Multidrug-Resistance Transporters?; New Method Identifies Proteins in Old Artwork

    ERIC Educational Resources Information Center

    King, Angela G.

    2006-01-01

    The X-ray structure of EmrD, a multidrug transporter protein from Escherichia coli, common bacteria known to cause several food-borne illnesses was determined by scientists at The Scripps Research Institute. The hydrophobic residues in the EmrD internal cavity are likely to contribute to the general mechanism transporting various compounds through…

  6. Elucidating a Key Anti-HIV-1 and Cancer-Associated Axis: The Structure of CCL5 (Rantes) in Complex with CCR5

    NASA Astrophysics Data System (ADS)

    Tamamis, Phanourios; Floudas, Christodoulos A.

    2014-06-01

    CCL5 (RANTES) is an inflammatory chemokine which binds to chemokine receptor CCR5 and induces signaling. The CCL5:CCR5 associated chemotactic signaling is of critical biological importance and is a potential HIV-1 therapeutic axis. Several studies provided growing evidence for the expression of CCL5 and CCR5 in non-hematological malignancies. Therefore, the delineation of the CCL5:CCR5 complex structure can pave the way for novel CCR5-targeted drugs. We employed a computational protocol which is primarily based on free energy calculations and molecular dynamics simulations, and report, what is to our knowledge, the first computationally derived CCL5:CCR5 complex structure which is in excellent agreement with experimental findings and clarifies the functional role of CCL5 and CCR5 residues which are associated with binding and signaling. A wealth of polar and non-polar interactions contributes to the tight CCL5:CCR5 binding. The structure of an HIV-1 gp120 V3 loop in complex with CCR5 has recently been derived through a similar computational protocol. A comparison between the CCL5 : CCR5 and the HIV-1 gp120 V3 loop : CCR5 complex structures depicts that both the chemokine and the virus primarily interact with the same CCR5 residues. The present work provides insights into the blocking mechanism of HIV-1 by CCL5.

  7. C5-C10 directly bonded tetrodotoxin analogues: possible biosynthetic precursors of tetrodotoxin from newts.

    PubMed

    Kudo, Yuta; Yamashita, Yoko; Mebs, Dietrich; Cho, Yuko; Konoki, Keiichi; Yasumoto, Takeshi; Yotsu-Yamashita, Mari

    2014-12-22

    The identification of novel tetrodotoxin (TTX, 1) analogues would significantly contribute to the elucidation of its biosynthetic pathway. In this study, the first C5-C10 directly bonded TTX analogues, 4,9-anhydro-10-hemiketal-5-deoxyTTX (2) and 4,9-anhydro-8-epi-10-hemiketal-5,6,11-trideoxyTTX (3), were found in the newt Cynops ensicauda popei by using a screening method involving HILIC-LC-MS/MS focused on the fragment ions of TTX analogues, and their structures were elucidated by spectroscopic methods. Compound 2 was detected in a wide range of newt species, and the 2 and TTX contents of 22 newt specimens were correlated (rs =0.88). Based on these results and its structural features, 2 was predicted to serve as a precursor of TTX that would be directly converted into 4,9-anhydroTTX (4) by Baeyer-Villiger-like oxidation or via 4,9-anhydro-5-deoxyTTX formed by cleavage of the C5-C10 bond. The bicyclic carbon skeletons of 2 and 3 suggested a possible monoterpene origin for TTX. PMID:25382791

  8. Sensitization of bleached rod photoreceptors by 11-cis-locked analogues of retinal.

    PubMed Central

    Corson, D W; Cornwall, M C; MacNichol, E F; Jin, J; Johnson, R; Derguini, F; Crouch, R K; Nakanishi, K

    1990-01-01

    Photoactivation of rhodopsin initiates both excitation and adaptation in vertebrate rod photoreceptors. Bleaching of rhodopsin to free opsin and all-trans-retinal in isolated rods produces a stable desensitization (bleaching adaptation) that is much larger than expected from pigment depletion alone. In our experiments, a 93% bleach produced a 500-fold increase in the light intensity required for saturation of the light response. This component of adaptation was 32-fold larger than the 16-fold increase expected from pigment depletion alone. 11-cis-Retinal, when delivered to isolated rods from liposomes, combines with free opsin to form a bleachable photopigment that fully restores sensitivity. 11-cis-Locked analogues of retinal combine with opsin to form unbleachable pigments in isolated bleached rods from the tiger salamander. They restore sensitivity to a substantial (16- to 25-fold) but incomplete extent. The analogues apparently relieve a stable component of adaptation when they interact with opsin. Because these analogues do not detectably excite rods, the structural requirements of both retinal and opsin for the relief of adaptation are different from those of excitation. The biochemical basis of light adaptation resulting from pigment bleaching and the minimum structural requirements of retinal for its relief remain to be determined. PMID:2395874

  9. Structural Basis for the Inhibition of Histone Deacetylase 8 (HDAC8), a Key Epigenetic Player in the Blood Fluke Schistosoma mansoni

    PubMed Central

    Marek, Martin; Kannan, Srinivasaraghavan; Hauser, Alexander-Thomas; Moraes Mourão, Marina; Caby, Stéphanie; Cura, Vincent; Stolfa, Diana A.; Schmidtkunz, Karin; Lancelot, Julien; Andrade, Luiza; Renaud, Jean-Paul; Oliveira, Guilherme; Sippl, Wolfgang; Jung, Manfred; Cavarelli, Jean; Pierce, Raymond J.; Romier, Christophe

    2013-01-01

    The treatment of schistosomiasis, a disease caused by blood flukes parasites of the Schistosoma genus, depends on the intensive use of a single drug, praziquantel, which increases the likelihood of the development of drug-resistant parasite strains and renders the search for new drugs a strategic priority. Currently, inhibitors of human epigenetic enzymes are actively investigated as novel anti-cancer drugs and have the potential to be used as new anti-parasitic agents. Here, we report that Schistosoma mansoni histone deacetylase 8 (smHDAC8), the most expressed class I HDAC isotype in this organism, is a functional acetyl-L-lysine deacetylase that plays an important role in parasite infectivity. The crystal structure of smHDAC8 shows that this enzyme adopts a canonical ?/? HDAC fold, with specific solvent exposed loops corresponding to insertions in the schistosome HDAC8 sequence. Importantly, structures of smHDAC8 in complex with generic HDAC inhibitors revealed specific structural changes in the smHDAC8 active site that cannot be accommodated by human HDACs. Using a structure-based approach, we identified several small-molecule inhibitors that build on these specificities. These molecules exhibit an inhibitory effect on smHDAC8 but show reduced affinity for human HDACs. Crucially, we show that a newly identified smHDAC8 inhibitor has the capacity to induce apoptosis and mortality in schistosomes. Taken together, our biological and structural findings define the framework for the rational design of small-molecule inhibitors specifically interfering with schistosome epigenetic mechanisms, and further support an anti-parasitic epigenome targeting strategy to treat neglected diseases caused by eukaryotic pathogens. PMID:24086136

  10. Keys to Soil Taxonomy

    NSDL National Science Digital Library

    United States Department of Agriculture, National Cooperative Soil Survey

    This United States Department of Agriculture (USDA) publication (11th edition, 2010) contains taxonomic keys necessary for the classification of soils in a form easily used in the field. The book describes soils in general, how to differentiate between them, and how the identification process works. The taxonomic key includes all known soil types, including mollisols, oxisols, alfisols, and others.

  11. Atsena Otie Key Island

    USGS Multimedia Gallery

    Atsena Otie Key is one of thirteen islands on Florida's Gulf Coast that make up Cedar Keys National Wildlife Refuge. Nearby waters support a multi-million dollar clam-farming industry. USGS documented pre-oil coastal conditions near the Refuge with baseline petrochemical measurements and aerial phot...

  12. Keys to Soil Taxonomy

    NSDL National Science Digital Library

    This United States Department of Agriculture (USDA) publication (9th edition, 2003) contains taxonomic keys necessary for the classification of soils in a form easily used in the field. The book describes soils in general, how to differentiate between them, and how the identification process works. The taxonomic key includes all known soil types, including mollisols, oxisols, alfisols, and others.

  13. Dichotomous Keys for Arthropods

    NSDL National Science Digital Library

    This reference tool allows students to identify an arthropod's order by making a series of guided decisions, such as six legs or more, well-developed or missing wing, and chewing or sucking mouthparts. The key, which includes only adult arthropods, is available as an interactive key on the AMNH's Web site that can be downloaded to your computer.

  14. Generalized minimum shift keying

    NASA Astrophysics Data System (ADS)

    Korn, I.

    1980-03-01

    A generalized minimum shift keying (GMSK) signal is defined, and its equivalence to a modified offset quadrature shift keying signal is shown. A simple formula for the spectrum of a GMSK signal is presented and the spectrum and out-of-band power are computed for two examples.

  15. Expanded response-surfaces: a new method to reconstruct paleoclimates from fossil pollen assemblages that lack modern analogues

    NASA Astrophysics Data System (ADS)

    Gonzales, L. M.; Williams, J. W.; Grimm, E. C.

    2009-12-01

    Pollen-based paleoclimatic interpretations of late-glacial to early Holocene climates (17-9 ka) in Midwestern North America are hampered by samples that lack modern analogues. Unresolved questions include the magnitude and direction of temperature seasonality (i.e. were these climates more or less seasonal than present) and the temporal changes in precipitation. Central to the no-analogue problem is the truncation of modern pollen-climate relationships for abundant late-glacial taxa such as Fraxinus. Here we present a new method called the expanded response-surface (ERS) method, developed to reconstruct climates from no-analogue pollen assemblages and applied to a high-resolution late-glacial pollen record from Crystal Lake, Illinois to test hypotheses about late-glacial climates. The key assumptions central to the ERS method are: (1) plant species and pollen abundances follow symmetrical unimodal distributions along climatic gradients, (2) taxa with truncated distributions in modern climate space occupy a subset of their fundamental niche, and (3) expansion of truncated distributions by mirroring around the distributional mode recovers the portion of the fundamental niche not realized in the modern climate space. With the ERS method, we expanded modern pollen-climate relationships by mirroring pollen abundances for each taxon around a mode defined with respect to four climate axes (mean winter temperature, mean summer temperature, mean winter precipitation, and mean summer precipitation). The ERS method reconstructed past temperatures and precipitation during the height of no-analogue conditions (14?160-12?370 cal yr BP) for 37% of the Crystal Lake samples where techniques that employed only modern observational data found matches for only 13% of the fossil samples. The total climate space of the expanded taxa set allowed analogue matches under more seasonal-than-present climates with higher-than-present precipitation. The ERS climate reconstructions for the height of no-analogue conditions indicated cooler-than-present summer and winter temperatures, similar-to-present seasonal range in temperatures, higher-than-present winter precipitation, and similar-to-present summer precipitation. These results thus suggest that high moisture availability helped drive the formation of the Midwestern no-analogue communities with high Fraxinus nigra abundances, but do not show higher-than-present temperature seasonality notwithstanding the higher-than-present insolation seasonality at this time. During the no-analogue late-glacial interval, Picea mariana, F. nigra, and Larix stands probably grew on low-lying, poorly drained soils in the Crystal Lake region; whereas Abies, Picea glauca, Quercus, and Ostrya/ Carpinus grew on upland positions with better soil drainage.

  16. Evaluation of the antioxidant activity of capsiate analogues in polar, nonpolar, and micellar media.

    PubMed

    Reddy, Kunduru K; Ravinder, Thumu; Prasad, Rachapudi B N; Kanjilal, Sanjit

    2011-01-26

    Synthesis of 10 capsiate analogues was conducted by lipase-mediated (Novozyme 435) esterification of vanillyl alcohol with different fatty acids. The antioxidant activity of the synthesized capsiates was evaluated using three in vitro assays: DPPH radical scavenging assay (polar medium), Rancimat assay (nonpolar medium), and autoxidation of linoleic acid (micellar medium). The objective of this study is to find the influence of structural characteristics of the alkyl chain of capsiate analogues on their antioxidant activity. In these assays, BHT and ?-tocopherol were used as reference compounds. Both DPPH and Rancimat assays did not show any specific trend of antioxidant activity with the increase in lipophilicity and also with the type of fatty acids grafted to the phenolic moiety. In the Tween 20 micellar system for the inhibition of autoxidation of linoleic acid, vanillyl ester attached to a C18 alkyl chain (vanillyl stearate, oleate, and ricinoleate) exhibited maximum inhibition of autoxidation of linoleic acid. PMID:21166418

  17. Monocarbonyl curcumin analogues: heterocyclic pleiotropic kinase inhibitors that mediate anticancer properties.

    PubMed

    Brown, Andrew; Shi, Qi; Moore, Terry W; Yoon, Younghyoun; Prussia, Andrew; Maddox, Clinton; Liotta, Dennis C; Shim, Hyunsuk; Snyder, James P

    2013-05-01

    Curcumin is a biologically active component of curry powder. A structurally related class of mimetics possesses similar anti-inflammatory and anticancer properties. Mechanism has been examined by exploring kinase inhibition trends. In a screen of 50 kinases relevant to many forms of cancer, one member of the series (4, EF31) showed ?85% inhibition for 10 of the enzymes at 5 ?M, while 22 of the proteins were blocked at ?40%. IC50 values for an expanded set of curcumin analogues established a rank order of potencies, and analyses of IKK? and AKT2 enzyme kinetics for 4 revealed a mixed inhibition model, ATP competition dominating. Our curcumin mimetics are generally selective for Ser/Thr kinases. Both selectivity and potency trends are compatible with protein sequence comparisons, while modeled kinase binding site geometries deliver a reasonable correlation with mixed inhibition. Overall, these analogues are shown to be pleiotropic inhibitors that operate at multiple points along cell signaling pathways. PMID:23550937

  18. 2-Acylamido Analogues of N-Acetylglucosamine Prime Formation of Chitin Oligosaccharides by Yeast Chitin Synthase 2*

    PubMed Central

    Gyore, Jacob; Parameswar, Archana R.; Hebbard, Carleigh F. F.; Oh, Younghoon; Bi, Erfei; Demchenko, Alexei V.; Price, Neil P.; Orlean, Peter

    2014-01-01

    Chitin, a homopolymer of ?1,4-linked N-acetylglucosamine (GlcNAc) residues, is a key component of the cell walls of fungi and the exoskeletons of arthropods. Chitin synthases transfer GlcNAc from UDP-GlcNAc to preexisting chitin chains in reactions that are typically stimulated by free GlcNAc. The effect of GlcNAc was probed by using a yeast strain expressing a single chitin synthase, Chs2, by examining formation of chitin oligosaccharides (COs) and insoluble chitin, and by replacing GlcNAc with 2-acylamido analogues of GlcNAc. Synthesis of COs was strongly dependent on inclusion of GlcNAc in chitin synthase incubations, and N,N?-diacetylchitobiose (GlcNAc2) was the major reaction product. Formation of both COs and insoluble chitin was also stimulated by GlcNAc2 and by N-propanoyl-, N-butanoyl-, and N-glycolylglucosamine. MALDI analyses of the COs made in the presence of 2-acylamido analogues of GlcNAc showed they that contained a single GlcNAc analogue and one or more additional GlcNAc residues. These results indicate that Chs2 can use certain 2-acylamido analogues of GlcNAc, and likely free GlcNAc and GlcNAc2 as well, as GlcNAc acceptors in a UDP-GlcNAc-dependent glycosyltransfer reaction. Further, formation of modified disaccharides indicates that CSs can transfer single GlcNAc residues. PMID:24619411

  19. Modifications outside the proteinase binding loop in Cucurbita maxima trypsin inhibitor III (CMTI-III) analogues change the binding energy with bovine beta-trypsin.

    PubMed

    Ja?kiewicz, A; Lis, K; Rózycki, J; Kupryszewski, G; Rolka, K; Ragnarsson, U; Zbyryt, T; Wilusz, T

    1998-10-01

    Five 26-peptide analogues of the trypsin inhibitor [Pro18]CMTI-III containing Leu or Tyr in position 7 and Val or Tyr in position 27: 1 (Leu7, Tyr27), 2 (Tyr7, Val27), 3 (Tyr7, Tyr27), 4 (Leu7, Val27) and 5 (Leu7, Ala18, Tyr27) were synthesized by the solid-phase method. Analogues 1-4 displayed Ka with bovine beta-trypsin of the same order of magnitude as the wild CMTI-III inhibitor, whereas for analogue 5, this value was lower by about 3 orders of magnitude. This indicated that for the analogues with Pro (but not with Ala) in position 18, the side-chain interactions between positions 7 and 27 did not play a critical role for the stabilization of the active structure. In addition, these results also suggest that Tyr7 is involved in an additional aromatic interaction with position 41 of the enzyme. PMID:9781673

  20. A Keying Method for a Nested Relational Database Management System

    Microsoft Academic Search

    Z. Meral Özsoyoglu; Jian Wang

    1992-01-01

    The authors discuss the keying methods that are proposed in the literature and introduce the external keying method which aims to restore the structure of tuples that is lost by unnesting a relation valued attribute in a nested relation. As opposed to the previous keying methods, it does not store the keying information within the relation instance which can be

  1. Structural and Functional Studies of Nonstructural Protein 2 of the Hepatitis C Virus Reveal Its Key Role as Organizer of Virion Assembly

    PubMed Central

    Jirasko, Vlastimil; Montserret, Roland; Lee, Ji Young; Gouttenoire, Jérôme; Moradpour, Darius; Penin, Francois; Bartenschlager, Ralf

    2010-01-01

    Non-structural protein 2 (NS2) plays an important role in hepatitis C virus (HCV) assembly, but neither the exact contribution of this protein to the assembly process nor its complete structure are known. In this study we used a combination of genetic, biochemical and structural methods to decipher the role of NS2 in infectious virus particle formation. A large panel of NS2 mutations targeting the N-terminal membrane binding region was generated. They were selected based on a membrane topology model that we established by determining the NMR structures of N-terminal NS2 transmembrane segments. Mutants affected in virion assembly, but not RNA replication, were selected for pseudoreversion in cell culture. Rescue mutations restoring virus assembly to various degrees emerged in E2, p7, NS3 and NS2 itself arguing for an interaction between these proteins. To confirm this assumption we developed a fully functional JFH1 genome expressing an N-terminally tagged NS2 demonstrating efficient pull-down of NS2 with p7, E2 and NS3 and, to a lower extent, NS5A. Several of the mutations blocking virus assembly disrupted some of these interactions that were restored to various degrees by those pseudoreversions that also restored assembly. Immunofluorescence analyses revealed a time-dependent NS2 colocalization with E2 at sites close to lipid droplets (LDs) together with NS3 and NS5A. Importantly, NS2 of a mutant defective in assembly abrogates NS2 colocalization around LDs with E2 and NS3, which is restored by a pseudoreversion in p7, whereas NS5A is recruited to LDs in an NS2-independent manner. In conclusion, our results suggest that NS2 orchestrates HCV particle formation by participation in multiple protein-protein interactions required for their recruitment to assembly sites in close proximity of LDs. PMID:21187906

  2. Behavioral profiles in rats distinguish among "ecstasy," methamphetamine and 2,5-dimethoxy-4-iodoamphetamine: Mixed effects for "ecstasy" analogues.

    PubMed

    Quinteros-Muñoz, David; Sáez-Briones, Patricio; Díaz-Véliz, Gabriela; Mora-Gutiérrez, Sergio; Rebolledo-Fuentes, Marco; Cassels, Bruce K

    2010-10-01

    3,4-methylenedioxymethamphetamine (MDMA; "ecstasy") is a psychoactive drug structurally related to other phenylisopropylamines acting as stimulants or hallucinogens in humans. Although MDMA has a pharmacological identity of its own, the distinction of its acute effects from those of stimulants or even hallucinogens is controversial. In this work, dose-response curves (0.25, 0.5, 1, 3, 5, and 10 mg/kg) representing the acute in vivo effects of MDMA were compared with those of a structurally related stimulant (methamphetamine, MA) and a hallucinogenic analogue (2,5-dimethoxy-4-iodoamphetamine, DOI) in a set of behavioral protocols in rats, including spontaneous psychomotor activity, anxiolytic/anxiogenic-like effects and active avoidance conditioning responses. The behavioral profiles obtained allowed us to differentiate among racemic MDMA, MA, and DOI at different dose ranges. In addition, the evaluation of four MDMA analogues (1, 5, and 10 mg/kg) comprising two well-known MDMA analogues (MDA [3,4-methylenedioxyamphetamine] and MDE (N-ethyl-MDA, believed to substitute for MDMA) and two other structural analogues (MDOH [N-hydroxy-MDA] and MMDA-2 [2-methoxy-4,5-methylenedioxyamphetamine]) showed that none of these exactly resembles MDMA in their pharmacological profiles, highlighting the unique character of this prototypical entactogen. In fact, their effects exhibited similarities with the behavioral profiles of either MA or DOI, as well as novel profiles in specific behavioral paradigms. PMID:20939666

  3. Analogue Models Of Volcanic Spreading At Mt. Vesuvius

    NASA Astrophysics Data System (ADS)

    De Matteo, Ada; Castaldo, Raffaele; D'Auria, Luca; James, Michael; Lane, Steve; Massa, Bruno; Pepe, Susi; Tizzani, Pietro

    2015-04-01

    Somma-Vesuvius is a quiescent strato-volcano of the Neapolitan district, southern Italy, for which various geophysical and geological evidences (e.g. geodetic measurements, geological and structural data, seismic profiles interpretations and surface deformation analysis with Differential Interferometric Synthetic Aperture Radar (DInSAR)) indicate ongoing spreading deformation. In this research we investigate the spreading deformation and associated surface deformation pattern by performing analogue experiments and comparing the results with actual ground deformation as measured using DInSAR data recorded between 1992 and 2010. Somma-Vesuvius consists of a volcanic cone (Gran Cono) lying within an asymmetric caldera (Somma). The Somma caldera is the result of at least 7 Plinian eruptions, the last of which was the 79 CE. Pompeii eruption. The current cone of Mt. Vesuvius grew within the caldera in the following centuries as the effect of continued explosive and effusive activity of the volcano. The volcano lies on a substratum consisting of a Mesozoic carbonatic basement, overlapped by Holocene clastic sediments and volcanic rocks. Our analogue models were built to simulate the shape of the Somma-Vesuvius top a scale of about 1:100000, emplaced on a sand layer (brittle behaviour) laid on a silicone layer (ductile behaviour). Models are based on the Fluid-dynamics Dimensionless Analysis (FDA), according to the Buckingham-? theorem. In this context, we considered few dimensionless parameters that allowed the setting of a reliable scaled model. To represent the complex Somma-Vesuvius geometry, an asymmetric model was built by setting a truncated cone (mimicking the topography of Somma edifice) topped by another small cone (mimicking the Gran Cono) shifted off the axis of the main cone. Different experiments were carried out in which the thickness of the basal sand layer and of the silicone one were varied. To quantify the vertical and horizontal displacements the models were monitored with three synchronised digital cameras, enabling sequential 3-D models to be derived using a photogrammetric technique. Finally, our models were compared with the 1992 - 2010 SBAS DInSAR measurements of ground deformations obtained using ERS-ENVISAT satellite images. The results show that analogue models are able to reproduce different styles of volcanic spreading and to reproduce the observed surface and deformation pattern. At the end our models show a deformation rather similar to the actual deformation pattern of the Somma-Vesuvius, both in the direction and in the intensity. Further studies will be devoted at find the best combination of parameters (silicone layer thickness and viscosity) to fit observations and to introduce a tridimensional rigid based topography. These studies will be implemented also with new structural and surface deformation (DinSAR) data and will be integrated with a numerical modelling.

  4. Analogue models of subduction megathrust earthquakes: improving rheology and monitoring technique

    NASA Astrophysics Data System (ADS)

    Brizzi, Silvia; Corbi, Fabio; Funiciello, Francesca; Moroni, Monica

    2015-04-01

    Most of the world's great earthquakes (Mw > 8.5, usually known as mega-earthquakes) occur at shallow depths along the subduction thrust fault (STF), i.e., the frictional interface between the subducting and overriding plates. Spatiotemporal occurrences of mega-earthquakes and their governing physics remain ambiguous, as tragically demonstrated by the underestimation of recent megathrust events (i.e., 2011 Tohoku). To help unravel seismic cycle at STF, analogue modelling has become a key-tool. First properly scaled analogue models with realistic geometries (i.e., wedge-shaped) suitable for studying interplate seismicity have been realized using granular elasto-plastic [e.g., Rosenau et al., 2009] and viscoelastic materials [i.e., Corbi et al., 2013]. In particular, viscoelastic laboratory experiments realized with type A gelatin 2.5 wt% simulate, in a simplified yet robust way, the basic physics governing subduction seismic cycle and related rupture process. Despite the strength of this approach, analogue earthquakes are not perfectly comparable to their natural prototype. In this work, we try to improve subduction seismic cycle analogue models by modifying the rheological properties of the analogue material and adopting a new image analysis technique (i.e., PEP - ParticlE and Prediction velocity). We test the influence of lithosphere elasticity by using type A gelatin with greater concentration (i.e., 6 wt%). Results show that gelatin elasticity plays important role in controlling seismogenic behaviour of STF, tuning the mean and the maximum magnitude of analogue earthquakes. In particular, by increasing gelatin elasticity, we observe decreasing mean magnitude, while the maximum magnitude remains the same. Experimental results therefore suggest that lithosphere elasticity could be one of the parameters that tunes seismogenic behaviour of STF. To increase gelatin elasticity also implies improving similarities with their natural prototype in terms of coseismic duration and rupture width. Experimental monitoring has been performed by means of both PEP and PIV (i.e., Particle Image Velocimetry) algorithms. PEP differs from classic cross-correlation techniques (i.e., PIV) in its ability to provide sparse velocity vectors at points coincident with particle barycentre positions, allowing a lagrangian description of the velocity field and a better spatial resolution (i.e., ? 0.03 mm2) with respect to PIV. Results show that PEP algorithm is able to identify a greater number of analogue earthquakes (i.e., ? 20% more than PIV algorithm), decreasing the minimum detectable magnitude from 6.6 to 4.5. Furthermore, earthquake source parameters (e.g., hypocentre position, rupture limits and slip distribution) are more accurately defined. PEP algorithm is then suitable to potentially gain new insights on seismogenic process of STF, by extending the analysable magnitude range of analogue earthquakes and having implications on applicability of scaling relationship, such as Gutenberg - Richter law, to experimental results.

  5. Optical key system

    DOEpatents

    Hagans, Karla G. (Livermore, CA); Clough, Robert E. (Danville, CA)

    2000-01-01

    An optical key system comprises a battery-operated optical key and an isolated lock that derives both its operating power and unlock signals from the correct optical key. A light emitting diode or laser diode is included within the optical key and is connected to transmit a bit-serial password. The key user physically enters either the code-to-transmit directly, or an index to a pseudorandom number code, in the key. Such person identification numbers can be retained permanently, or ephemeral. When a send button is pressed, the key transmits a beam of light modulated with the password information. The modulated beam of light is received by a corresponding optical lock with a photovoltaic cell that produces enough power from the beam of light to operate a password-screen digital logic. In one application, an acceptable password allows a two watt power laser diode to pump ignition and timing information over a fiberoptic cable into a sealed engine compartment. The receipt of a good password allows the fuel pump, spark, and starter systems to each operate. Therefore, bypassing the lock mechanism as is now routine with automobile thieves is pointless because the engine is so thoroughly disabled.

  6. PublicPublic--Key EncryptionKey Encryption Public-key, or asymmetric encryption

    E-print Network

    Fisher, Michael

    COMP 522 PublicPublic--Key EncryptionKey Encryption COMP 522 Public-key, or asymmetric encryption Public-key encryption techniques. It is particular and most important kind of Asymmetric encryption (or asymmetric key encryption): · One key is used for encryption (usually publicly known, public key); · Another

  7. Acoustic analogue of graphene: observation of Dirac cones in acoustic surface waves.

    PubMed

    Torrent, Daniel; Sánchez-Dehesa, José

    2012-04-27

    We demonstrate the presence of Dirac cones in the dispersion relation of acoustic waves propagating on the surface of a plate of methyl methacrylate containing a honeycomb lattice of cylindrical boreholes. This structure represents the acoustic analogue of graphene, the cylindrical cavities playing the role of carbon atoms while acoustic surface waves are the equivalent of electronic waves in graphene. Analytical expressions for the Dirac frequency and Dirac velocity in acoustics are given as a function of the radius and depth of boreholes. These parameters have been experimentally determined for a constructed structure and the data are in fairly good agreement with the predicted values. PMID:22680870

  8. Key Regression: Enabling Efficient Key Distribution for Secure Distributed Storage

    Microsoft Academic Search

    Kevin Fu; Seny Kamara; Yoshi Kohno

    2006-01-01

    The Plutus file system introduced the notion of key rotation as a means to derive a sequence of temporally- related keys from the most recent key. In this paper we show that, despite natural intuition to the contrary, key rotation schemes cannot generically be used to key other cryptographic objects; in fact, keying an encryp- tion scheme with the output

  9. Structure and metamorphism of the granitic basement around Antananarivo: A key to the Pan-African history of central Madagascar and its Gondwana connections

    NASA Astrophysics Data System (ADS)

    NéDéLec, Anne; Ralison, Bruno; Bouchez, Jean-Luc; GréGoire, Vincent

    2000-10-01

    The Precambrian basement of Madagascar acquired a polyphase imprint during the Pan-African orogeny. In northern central Madagascar, emplacement of stratoid alkaline granites at midcrustal depth (4-5 kbars) led to formation of a layered crust in a postcollisional extensional regime at 630 Ma (D1). Subsequently, the structures of the stratoid granites were rotated by the sinistral and transpressive E-W Antananarivo flexure (or virgation) zone (D2). East of Antananarivo the structures of the D1 layered crust and the D2 virgation are crosscut by the steeply dipping N-S foliations of the Angavo belt. Lineations gently plunging to the north attest that the Angavo belt is a major strike-slip shear zone that formed under low-pressure granulitic conditions (3 kbars, 790°C). The nearby porphyritic Carion granite was emplaced at the end of this period of N-S shearing (D3), which can thus be no younger than 530 Ma. Late-Pan-African (580-550 Ma) strike-slip motion along broadly N-S shear zones has been recognized elsewhere in Madagascar and in its Gondwana connections. Continuation of the Angavo belt as one of the high strain belts of the Arabian-Nubian Shield is discussed in the general framework of Gondwana assembly.

  10. X-ray structural characterization of the bis-guanine derivative of a cisplatin analogue having just one proton on each coordinated nitrogen and a head-to-head conformation: [Pt{(+/-)-N,N'-dimethyl-2,3-diaminobutane}(9-ethyl-guanine)2]dinitrate.

    PubMed

    Intini, Francesco P; Cini, Renzo; Tamasi, Gabriella; Hursthouse, Michael B; Marzilli, Luigi G; Natile, Giovanni

    2010-09-01

    The X-ray structural and NMR characterization of a bis-guanine derivative of a cisplatin analogue designed to reduce the rate of the Pt-N7 rotation of the coordinated guanine nucleobases by more than 1-million-fold is reported. The [Pt{(+/-)-Me(2)dab}(9-EtG)(2)](NO(3))(2) (Me(2)dab = N,N'-dimethyl-2,3-diaminobutane, 9-EtG = 9-ethyl-guanine) complex crystallizes in the P2(1)/n space group, and the crystal contains a racemic mixture of complex molecules. The data were collected at 120 +/- 2 K, and the crystal and molecular structure (comprising one disordered nitrate) were resolved and refined to conventional agreement factors of R1 = 0.0270 and wR2 = 0.0565. The guanine ligands assume the less common head-to-head (HH) orientation, disclosing full details of the intramolecular relationships between cis guanines and between guanine and cis amine. Moreover, an understanding has been gained of the steric factors determining induction of asymmetry (from carbons to adjacent nitrogen atoms) and puckering of the chelate ring (delta or lambda for R,S,S,R or S,R,R,S configurations at the N,C,C,N chelate-ring atoms, respectively) within the Me(2)dab ligand. The chemical shift separation between H8 signals of the two HT atropisomers and between the two H8 signals of the single HH atropisomer can be explained in terms of canting of the nucleobases relative to the coordination plane and in terms of the different relationships between the H8 proton of one guanine and the shielding zone of the cis guanine. Furthermore, for each configuration of the Me(2)dab ligand (R,S,S,R or S,R,R,S), the NMR data indicate that the handedness of canting is similar for the two guanines in all three (two HT and one HH) conformers (R canting for R,S,S,R and L canting for S,R,R,S configuration). PMID:20799737

  11. Interferon-free strategies with a nucleoside/nucleotide analogue.

    PubMed

    Feld, Jordan J

    2014-02-01

    A key to effective interferon- (IFN-) free therapy for hepatitis C virus (HCV) infection is a direct-acting antiviral (DAA) with a high barrier to resistance that can act as the backbone to any regimen. Ideally, this agent should also be active against all HCV genotypes, be well tolerated and have few drug interactions. Nucleoside/nucleotide analogues (NAs) that inhibit the function of the HCV RNA-dependent-RNA polymerase fit these requirements and thus hold promise as a cornerstone for new IFN-free regimens. To date, the issue with this class of agents has been toxicity. Numerous NAs in early clinical development have led to significant toxicity leading to their abandonment. However, sofosbuvir, a prodrug of a uridine NA, has moved through development with a clean-safety profile leading to its recent approval. When combined with ribavirin (RBV) alone, sofosbuvir is effective against genotype 2 and even genotype 3 if duration is extended. There are currently limited data with this combination in genotype 1; however, when sofosbuvir is combined with other DAAs of different classes, it is highly effective in almost all patients. To date, sofosbuvir has been studied with protease, NS5A, and nonnucleoside HCV polymerase inhibitors, including as part of a fixed-dose combination single tablet with the NS5A inhibitor ledipasvir, with very high rates of SVR with as little as 8 weeks of therapy. Combining two DAAs to sofosbuvir may shorten therapy even further. Because of the poor replicative fitness of the S282T sofosbuvir-resistant variant, resistance to sofosbuvir has not been a significant clinical issue in trials thus far. In addition to sofosbuvir, other NAs are in early-stage development. Provided unanticipated toxicity does not emerge, NAs are likely to play a major role as a backbone for future HCV therapy. The rationale for using this class of agents and the clinical data available to date are reviewed. PMID:24782257

  12. SCIENCE MATTERS KEY CHAIN

    NSDL National Science Digital Library

    1900-01-01

    Brushed nickel key chain commemorating the launch of the new Science Matters initiative. Limited edition. All proceeds from the sale of this item go to fund the John Glenn Center for Science Education.

  13. Public-Key Steganography

    Microsoft Academic Search

    Luis Von Ahn; Nicholas J. Hopper

    2004-01-01

    Informally, a public-key steganography protocol allows two parties, who have never met or exchanged a secret, to send hidden mes- sages over a public channel so that an adversary cannot even detect that these hidden messages are being sent. Unlike previous settings in which provable security has been applied to steganography, public-key steganography is information-theoretically impossible. In this work we

  14. Black swans and bu-erflies: analogues of atmospheric

    E-print Network

    Saussol, Benoît

    & Extreme Events #12;Circula:on analogues (1) · Reference database R, containing) Storm Dirk Workshop Rare & Extreme Events 6 #12;Example (2) Workshop Rare LSCE & IPSL Gif-sur-Yve-e 1 Workshop Rare & Extreme Events #12;Mo

  15. Effects of Prostaglandin Analogues on Aqueous Humor Outflow Pathways

    PubMed Central

    Winkler, Nelson S.

    2014-01-01

    Abstract Elevated intraocular pressure (IOP) is the most prevalent risk factor for glaucoma. All treatments, whether surgical or pharmaceutical, are aimed at lowering IOP. Prostaglandin analogues are a first line therapy for glaucoma due to their ability to reduce IOP, once-daily dosing, efficacy, and minimal side-effect profile. Whereas prostaglandin analogues have been known to alter aqueous humor outflow through the unconventional (uveoscleral) pathway, more recent evidence suggests their action also occurs through the conventional (trabecular) pathway. Understanding how prostaglandin analogues successfully lower IOP is important, as this information may lead to the discovery of new molecular targets for future therapeutic intervention. This review explores the current understanding of prostaglandin analogue biology as it pertains to IOP reduction and improved aqueous humor outflow facility. PMID:24359106

  16. An antibacterial hydroxy fusidic acid analogue from Acremonium crotocinigenum

    E-print Network

    Griffith, Gareth

    An antibacterial hydroxy fusidic acid analogue from Acremonium crotocinigenum Liam Evans a , John N reserved. Keywords: Acremonium crotocinigenum; Fusidane triterpene; Fusidic acid; Antibacterial; MRSA; MDR bioautography, to qualitatively indicate the presence of antibacterial compounds, facilitating the isolation

  17. Biomimetic cochlea filters : from modelling, design to analogue VLSI implementation 

    E-print Network

    Wang, Shiwei

    2014-11-27

    This thesis presents a novel biomimetic cochlea filter which closely resembles the biological cochlea behaviour. The filter is highly feasible for analogue very-large-scale integration (VLSI) circuits, which leads to a ...

  18. Upheaval Dome, An Analogue Site for Gale Center

    NASA Technical Reports Server (NTRS)

    Conrad, P. G.; Eignebrode, J. L.

    2011-01-01

    We propose Upheaval Dome in southeastern Utah as an impact analogue site on Earth to Mars Science Laboratory candidate landing site Gale Crater. The genesis of Upheaval Dome was a mystery for some time--originally thought to be a salt dome. The 5 km crater was discovered to possess shocked quartz and other shock metamorphic features just a few years ago, compelling evidence that the crater was formed by impact, although the structural geology caused Shoemaker and Herkenhoff to speculate an impact origin some 25 years earlier. The lithology of the crater is sedimentary. The oldest rocks are exposed in the center of the dome, upper Permian sandstones, and progressively younger units are well exposed moving outward from the center. These are Triassic sandstones, siltstones and shales, which are intruded by clastic dikes. There are also other clay-rich strata down section, as is the case with Gale Crater. There is significant deformation in the center of the crater, with folding and steeply tilted beds, unlike the surrounding Canyonlands area, which is relatively undeformed. The rock units are well exposed at Upheaval Dome, and there are shatter cones, impactite fragments, shocked quartz grains and melt rocks present. The mineral shock features suggest that the grains were subjected to dynamic pressures> 10 GPa.

  19. Synthesis and biological evaluations of a series of thaxtomin analogues.

    PubMed

    Zhang, Hongbo; Wang, Qingpeng; Ning, Xin; Hang, Hang; Ma, Jing; Yang, Xiande; Lu, Xiaolin; Zhang, Jiabao; Li, Yonghong; Niu, Congwei; Song, Haoran; Wang, Xin; Wang, Peng George

    2015-04-15

    Thaxtomins are a unique family of phytotoxins with unique 4-nitroindole and diketopiperazine fragments possessing potential herbicidal activities. This work presents the total synthesis of natural product thaxtomin C and its analogues. The extensive structure-activity relationship study screens four effective compounds, including thaxtomin A and thaxtomin C. It is indicated that 4-nitro indole fragment is essential for phytotoxicity, while benzyl and m-hydroxybenzyl substituents on the diketopiperazine ring are favorable for the efficacy. The N-methylations on indole and diketopiperazine show weak influence on the herbicidal activities. The four selected compounds show effective herbicidal activities against Brassica campestris, Amaranthus retroflexus, and Abutilon theophrasti, which are comparable or better than dichlobenil, even at a dosage of 187.5 g ha(-1). Moreover, these four compounds show good crop-selective properties to different crops and exhibit moderate protoporphyrinogen oxidase (PPO) enzyme inhibition. The antifungal results indicate that thaxtomin C displays inhibition to a wide range of fungi. PMID:25804187

  20. Dimerization of truncated melittin analogues results in cytolytic peptides.

    PubMed Central

    Rivett, D E; Kirkpatrick, A; Hewish, D R; Reilly, W; Werkmeister, J A

    1996-01-01

    A synthetic peptide with the sequence of the first 20 residues of melittin and terminating with an additional cysteine amide was found to have cytolytic activity similar to that of melittin. It was apparent from MS data that the cysteine-terminating peptides had formed disulphide dimers. A peptide in which the thiol was blocked by iodoacetate showed no activity, whereas the same peptide blocked by acetamidomethyl showed activity marginally less haemolytic than that of melittin. Cytolytic activity of melittin analogues comprising the full 26 residues could be obtained with wide sequence permutations providing that a general amphipathic helical structure was preserved. In contrast, the activity of the dimers was dependent not only on retention of an amphipathic helix but also on certain individual residues and a free positive charge. A free N-terminus was essential for haemolytic activity. In addition, a lysine or arginine residue at position 7 and a proline at position 14 were found to be necessary for activity, although it was apparent that additional residues are important for retention of the full lytic potential. PMID:8687396

  1. Irradiation studies of astrophysical ice analogues

    NASA Astrophysics Data System (ADS)

    Holton, Philip D.

    In this thesis the formation of molecular species in cold icy mantles, typical of those in the interstellar medium (ISM) has been studied. The construction of an ultra high vacuum system for the formation and containment of these astrophysical ice analogues is described. The method of preparation of these ices is detailed and analysis methodologies are discussed. VUV spectra of molecular ices (e.g. SO2, CH3NH2, OCS) measured on the UV1 beam line of the Astrid Synchrotron facility at the University of Aarhus in Denmark, are presented. Molecular synthesis (e.g. CO3, CO, H2CO3) induced by ion irradiated CO2/H 2O ices using facilities at Queens University Belfast are also reported. In particular this thesis focuses on the irradiation studies of the binary ice mixture of Methylamine (CH3NH2) and Carbon Dioxide (CO2). The results of irradiation of CH3NH2 and CO2 binary ice mixtures by ultraviolet photons, and electrons are presented. The apparent production of the amino acid - glycine - in our irradiated samples is discussed together with possible production processes.

  2. A positive Grassmannian analogue of the permutohedron

    E-print Network

    Williams, Lauren K

    2015-01-01

    The classical permutohedron Perm is the convex hull of the points (w(1),...,w(n)) in R^n where w ranges over all permutations in the symmetric group. This polytope has many beautiful properties -- for example it provides a way to visualize the weak Bruhat order: if we orient the permutohedron so that the longest permutation w_0 is at the "top" and the identity e is at the "bottom," then the one-skeleton of Perm is the Hasse diagram of the weak Bruhat order. Equivalently, the paths from e to w_0 along the edges of Perm are in bijection with the reduced decompositions of w_0. Moreover, the two-dimensional faces of the permutohedron correspond to braid and commuting moves, which by the Tits Lemma, connect any two reduced expressions of w_0. In this note we introduce some polytopes Br(k,n) (which we call bridge polytopes) which provide a positive Grassmannian analogue of the permutohedron. In this setting, BCFW bridge decompositions of reduced plabic graphs play the role of reduced decompositions. We define Br(k,...

  3. Stingray placental analogues: structure of trophonemata in Rhinoptera bonasus.

    PubMed

    Hamlett, W C; Wourms, J P; Smith, J W

    1985-10-01

    The cownose ray, Rhinoptera bonasus, displays a non-placental form of viviparity since direct maternal-embryonic connections are lacking. Early stage embryos depend on yolk reserves for growth to 215 mm disc width; growth to term, 405 mm disc width, is effected by ingestion of uterine histotrophe. During late gestation, the maternal uterine epithelium possesses 2-3 cm long spatulate, villiform appendages, termed trophonemata. These secrete histotrophe, which is a viscous, nutrient fluid. Scanning electron microscopy of the trophonematal surface reveals branching ridges, each of which is supplied by a capillary. The secretory unit is composed of 8-10 cells joined by extensive junctional complexes. Characteristically, secretory cells have a rough endoplasmic reticulum whose irregular cisternae are grossly distended and filled with low density flocculent material. Uncoated vesicles are given off by an extensive juxtanuclear Golgi complex. Coated vesicles are also present, but are not directly associated with the Golgi complex. Electron dense granules, larger lysosome-like vesicles, and multivesicular bodies are in the vicinity of the Golgi. PMID:4078946

  4. The atomic resolution structure of human AlkB homolog 7 (ALKBH7), a key protein for programmed necrosis and fat metabolism.

    PubMed

    Wang, Guoqiang; He, Qingzhong; Feng, Chong; Liu, Yang; Deng, Zengqin; Qi, Xiaoxuan; Wu, Wei; Mei, Pinchao; Chen, Zhongzhou

    2014-10-01

    ALKBH7 is the mitochondrial AlkB family member that is required for alkylation- and oxidation-induced programmed necrosis. In contrast to the protective role of other AlkB family members after suffering alkylation-induced DNA damage, ALKBH7 triggers the collapse of mitochondrial membrane potential and promotes cell death. Moreover, genetic ablation of mouse Alkbh7 dramatically increases body weight and fat mass. Here, we present crystal structures of human ALKBH7 in complex with Mn(II) and ?-ketoglutarate at 1.35 Å or N-oxalylglycine at 2.0 Å resolution. ALKBH7 possesses the conserved double-stranded ?-helix fold that coordinates a catalytically active iron by a conserved HX(D/E) … Xn … H motif. Self-hydroxylation of Leu-110 was observed, indicating that ALKBH7 has the potential to catalyze hydroxylation of its substrate. Unlike other AlkB family members whose substrates are DNA or RNA, ALKBH7 is devoid of the "nucleotide recognition lid" which is essential for binding nucleobases, and thus exhibits a solvent-exposed active site; two loops between ?-strands ?6 and ?7 and between ?9 and ?10 create a special outer wall of the minor ?-sheet of the double-stranded ?-helix and form a negatively charged groove. These distinct features suggest that ALKBH7 may act on protein substrate rather than nucleic acids. Taken together, our findings provide a structural basis for understanding the distinct function of ALKBH7 in the AlkB family and offer a foundation for drug design in treating cell death-related diseases and metabolic diseases. PMID:25122757

  5. Relative contributions of set-asides and tree retention to the long-term availability of key forest biodiversity structures at the landscape scale.

    PubMed

    Roberge, Jean-Michel; Lämås, Tomas; Lundmark, Tomas; Ranius, Thomas; Felton, Adam; Nordin, Annika

    2015-05-01

    Over previous decades new environmental measures have been implemented in forestry. In Fennoscandia, forest management practices were modified to set aside conservation areas and to retain trees at final felling. In this study we simulated the long-term effects of set-aside establishment and tree retention practices on the future availability of large trees and dead wood, two forest structures of documented importance to biodiversity conservation. Using a forest decision support system (Heureka), we projected the amounts of these structures over 200 years in two managed north Swedish landscapes, under management scenarios with and without set-asides and tree retention. In line with common best practice, we simulated set-asides covering 5% of the productive area with priority to older stands, as well as ?5% green-tree retention (solitary trees and forest patches) including high-stump creation at final felling. We found that only tree retention contributed to substantial increases in the future density of large (DBH ?35 cm) deciduous trees, while both measures made significant contributions to the availability of large conifers. It took more than half a century to observe stronger increases in the densities of large deciduous trees as an effect of tree retention. The mean landscape-scale volumes of hard dead wood fluctuated widely, but the conservation measures yielded values which were, on average over the entire simulation period, about 2.5 times as high as for scenarios without these measures. While the density of large conifers increased with time in the landscape initially dominated by younger forest, best practice conservation measures did not avert a long-term decrease in large conifer density in the landscape initially comprised of more old forest. Our results highlight the needs to adopt a long temporal perspective and to consider initial landscape conditions when evaluating the large-scale effects of conservation measures on forest biodiversity. PMID:25745845

  6. Structural Basis for Substrate Specificity in ArnB. A Key Enzyme in the Polymyxin Resistance Pathway of Gram-Negative Bacteria

    PubMed Central

    2015-01-01

    Cationic Antimicrobial Peptides (CAMPs) represent a first line of defense against bacterial colonization. When fighting Gram-negative bacteria, CAMPs initially interact electrostatically with the negatively charged phosphate groups in lipid A and are thought to kill bacteria by disrupting their membrane integrity. However, many human pathogens, including Salmonella and Pseudomonas, have evolved lipid A modification mechanisms that result in resistance to CAMPs and related antibiotics such as Colistin. The addition of 4-amino-4-deoxy-l-Arabinose (Ara4N) to a phosphate group in lipid A is one such modification, frequently found in Pseudomonas isolated from cystic fibrosis patients. The pathway for biosynthesis of Ara4N-lipid A requires conversion of UDP-Glucuronic acid into UDP-Ara4N and subsequent transfer of the amino-sugar to lipid A. ArnB is a pyridoxal-phosphate (PLP) dependent transaminase that catalyzes a crucial step in the pathway: synthesis of UDP-Ara4N from UDP-4-keto-pentose. Here we present the 2.3 Å resolution crystal structure of an active site mutant of ArnB (K188A) in complex with the reaction intermediate aldimine formed by UDP-Ara4N and PLP. The sugar–nucleotide binding site is in a cleft between the subunits of the ArnB dimer with the uracil buried at the interface and the UDP ribose and phosphate groups exposed to the solvent. The Ara4N moiety is found in the 4C1 conformation and its positioning, stabilized by interactions with both the protein and cofactor, is compatible with catalysis. The structure suggests strategies for the development of specific inhibitors that may prove useful in the treatment of resistant bacteria such as Pseudomonas found in cystic fibrosis patients. PMID:24460375

  7. Artificial extracellular matrix proteins containing phenylalanine analogues biosynthesized in bacteria using T7 expression system and the PEGylation.

    PubMed

    Takasu, Akinori; Kondo, Shiori; Ito, Akihiro; Furukawa, Yuya; Higuchi, Masahiro; Kinoshita, Takatoshi; Kwon, Inchan

    2011-10-10

    In vivo incorporation of phenylalanine (Phe) analogues into an artificial extracellular matrix protein (aECM-CS5-ELF) was accomplished using a bacterial expression host that harbors the mutant phenylalanyl-tRNA synthetase (PheRS) with an enlarged binding pocket. Although the Ala294Gly/Thr251Gly mutant PheRS (PheRS**) under the control of T5 promoter allows incorporation of some Phe analogues into a protein, the T5 system is not suitable for material science studies because the amount of materials produced is not sufficient due to the moderate strength of the T5 promoter. This limitation can be overcome by using a pair of T7 promoter and T7 RNA polymerase instead. In the T7 expression system, it is difficult, however, to achieve a high incorporation level of Phe analogues, due to competition of Phe analogues for incorporation with the residual Phe that is required for synthesis of active T7 RNA polymerase. In this study, we prepared the PheRS** under T7 promoter and optimized culture condition to improve both the incorporation level of recombinant aECM protein and the incorporation level of Phe analogues. Incorporation and expression levels tend to increase in the case of p-azidophenylalanine, p-iodophenylalanine, and p-acetylphenylalanine. We evaluated the lower critical transition temperature, which is dependent on the incorporation ratio and the turbidity decreased when the incorporation level increased. Circular dichromism measurement indicated that this tendency is based on conformational change from random coil to ?-turn structure. We demonstrated that polyethylene glycol (PEG) can be conjugated at reaction site of Phe analogues incorporated. We also demonstrated that the increased hydrophilicity of elastin-like sequences in the aECM-CS5-ELF made by PEG conjugation could suppress nonspecific adhesion of human umbilical vein endothelial cells (HUVEC). PMID:21823658

  8. Analogue modelling of salt diapirism induced by differential loading

    NASA Astrophysics Data System (ADS)

    Warsitzka, Michael; Kley, Jonas; Kukowski, Nina; Jähne, Fabian

    2010-05-01

    In salt tectonics, two general concepts exist to explain salt diapirism. First, the theory of active piercement by Trusheim (1960) states that salt rises up and pierces its overburden autonomously by buoyancy forces. Second, the theory of reactive piercement by Vendeville and Jackson (1992) considers a tectonic stress field responsible for initiation of salt uplift and has been tested in many analogue experiments. In this study, we investigated the hypothesis in which salt diapir formation is activated by sedimentary processes alone, i.e. without a tectonic trigger. Our models consisted of a viscous silicone layer simulating rock salt overlain by layers of sand that mimic brittle behaviour in natural overburden sediments. The experiments were monitored with a high-resolution strain analysis tool based on digital image correlation (particle image velocimetry, PIV). Deformation in the silicone was initiated by a lateral variation in the thickness or density of the overburden, which established a differential loading on the silicone layer. Subsequent sedimentation in certain time intervals forced the silicone to rise up and break through the initial sand layer by buoyancy forces. The model results support the hypothesis of active piercement of diapirs. Uplift of the silicone and creation of a pillow structure with a significant elevation can be achieved if the overburden does not exceed a critical thickness and if the load gradient in the overburden reaches a minimum value. Then, ongoing sedimentation in adjacent areas increases the lateral load gradient until the buoyancy force in the silicone is high enough to overcome the shear strength of the sand. Synkinematic sedimentation produces some typical strata geometries in the sand layer that can also be observed in nature, e.g. drag folds bordering the diapirs and layer thickening in the peripherical rim synclines. The creation of one diapir and its peripherical sinks induces a lateral migration of the deformation to the adjoining areas. This leads to further generation of diapirs in a purely "halokinetic" way. The potential to form these "secondary diapirs" (Parker and McDowell, 1955) basically depends on the thickness of the silicone layer and on the sedimentation rate. The deformation paths and the strains in the experiments can be well observed with the PIV, which offers a new application in the analogue modelling of salt diapirism. Our experiments contribute new insights in the discussion of diapir formation. They show that sedimentary processes can initiate diapirism without any tectonic influence if the salt movement starts early after its deposition. Additionally, the model results provide a validation of the theory of "salt-stock families" in the Northwest German Basin (Sannemann, 1965) in the light of new analogue modelling techniques. References Parker, T.J., McDowell, A.N. (1955): Model studies of salt-dome tectonics, Bulletin of the American Association of Petroleum Geologists, vol. 39, no. 12, p. 2384-2471 Sannemann, D. (1965): Salt-stock families in Northwestern Germany, Bulletin of the American Association of Petroleum Geologists, vol. 49. p. 261-270. Trusheim, F. (1960): Mechanism of salt migration in Northern Germany, Bulletin of the American Association of Petroleum Geologists, vol. 44, no. 9, p. 1519-1540. Vendeville, B.C. and Jackson, M. P. A. (1992): The rise of diapirs during thin-skinned extension, Marine and Petroleum Geology, vol. 9, no. 4, p. 331-353.

  9. An electrical analogue of the entire human circulatory system

    Microsoft Academic Search

    L. de Pater; Jw. van den Berg

    1964-01-01

    To study the human cardiovascular system an electrical analogue has been designed. This analogue consists of two parts: An\\u000a active part, the heart; and a passive part, the vessels. A fourfold pulse generator represents the action of the heart. The\\u000a various parameters such as heart rate, A.V. delay, duration of systole and diastole, contraction speed and contraction force\\u000a can be

  10. Synthesis of new bioisosteric hemiasterlin analogues with extremely high cytotoxicity.

    PubMed

    Dang, Thi Tuyet Anh; Pham, The Chinh; Ngo, Quoc Anh; Vu, Thi Thu Ha; Nguyen, Tien Dung; Doan, Duy Tien; Ba, Thi Cham; Jean, M; van de Weghe, P; Nguyen, Van Tuyen

    2014-11-15

    In this Letter, the synthesis and the evaluation of the cytotoxicity of new hemiasterlin analogues were reported. The indole moiety was replaced respectively by benzofurane, naphthalene and 4-bromobenzene groups. Most of these derivatives possess strong cytotoxic activity on two human tumour cell lines (KB and Hep-G2), and some analogues showed comparable cytotoxic activity to that observed for paclitaxel and ellipticine, against KB and Hep-G2 cancer cell lines. PMID:25442315

  11. Timestamps in key distribution protocols

    Microsoft Academic Search

    Dorothy E. Denning; Giovanni Maria Sacco

    1981-01-01

    The distribution of keys in a computer network using single key or public key encryption is discussed. We consider the possibility that communication keys may be compromised, and show that key distribution protocols with timestamps prevent replays of compromised keys. The timestamps have the additional benefit of replacing a two-step handshake.

  12. Synthesis and biological activity of new conformationally restricted analogues of pepstatin.

    PubMed

    Szewczuk, Z; Rebholz, K L; Rich, D H

    1992-01-01

    A new statine derivative, 3-hydroxy-4-amino-5-mercaptopentanoic acid; cysteinylstatine (CySta), was synthesized and used to prepare a series of conformationally restricted analogues of pepstatin (Iva-Val-Val-Sta-Ala-Sta) in which the conformational constraint was introduced via a bis-sulfide connecting the appropriately substituted residues in the P1 and the P3 inhibitor side chains. The precursor peptide, Iva-Cys-Val-CySta-Ala-Iaa, was synthesized and alkylated with a series of dibromoalkanes and alkenes to produce the cyclic structures. This strategy permitted the carbon atom spacing between the P1 and the P3 inhibitor side chains to be systematically varied so as to produce inhibitors with 15-, 16-, and 17-membered ring systems. Additional non-cyclic analogues were synthesized as controls by alkylating the bisthiol intermediates with methyl iodide. The inhibitory potency of the analogues were determined against porcine pepsin and penicillopepsin by using standard enzyme kinetic assays. The cyclic inhibitor were found to be potent inhibitors of both aspartic proteases; inhibitor that contained a trans-2-butene link between the two sulfur atoms was found to be the most potent inhibitor with a Ki less than 1 nM against pepsin and 3.94 nM against penicillopepsin. This series of compounds illustrates a new type of conformational restriction that can be used to probe for the bioactive conformation of peptides. PMID:1478780

  13. Potent Fluorinated Agelastatin Analogues for Chronic Lymphocytic Leukemia: Design, Synthesis, and Pharmacokinetic Studies

    PubMed Central

    2015-01-01

    Chronic lymphocytic leukemia (CLL) is the most common lymphoid neoplasia in Western societies and is currently incurable. Multiple treatment options are practiced, but the available small molecule drugs suffer from dose-limiting toxicity and undesirable side effects. The need for new, less toxic treatments is a pressing concern. Here, we demonstrate that (?)-agelastatin A (1a), a pyrrole-imidazole alkaloid obtained from a marine sponge, exhibits potent in vitro activity against primary cell lines of CLL and disclose the synthesis of several analogues that are equipotent or exceed the potency of the natural product. The novel synthetic analogue, 13-debromo-13-trifluoromethyl agelastatin A (1j), showed higher activity than the natural product when tested against the same cell lines and is the most potent agelastatin derivative reported to date. A detailed in vitro structure–activity relationship of 1a in CLL compared to that of 22 synthetic analogues is described along with preliminary in vivo pharmacokinetic and metabolism studies on the most potent compounds. PMID:24673739

  14. Potent fluorinated agelastatin analogues for chronic lymphocytic leukemia: design, synthesis, and pharmacokinetic studies.

    PubMed

    Stout, E Paige; Choi, Michael Y; Castro, Januario E; Molinski, Tadeusz F

    2014-06-26

    Chronic lymphocytic leukemia (CLL) is the most common lymphoid neoplasia in Western societies and is currently incurable. Multiple treatment options are practiced, but the available small molecule drugs suffer from dose-limiting toxicity and undesirable side effects. The need for new, less toxic treatments is a pressing concern. Here, we demonstrate that (-)-agelastatin A (1a), a pyrrole-imidazole alkaloid obtained from a marine sponge, exhibits potent in vitro activity against primary cell lines of CLL and disclose the synthesis of several analogues that are equipotent or exceed the potency of the natural product. The novel synthetic analogue, 13-debromo-13-trifluoromethyl agelastatin A (1j), showed higher activity than the natural product when tested against the same cell lines and is the most potent agelastatin derivative reported to date. A detailed in vitro structure-activity relationship of 1a in CLL compared to that of 22 synthetic analogues is described along with preliminary in vivo pharmacokinetic and metabolism studies on the most potent compounds. PMID:24673739

  15. Immunoactivity of protein conjugates of carba analogues from Neisseria meningitidis a capsular polysaccharide.

    PubMed

    Gao, Qi; Tontini, Marta; Brogioni, Giulia; Nilo, Alberto; Filippini, Sara; Harfouche, Carole; Polito, Laura; Romano, Maria R; Costantino, Paolo; Berti, Francesco; Adamo, Roberto; Lay, Luigi

    2013-11-15

    Neisseria meningitidis type A (MenA) is a Gram-negative encapsulated bacterium that is a major cause of epidemic meningitis, especially in the sub-Saharan region of Africa. The development and manufacture of a liquid glycoconjugate vaccine against MenA are hampered by the poor hydrolytic stability of its capsular polysaccharide (CPS), consisting of (1?6)-linked 2-acetamido-2-deoxy-?-d-mannopyranosyl phosphate repeating units. The replacement of the ring oxygen with a methylene group to generate a carbocyclic analogue leads to enhancement of its chemical stability. Herein, we report conjugation of carbocyclic analogue monomer, dimer, and trimer to the protein carrier CRM197. After immunization in mice, only the conjugated trimer was able to induce specific anti-MenA polysaccharide IgG antibodies with in vitro bactericidal activity, although to a lesser extent than pentadecamer and hexamer oligomers obtained from mild acid hydrolysis of the native polysaccharide conjugated to the same protein carrier. This study represents the first proof-of-concept that hydrolytically stable structural analogues of saccharide antigens can be used for the development of efficacious antimicrobial preventative therapies. Conjugates with longer carbocyclic oligomers and/or precise acetylation patterns could further increase the induced immune response to a level comparable with those of commercially available anti-meningococcal glycoconjugate vaccines. PMID:24000773

  16. Membrane-Targeting DCAP Analogues with Broad-Spectrum Antibiotic Activity against Pathogenic Bacteria.

    PubMed

    Hurley, Katherine A; Heinrich, Victoria A; Hershfield, Jeremy R; Demons, Samandra T; Weibel, Douglas B

    2015-04-01

    We performed a structure-activity relationship study of 2-((3-(3,6-dichloro-9H-carbazol-9-yl)-2-hydroxypropyl)amino)-2-(hydroxymethyl)propane-1,3-diol (DCAP), which is an antibacterial agent that disrupts the membrane potential and permeability of bacteria. The stereochemistry of DCAP had no effect on the biological activity of DCAP. The aromaticity and electronegativity of the chlorine-substituted carbazole was required for activity, suggesting that its planar and dipolar characteristics orient DCAP in membranes. Increasing the hydrophobicity of the tail region of DCAP enhanced its antibiotic activity. Two DCAP analogues displayed promising antibacterial activity against the BSL-3 pathogens Bacillus anthracis and Francisella tularensis. Codosing DCAP analogues with ampicillin or kanamycin increased their potency. These studies demonstrate that DCAP and its analogues may be a promising scaffold for developing chemotherapeutic agents that bind to bacterial membranes and kill strains of slow-growing or dormant bacteria that cause persistent infections. PMID:25941556

  17. Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature.

    PubMed

    Anand, Preetha; Thomas, Sherin G; Kunnumakkara, Ajaikumar B; Sundaram, Chitra; Harikumar, Kuzhuvelil B; Sung, Bokyung; Tharakan, Sheeja T; Misra, Krishna; Priyadarsini, Indira K; Rajasekharan, Kallikat N; Aggarwal, Bharat B

    2008-12-01

    Curcumin, a yellow pigment present in the Indian spice turmeric (associated with curry powder), has been linked with suppression of inflammation; angiogenesis; tumorigenesis; diabetes; diseases of the cardiovascular, pulmonary, and neurological systems, of skin, and of liver; loss of bone and muscle; depression; chronic fatigue; and neuropathic pain. The utility of curcumin is limited by its color, lack of water solubility, and relatively low in vivo bioavailability. Because of the multiple therapeutic activities attributed to curcumin, however, there is an intense search for a "super curcumin" without these problems. Multiple approaches are being sought to overcome these limitations. These include discovery of natural curcumin analogues from turmeric; discovery of natural curcumin analogues made by Mother Nature; synthesis of "man-made" curcumin analogues; reformulation of curcumin with various oils and with inhibitors of metabolism (e.g., piperine); development of liposomal and nanoparticle formulations of curcumin; conjugation of curcumin prodrugs; and linking curcumin with polyethylene glycol. Curcumin is a homodimer of feruloylmethane containing a methoxy group and a hydroxyl group, a heptadiene with two Michael acceptors, and an alpha,beta-diketone. Structural homologues involving modification of all these groups are being considered. This review focuses on the status of all these approaches in generating a "super curcumin.". PMID:18775680

  18. The role of new basal insulin analogues in the initiation and optimisation of insulin therapy in type 2 diabetes.

    PubMed

    Baxter, Mike A

    2008-12-01

    Intensive insulin therapy aimed at achieving normoglycaemia is becoming increasingly accepted in the treatment of type 2 diabetes (T2DM) to reduce the risk of diabetes-related complications. Insulin therapy is increasingly combined with oral antidiabetic drugs (OADs) to moderate insulin dosage, reduce weight gain and confer cardiovascular protection. However, traditional insulins are associated with limitations that may act as barriers to initiation, and intensive use of insulin therapy. The advent of newer, longer-acting, basal insulin analogues, such as insulin glargine (glargine) and insulin detemir (detemir), offer improved pharmacokinetic and pharmacodynamic profiles compared with neutral protamine Hagedorn insulin (NPH). This potentially provides concomitant improvements in safety, efficacy and variability of glycaemic control. This paper reviews the properties of these new long-acting, basal insulin analogues and their potential roles in facilitating the initiation and optimisation of insulin therapy. Studies that reported the use of insulin and insulin analogues for the treatment of T2DM were identified using Medline. Key search terms included: 'insulin glargine', 'insulin detemir', 'NPH insulin', 'basal insulin', 'long-acting insulin', 'insulin analogue', 'pharmacokinetics', 'pharmacodynamics', 'dose titration', 'algorithms' and 'type 2 diabetes'. Abstracts presented at the American Diabetes Association and the European Association for the Study of Diabetes annual congresses were also searched. The data show that the long-acting insulin analogues glargine and detemir both offer a low risk of hypoglycaemia and improved glycaemic control. Aggressive dose titration with glargine and detemir facilitates attainment of glycaemic control targets. The goal of achieving good glycaemic control with a low risk of hypoglycaemia may be more feasible with newer insulin therapies as part of a simple basal insulin regimen with continued OADs. PMID:18766296

  19. The FHA domain determines Drosophila Chk2/Mnk localization to key mitotic structures and is essential for early embryonic DNA damage responses.

    PubMed

    Takada, Saeko; Collins, Eric R; Kurahashi, Kayo

    2015-05-15

    DNA damage responses, including mitotic centrosome inactivation, cell-cycle delay in mitosis, and nuclear dropping from embryo cortex, maintain genome integrity in syncytial Drosophila embryos. A conserved signaling kinase, Chk2, known as Mnk/Loki, is essential for the responses. Here we demonstrate that functional EGFP-Mnk expressed from a transgene localizes to the nucleus, centrosomes, interkinetochore/centromere region, midbody, and pseudocleavage furrows without DNA damage and in addition forms numerous foci/aggregates on mitotic chromosomes upon DNA damage. We expressed EGFP-tagged Mnk deletion or point mutation variants and investigated domain functions of Mnk in vivo. A triple mutation in the phosphopeptide-binding site of the forkhead-associated (FHA) domain disrupted normal Mnk localization except to the nucleus. The mutation also disrupted Mnk foci formation on chromosomes upon DNA damage. FHA mutations and deletion of the SQ/TQ-cluster domain (SCD) abolished Mnk transphosphorylations and autophosphorylations, indicative of kinase activation after DNA damage. A potent NLS was found at the C-terminus, which is required for normal Mnk function. We propose that the FHA domain in Mnk plays essential dual functions in mediating embryonic DNA damage responses by means of its phosphopeptide-binding ability: activating Mnk in the nucleus upon DNA damage and recruiting Mnk to multiple subcellular structures independently of DNA damage. PMID:25808488

  20. Analogue modeling of dike intrusions: insight into rift formation and evolution

    NASA Astrophysics Data System (ADS)

    Trippanera, Daniele; Ruch, Joel; Acocella, Valerio; Giordano, Andrea; Rivalta, Eleonora

    2014-05-01

    Recent data have demonstrated that magma emplacement may play a major role in reactivating pre-existing faults during discrete rifting episodes. However, the role played by magma in shaping the geometry of rifts structures, such as normal faults and extension fractures, and how they evolve in time remains still debated. We address these questions by means of analogue models of dike intrusions. Our setup consists of a sandbox with a basal slot progressively filled with iron sheets (the dikes analogue). We simulate the upper brittle crust with dry crushed silica sand. Using this material, 1 cm in the models corresponds to approximately 200 m in nature. In particular, we tested the effect of varying the depth to the intrusions (1-8 cm) and the geometry of the top of the intrusion complex (sharp or flat top). The vertical and horizontal deformation at the surface have been monitored by cameras and laser scan, with sub-millimeter resolution. These tools allow us to use the Time Series and Particle Image Velocimetry (PIV) technique to quantify and reconstruct the time evolution of rift development. In addition, the cross sections of each model reveal the geometry, kinematics and temporal evolution of the structures forming the rift. Our results show that a depression forms at the surface upon intrusion of several dikes. The depression is bordered by outer inward normal faults and, in the case of deeper intrusions with flat top, also by inner arcuate normal/reverse faults. Therefore, we find the shape and the kinematics of the faults and the deformation pattern at surface depend on the dike tip geometry and intrusion depth. We compared the structures observed in the analogue models with examples from natural cases observed along divergent plate boundaries (including Iceland and Ethiopia) and episodes of dike intrusions as revealed by geodetic data. We find a close similarity between the models and their natural prototypes and most of the variability of the rift structures observed in the field can be reconciled with analogue intrusion-induced structures in our models. This suggests that rift structure and evolution along divergent plate boundaries may be largely magma-induced.

  1. Alanine analogues of [D-Trp]CJ-15,208: novel opioid activity profiles and prevention of drug- and stress-induced reinstatement of cocaine-seeking behaviour

    PubMed Central

    Aldrich, J V; Senadheera, S N; Ross, N C; Reilley, K A; Ganno, M L; Eans, S E; Murray, T F; McLaughlin, J P

    2014-01-01

    BACKGROUND AND PURPOSE The novel macrocyclic peptide cyclo[Phe-D-Pro-Phe-D-Trp] ([D-Trp]CJ-15,208) exhibits ? opioid (KOP) receptor antagonist activity in both in vitro and in vivo assays. The four alanine analogues of this peptide were synthesized and characterized both in vitro and in vivo to assess the contribution of different amino acid residues to the activity of [D-Trp]CJ-15,208. EXPERIMENTAL APPROACH The peptides were synthesized by a combination of solid phase peptide synthesis and cyclization in solution. The analogues were evaluated in vitro in receptor binding and functional assays, and in vivo with mice using a tail-withdrawal assay for antinociceptive and opioid antagonist activity. Mice demonstrating extinction of cocaine conditioned-place preference (CPP) were pretreated with selected analogues to evaluate prevention of stress or cocaine-induced reinstatement of CPP. KEY RESULTS The alanine analogues displayed pharmacological profiles in vivo distinctly different from [D-Trp]CJ-15,208. While the analogues exhibited varying opioid receptor affinities and ? and ? opioid receptor antagonist activity in vitro, they produced potent opioid receptor-mediated antinociception (ED50 = 0.28–4.19 nmol, i.c.v.) in vivo. Three of the analogues also displayed KOP receptor antagonist activity in vivo. Pretreatment with an analogue exhibiting both KOP receptor agonist and antagonist activity in vivo prevented both cocaine- and stress-induced reinstatement of cocaine-seeking behaviour in the CPP assay in a time-dependent manner. CONCLUSIONS AND IMPLICATIONS These unusual macrocyclic peptides exhibit in vivo opioid activity profiles different from the parent compound and represent novel compounds for potential development as therapeutics for drug abuse and possibly as analgesics. PMID:24588614

  2. Studies on two types of PTP1B inhibitors for the treatment of type 2 diabetes: Hologram QSAR for OBA and BBB analogues.

    PubMed

    Cheng, Yuanhua; Zhou, Mei; Tung, Chen-Ho; Ji, Mingjuan; Zhang, Fushi

    2010-06-01

    Hologram quantitative structure-activity relationships (HQSAR) analysis were conducted on two series of PTP1B inhibitors, 39 2-(oxalylamino) benzoic acid (OBA) analogues and 60 benzofuran and benzothiophene biphenyls (BBB) analogues. The optimal HQSAR model of the OBA analogue has q(2)=0.592 and r(2)=0.940, while the optimal HQSAR model for the BBB analogues shows q(2)=0.667 and r(2)=0.863. Two models were employed to predict the biological activities of two test sets. For OBA analogues, the optimal model was validated by an external test set of six compounds with satisfactory predictive r(2) value of 0.786. For BBB analogues, the optimal model shows satisfactory predictive r(2) value of 0.866 for an external test set of 10 compounds. The contribution maps derived from the optimal HQSAR models are consistent with the biological activities of the studied compounds. Two virtual combinatorial libraries were designed and screened by the optimal HQSAR models and potential candidates with high predictive biological activities were discovered. This work may provide valuable information for future design of more promising inhibitors for PTP1B. PMID:20452766

  3. Computational chemical analysis of [FeFe] hydrogenase H-cluster analogues to discern catalytically relevant features of the natural diatomic ligand configuration.

    PubMed

    Chang, Christopher H

    2011-08-11

    Density functional theoretical models of the electronic structure of several configurational isomers and analogues of the [2Fe](H) H-cluster in [FeFe] hydrogenase were analyzed to identify distinguishing features of the canonical cofactor structure potentially relevant to catalysis. Collective analysis of geometric changes over models of oxidized and reduced [2Fe] clusters highlighted movement of the bridging carbonyl and anticorrelation of the proximal and distal Fe-C(terminal) bonds as key explanatory factors for variance over the considered models. Charge and bond order analysis suggest that as the bridging carbonyl favors the distal iron upon reduction, bonding simultaneously becomes more ionic in nature, raising the possibility of simple electrostatic stabilization as a factor in charge accumulation prior to ultimate H(2) creation and release. Frontier orbital energies show cis and trans arrangements of cyanide on the Fe-Fe core to have distinctive energies from the other models, which may be important for redox poise. Altogether, few factors qualitatively distinguish the cis- from the trans-cyano configurations, which may in fact enhance catalytic robustness under conditions leading to exchange of the bridging and terminal carbonyl ligands. However, the naturally occurring trans configuration possesses two distinct donor-metal-acceptor S-Fe-C(O) interactions, which might play a role in enforcing a low-spin ground state for the hydridic mechanism of H(2) production. PMID:21682274

  4. Mediated semiquantum key distribution

    NASA Astrophysics Data System (ADS)

    Krawec, Walter O.

    2015-03-01

    In this work, we design a quantum key distribution protocol, allowing two limited semiquantum or "classical" users to establish a shared secret key with the help of a fully quantum server. A semiquantum user can prepare and measure qubits only in the computational basis and so must rely on this quantum server to produce qubits in alternative bases and also to perform alternative measurements. However, we assume that the server is untrusted and we prove the unconditional security of our protocol even in the worst case: when this quantum server is an all-powerful adversary. We also compute a lower bound of the key rate of our protocol, in the asymptotic scenario, as a function of the observed error rate in the channel, allowing us to compute the maximally tolerated error of our protocol. Our results show that a semiquantum protocol may hold similar security to a fully quantum one.

  5. Conformational restriction of the phenylalanine residue in a cyclic opioid peptide analogue: effects on receptor selectivity and stereospecificity.

    PubMed

    Schiller, P W; Weltrowska, G; Nguyen, T M; Lemieux, C; Chung, N N; Marsden, B J; Wilkes, B C

    1991-10-01

    In an effort to determine the effect of side chain conformational restriction on opioid receptor selectivity, the cyclic phenylalanine analogues 2-aminoindan-2-carboxylic acid (Aic), 2-aminotetralin-2-carboxylic acid (Atc), and tetrahydroisoquinoline-3-carboxylic acid (Tic) were substituted for Phe in the potent cyclic opioid peptide analogue H-Tyr-D-Orn-Phe-Glu-NH2, which lacks significant opioid receptor selectivity. Compounds were tested in mu- and delta-opioid receptor representative binding assays and bioassays in vitro. The analogue H-Tyr-D-Orn-Aic-Glu-NH2 was found to be a potent agonist with high preference of mu receptors over delta receptors. Opening of the five-membered ring of Aic in the latter peptide, as achieved through substitution of C alpha-methylphenylalanine or o-methylphenylalanine, resulted in only slightly selective compounds, indicating that the high mu selectivity of the Aic analogue is exclusively the consequence of the imposed side chain conformational restriction. Both diastereoisomers of H-Tyr-D-Orn-(D,L)-Atc-Glu-NH2 were highly mu-selective and, in contrast to the weak affinity observed with the D-Phe3 analogue as compared to the L-Phe3 analogue, both had similar potency. Thus, stereospecificity was lost as a consequence of side chain conformational restriction. Further structure-activity data obtained with analogues containing L- or D-homophenylalanine (Hfe) or 3-(1'-naphthyl)alanine (Nap) in place of Phe3 and consideration of geometric interrelationships between Nap and the L and D isomers of Atc, Hfe, and Phe led to the proposal that the D-Phe3 and the D-Atc3 analogue may have different modes of binding to the receptor. The very low potency observed with H-Tyr-D-Orn-N alpha MePhe-Glu-NH2 (N alpha MePhe = N alpha-methylphenylalanine) and H-Tyr-D-Orn-Tic-Glu-NH2 indicated that N alpha-alkylation at the 3-position is detrimental to activity. PMID:1656045

  6. Myosin Binding Protein C Positioned to Play a Key Role in Regulation of Muscle Contraction: Structure and Interactions of Domain C1

    PubMed Central

    Ababou, Abdessamad; Rostkova, Elena; Mistry, Shreena; Masurier, Clare Le; Gautel, Mathias; Pfuhl, Mark

    2008-01-01

    Myosin binding protein C (MyBP-C) is a thick filament protein involved in the regulation of muscle contraction. Mutations in the gene for MyBP-C are the second most frequent cause of hypertrophic cardiomyopathy. MyBP-C binds to myosin with two binding sites, one at its C-terminus and another at its N-terminus. The N-terminal binding site, consisting of immunoglobulin domains C1 and C2 connected by a flexible linker, interacts with the S2 segment of myosin in a phosphorylation-regulated manner. It is assumed that the function of MyBP-C is to act as a tether that fixes the S1 heads in a resting position and that phosphorylation releases the S1 heads into an active state. Here, we report the structure and binding properties of domain C1. Using a combination of site-directed mutagenesis and NMR interaction experiments, we identified the binding site of domain C1 in the immediate vicinity of the S1–S2 hinge, very close to the light chains. In addition, we identified a zinc binding site on domain C1 in close proximity to the S2 binding site. Its zinc binding affinity (Kd of approximately 10–20 ?M) might not be sufficient for a physiological effect. However, the familial hypertrophic cardiomyopathy-related mutation of one of the zinc ligands, glutamine 210 to histidine, will significantly increase the binding affinity, suggesting that this mutation may affect S2 binding. The close proximity of the C1 binding site to the hinge, the light chains and the S1 heads also provides an explanation for recent observations that (a) shorter fragments of MyBP-C unable to act as a tether still have an effect on the actomyosin ATPase and (b) as to why the myosin head positions in phosphorylated wild-type mice and MyBP-C knockout mice are so different: Domain C1 bound to the S1–S2 hinge is able to manipulate S1 head positions, thus influencing force generation without tether. The potentially extensive extra interactions of C1 are expected to keep it in place, while phosphorylation dislodges the C1–C2 linker and domain C2. As a result, the myosin heads would always be attached to a tether that has phosphorylation-dependent length regulation. PMID:18926831

  7. Myosin binding protein C positioned to play a key role in regulation of muscle contraction: structure and interactions of domain C1.

    PubMed

    Ababou, Abdessamad; Rostkova, Elena; Mistry, Shreena; Le Masurier, Clare; Gautel, Mathias; Pfuhl, Mark

    2008-12-19

    Myosin binding protein C (MyBP-C) is a thick filament protein involved in the regulation of muscle contraction. Mutations in the gene for MyBP-C are the second most frequent cause of hypertrophic cardiomyopathy. MyBP-C binds to myosin with two binding sites, one at its C-terminus and another at its N-terminus. The N-terminal binding site, consisting of immunoglobulin domains C1 and C2 connected by a flexible linker, interacts with the S2 segment of myosin in a phosphorylation-regulated manner. It is assumed that the function of MyBP-C is to act as a tether that fixes the S1 heads in a resting position and that phosphorylation releases the S1 heads into an active state. Here, we report the structure and binding properties of domain C1. Using a combination of site-directed mutagenesis and NMR interaction experiments, we identified the binding site of domain C1 in the immediate vicinity of the S1-S2 hinge, very close to the light chains. In addition, we identified a zinc binding site on domain C1 in close proximity to the S2 binding site. Its zinc binding affinity (K(d) of approximately 10-20 microM) might not be sufficient for a physiological effect. However, the familial hypertrophic cardiomyopathy-related mutation of one of the zinc ligands, glutamine 210 to histidine, will significantly increase the binding affinity, suggesting that this mutation may affect S2 binding. The close proximity of the C1 binding site to the hinge, the light chains and the S1 heads also provides an explanation for recent observations that (a) shorter fragments of MyBP-C unable to act as a tether still have an effect on the actomyosin ATPase and (b) as to why the myosin head positions in phosphorylated wild-type mice and MyBP-C knockout mice are so different: Domain C1 bound to the S1-S2 hinge is able to manipulate S1 head positions, thus influencing force generation without tether. The potentially extensive extra interactions of C1 are expected to keep it in place, while phosphorylation dislodges the C1-C2 linker and domain C2. As a result, the myosin heads would always be attached to a tether that has phosphorylation-dependent length regulation. PMID:18926831

  8. Structures and functions of insect arylalkylamine N-acetyltransferase (iaaNAT); a key enzyme for physiological and behavioral switch in arthropods

    PubMed Central

    Hiragaki, Susumu; Suzuki, Takeshi; Mohamed, Ahmed A. M.; Takeda, Makio

    2015-01-01

    The evolution of N-acetyltransfeases (NATs) seems complex. Vertebrate arylalkylamine N-acetyltransferase (aaNAT) has been extensively studied since it leads to the synthesis of melatonin, a multifunctional neurohormone prevalent in photoreceptor cells, and is known as a chemical token of the night. Melatonin also serves as a scavenger for reactive oxygen species. This is also true with invertebrates. NAT therefore has distinct functional implications in circadian function, as timezymes (aaNAT), and also xenobiotic reactions (arylamine NAT or simply NAT). NATs belong to a broader enzyme group, the GCN5-related N-acetyltransferase superfamily. Due to low sequence homology and a seemingly fast rate of structural differentiation, the nomenclature for NATs can be confusing. The advent of bioinformatics, however, has helped to classify this group of enzymes; vertebrates have two distinct subgroups, the timezyme type and the xenobiotic type, which has a wider substrate range including imidazolamine, pharmacological drugs, environmental toxicants and even histone. Insect aaNAT (iaaNAT) form their own clade in the phylogeny, distinct from vertebrate aaNATs. Arthropods are unique, since the phylum has exoskeleton in which quinones derived from N-acetylated monoamines function in coupling chitin and arthropodins. Monoamine oxidase (MAO) activity is limited in insects, but NAT-mediated degradation prevails. However, unexpectedly iaaNAT occurs not only among arthropods but also among basal deuterostomia, and is therefore more apomorphic. Our analyses illustrate that iaaNATs has unique physiological roles but at the same time it plays a role in a timezyme function, at least in photoperiodism. Photoperiodism has been considered as a function of circadian system but the detailed molecular mechanism is not well understood. We propose a molecular hypothesis for photoperiodism in Antheraea pernyi based on the transcription regulation of NAT interlocked by the circadian system. Therefore, the enzyme plays both unique and universal roles in insects. The unique role of iaaNATs in physiological regulation urges the targeting of this system for integrated pest management (IPM). We indeed showed a successful example of chemical compound screening with reconstituted enzyme and further attempts seem promising. PMID:25918505

  9. Design of potent substrate-analogue inhibitors of canine renin.

    PubMed

    Hui, K Y; Siragy, H M; Haber, E

    1992-08-01

    Through a systematic study of structure-activity relationships, we designed potent renin inhibitors for use in dog models. In assays against dog plasma renin at neutral pH, we found that, as in previous studies of rat renin inhibitors, the structure at the P2 position appears to be important for potency. The substitution of Val for His at this position increases potency by one order of magnitude. At the P3 position, potency appears to depend on a hydrophobic side chain that does not necessarily have to be aromatic. Our results also support the approach of optimizing potency in a renin inhibitor by introducing a moiety that promotes aqueous solubility (an amino group) at the C-terminus of the substrate analogue. In the design of potent dog plasma renin inhibitors, the influence of the transition-state residue 4(S)-amino-3(S)-hydroxy-5-cyclohexylpentanoic acid (ACHPA)-commonly used as a substitute for the scissile-bond dipeptide to boost potency-is not obvious, and appears to be sequence dependent. The canine renin inhibitor Ac-paF-Pro-Phe-Val-statine-Leu-Phe-paF-NH2 (compound 15; IC50 of 1.7 nM against dog plasma renin at pH 7.4; statine, 4(S)-amino-3(S)-hydroxy-6-methylheptanoic acid; paF, para-aminophenylalanine) had a potent hypotensive effect when infused intravenously into conscious, sodium-depleted, normotensive dogs. Also, compound 15 concurrently inhibited plasma renin activity and had a profound diuretic effect. PMID:1446972

  10. Key Drivers for the Nano FieldKey Drivers for the Nano Field Imaging is a key enabling technology for the nano field

    E-print Network

    Key Drivers for the Nano FieldKey Drivers for the Nano Field · Imaging is a key enabling technology for the nano field: ­ Transmission electron microscope (TEM) 1931 ­ Scanning electron microscope (SEM) 1981 of matter Laboratory for Intelligent Structural Technology University of Michigan Slide #31 8

  11. Analogue experiments as benchmarks for models of lava flow emplacement

    NASA Astrophysics Data System (ADS)

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

    2013-12-01

    During an effusive volcanic eruption, the crisis management is mainly based on the prediction of lava flow advance and its velocity. The spreading of a lava flow, seen as a gravity current, depends on its "effective rheology" and on the effusion rate. Fast-computing models have arisen in the past decade in order to predict in near real time lava flow path and rate of advance. This type of model, crucial to mitigate volcanic hazards and organize potential evacuation, has been mainly compared a posteriori to real cases of emplaced lava flows. The input parameters of such simulations applied to natural eruptions, especially effusion rate and topography, are often not known precisely, and are difficult to evaluate after the eruption. It is therefore not straightforward to identify the causes of discrepancies between model outputs and observed lava emplacement, whereas the comparison of models with controlled laboratory experiments appears easier. The challenge for numerical simulations of lava flow emplacement is to model the simultaneous advance and thermal structure of viscous lava flows. To provide original constraints later to be used in benchmark numerical simulations, we have performed lab-scale experiments investigating the cooling of isoviscous gravity currents. The simplest experimental set-up is as follows: silicone oil, whose viscosity, around 5 Pa.s, varies less than a factor of 2 in the temperature range studied, is injected from a point source onto a horizontal plate and spreads axisymmetrically. The oil is injected hot, and progressively cools down to ambient temperature away from the source. Once the flow is developed, it presents a stationary radial thermal structure whose characteristics depend on the input flow rate. In addition to the experimental observations, we have developed in Garel et al., JGR, 2012 a theoretical model confirming the relationship between supply rate, flow advance and stationary surface thermal structure. We also provide experimental observations of the effect of wind the surface thermal structure of a viscous flow, that could be used to benchmark a thermal heat loss model. We will also briefly present more complex analogue experiments using wax material. These experiments present discontinuous advance behavior, and a dual surface thermal structure with low (solidified) vs. high (hot liquid exposed at the surface) surface temperatures regions. Emplacement models should tend to reproduce these two features, also observed on lava flows, to better predict the hazard of lava inundation.

  12. Lava Flow Interactions with Topographic Obstacles: Morphologic Analysis, Analogue Modeling, and Molten Basalt Experiments

    NASA Astrophysics Data System (ADS)

    Dietterich, H. R.; Cashman, K. V.; Rust, A.; Lev, E.; Dietrich, J. T.

    2014-12-01

    Underlying topography controls lava flow emplacement by influencing flow paths, lengths, and advance rates. The morphology of the pre-eruptive surface provides input into lava flow models and the design of artificial diversion barriers, although the dynamics of interactions between topographic obstacles and lava flows are not well known. We investigate these factors by combining morphologic analysis of Hawaiian lava flows with scaling derived from analogue and molten basalt experiments. A comparison of pre- and post-eruptive topographic data shows that flows thicken on the upslope side of topographic barriers, a feature that has been employed to calculate flow velocities from simple energy conversion. Observations also document effects of flow branching and confinement on flow advance rate, with confined flows in Hawai'i traveling further and faster than those that branch. To explain these observations we perform laboratory experiments using Newtonian and Bingham analogue fluids, as well as molten basalt. Conditions of flow splitting and subsequent advance are defined using experiments with both V-shaped and cylindrical obstacles that divide an unconfined flow. Oblique linear obstacles are used to explore flow confinement and diversion. We find that the degree of thickening, which determines the height of an obstacle capable of holding back the flow, is controlled by both initial flow velocity and obstacle geometry. Key is the ability of the flow to pass around the obstacle, such that larger and wider obstacles cause greater thickening than smaller and narrower obstacles. Flow advance rate is largely unaffected by branching in the Newtonian analogue experiments, but decreases after splitting in the molten basalt experiments because of surface cooling. Interestingly, flows into oblique obstacles are diverted but travel faster. Together these data provide the basis for a theoretical description of the interaction dynamics of viscous (and cooling) lava flows with topographic obstacles. These results allow quantification of the effects of flow branching and diversion on subsequent flow advance, which is essential for both predicting and mitigating the effects of future lava flows.

  13. Copyright Some Key Questions

    E-print Network

    Ollivier-Gooch, Carl

    #12;#12;Copyright Matters! Some Key Questions and Answers for Teachers 2nd Edition, 2005 From the Authors The authors of Copyright Matters! are pleased to offer teachers this revised edition. It replaces the first edition published in 2000. Many changes have occurred in the area of copyright since that original

  14. Kidnapped in Key West

    NSDL National Science Digital Library

    Kerri Caudill

    2012-07-09

    This lesson is focused on the text Kidnapped in Key West. It integrates Florida history into this historical fiction piece that is rich with complex characters, events and mystery that will captivate every reader. The opportunities for in-depth inquiry both through conversation and writing are limitless. Through writing the students will develop and enhance their writing and language skills.

  15. Cryptographic Key Management System

    SciTech Connect

    No, author

    2014-02-21

    This report summarizes the outcome of U.S. Department of Energy (DOE) contract DE-OE0000543, requesting the design of a Cryptographic Key Management System (CKMS) for the secure management of cryptographic keys for the energy sector infrastructure. Prime contractor Sypris Electronics, in collaboration with Oak Ridge National Laboratories (ORNL), Electric Power Research Institute (EPRI), Valicore Technologies, and Purdue University's Center for Education and Research in Information Assurance and Security (CERIAS) and Smart Meter Integration Laboratory (SMIL), has designed, developed and evaluated the CKMS solution. We provide an overview of the project in Section 3, review the core contributions of all contractors in Section 4, and discuss bene#12;ts to the DOE in Section 5. In Section 6 we describe the technical construction of the CKMS solution, and review its key contributions in Section 6.9. Section 7 describes the evaluation and demonstration of the CKMS solution in different environments. We summarize the key project objectives in Section 8, list publications resulting from the project in Section 9, and conclude with a discussion on commercialization in Section 10 and future work in Section 11.

  16. Selecting Cryptographic Key Sizes

    Microsoft Academic Search

    Arjen K. Lenstra; Eric R. Verheul

    2001-01-01

    In this article we offer guidelines for the determination of key sizes forsymmetric cryptosystems, RSA, and discrete logarithm based cryptosystems bothover finite fields and over groups of elliptic curves over prime fields. Ourrecommendations are based on a set of explicitly formulated hypotheses, combinedwith existing data points about the cryptosystems.

  17. Multipartite secret key distillation and bound entanglement

    SciTech Connect

    Augusiak, Remigiusz; Horodecki, Pawel [Faculty of Applied Physics and Mathematics, Gdansk University of Technology, Narutowicza 11/12, 80-952 Gdansk (Poland) and ICFO-Institute Ciencies Fotoniques, Mediterranean Technology Park, 08860 Castelldefels (Barcelona) (Spain); Faculty of Applied Physics and Mathematics, Gdansk University of Technology, Narutowicza 11/12, 80-952 Gdansk (Poland)

    2009-10-15

    Recently it has been shown that quantum cryptography beyond pure entanglement distillation is possible and a paradigm for the associated protocols has been established. Here we systematically generalize the whole paradigm to the multipartite scenario. We provide constructions of new classes of multipartite bound entangled states, i.e., those with underlying twisted Greenberger-Horne-Zeilinger (GHZ) structure and nonzero distillable cryptographic key. We quantitatively estimate the key from below with the help of the privacy squeezing technique.

  18. Investigations into specificity of azepinomycin for inhibition of guanase: Discrimination between the natural heterocyclic inhibitor and its synthetic nucleoside analogues

    PubMed Central

    Chakraborty, Saibal; Shah, Niti H.; Fishbein, James C.; Hosmane, Ramachandra S.

    2012-01-01

    In our long and broad program to explore structure-activity relationships of the natural product azepinomycin and its analogues for inhibition of guanase, an important enzyme of purine salvage pathway of nucleic acid metabolism, it became necessary to investigate if the nucleoside analogues of the heterocycle azepinomycin, which are likely to be formed in vivo, would be more or less potent than the parent heterocycle. To this end, we have resynthesized both azepinomycin (1) and its two diastereomeric nucleoside analogues (2 and 3), employing a modified, more efficient procedure, and have biochemically screened all three compounds against a mammalian guanase. Our results indicate that the natural product is at least 200 times more potent toward inhibition of guanase as compared with its nucleoside analogues, with the observed Ki of azepinomycin (1) against the rabbit liver guanase = 2.5 (± 0.6) × 10?6 M, while Ki of Compound 2 =1.19 (± 0.02) × 10?4 M and that of Compound 3 = 1.29 (± 0.03) × 10?4 M. It is also to be noted that while IC50 value of azepinomycin against guanase in cell culture has long been reported, no inhibition studies nor Ki against a pure mammalian enzyme have ever been documented. In addition, we have, for the first time, determined the absolute stereochemistry of the 6-OH group of 2 and 3 using conformational analysis coupled with 2-D 1H NMR NOESY PMID:23084905

  19. Synthesis and antibacterial activities of cadiolides A, B and C and analogues.

    PubMed

    Boulangé, Agathe; Parraga, Javier; Galán, Abraham; Cabedo, Nuria; Leleu, Stéphane; Sanz, Maria Jesus; Cortes, Diego; Franck, Xavier

    2015-07-01

    The one-pot multicomponent synthesis of natural butenolides named cadiolides A, B, C and analogues has been realized. The antibacterial structure activity relationship shows that the presence of phenolic hydroxyl groups and the number and position of bromine atoms on the different aromatic rings are important features for antibacterial activity, besides it was demonstrated the tolerance of both benzene and furan ring at position 3 of the butenolide nucleus. Furthermore, none of the most relevant antibacterial compounds showed any cytotoxicity in freshly isolated human neutrophils. PMID:25913865

  20. Biological armors under impact--effect of keratin coating, and synthetic bio-inspired analogues.

    PubMed

    Achrai, B; Bar-On, B; Wagner, H D

    2015-01-01

    A number of biological armors, such as turtle shells, consist of a strong exoskeleton covered with a thin keratin coating. The mechanical role upon impact of this keratin coating has surprisingly not been investigated thus far. Low-velocity impact tests on the turtle shell reveal a unique toughening phenomenon attributed to the thin covering keratin layer, the presence of which noticeably improves the fracture energy and shell integrity. Synthetic substrate/coating analogues were subsequently prepared and exhibit an impact behavior similar to the biological ones. The results of the present study may improve our understanding, and even future designs, of impact-tolerant structures. PMID:25599251