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Potential Inhibitors (potential + inhibitor)
Selected AbstractsA Multimeric Quinacrine Conjugate as a Potential Inhibitor of Alzheimer's ,-Amyloid Fibril FormationCHEMBIOCHEM, Issue 6 2008Gunnar T. Dolphin Abstract Amyloid formation and accumulation of the amyloid ,-peptide (A,) in the brain is associated with Alzheimer's disease (AD) pathogenesis. Therefore, among the therapeutic approaches in development to fight the disease, the direct inhibition of the A, self-assembly process is currently widely investigated and is one of the most promising approaches. In this study we investigated the potential of a multimeric display of quinacrine derivatives, as compared to the monomer quinacrine, as a design principal for a novel class of inhibitors against A, fibril formation. The presented multimeric conjugate exhibits a cluster of four quinacrine derivatives on a rigid cyclopeptidic scaffold. Herein is reported the synthesis of the conjugate, together with the in vitro inhibitory evaluation of A,1,40 fibrils using the thioflavin T fluorescence assay, and imaging with atomic force microscopy. Our data show that the multimeric compound inhibits A,1,40 fibril formation with an IC50 value of 20±10 ,M, which contrasts with the nonactive monomeric analogue. This work suggests that assembling multiple copies of acridine moieties to a central scaffold, for multiple interactions, is a promising strategy for the engineering of inhibitors against A, fibril formation. [source] 2H-Pyrrolo[3,4-b][1,5]benzothiazepine Derivatives as Potential Inhibitors of HIV-1 Reverse Transcriptase.CHEMINFORM, Issue 40 2005Roberto Di Santo Abstract For Abstract see ChemInform Abstract in Full Text. [source] Synthesis of 2-Amino-4-oxo-5-substitutedbenzylthiopyrrolo[2,3-d]pyrimidines as Potential Inhibitors of Thymidylate Synthase.CHEMINFORM, Issue 27 2005Aleem Gangjee Abstract For Abstract see ChemInform Abstract in Full Text. [source] Synthesis of Benzylamides of Dipeptides as Potential Inhibitors of Plasmin.CHEMINFORM, Issue 6 2004K. Midura-Nowaczek No abstract is available for this article. [source] Synthesis Access to 2-Amido-5-aryl-8-methoxy-triazolopyridine and 2-Amido-5-morpholino-8-methoxy-triazolopyridine Derivatives as Potential Inhibitors of the Adenosine Receptor Subtypes.CHEMINFORM, Issue 49 2003Matthias Nettekoven Abstract For Abstract see ChemInform Abstract in Full Text. [source] ChemInform Abstract: Combinatorial Synthesis of 5-Aryl-[1,2,4]-triazolo-[1,5-a]-pyridine Derivatives as Potential Inhibitors of the Adenosine 2A Receptor.CHEMINFORM, Issue 15 2002Matthias Nettekoven Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] Synthesis of a Fusion-Isomeric Cellobionoimidazole and Its Evaluation against the syn -Protonating Glycosidase Cel7AHELVETICA CHIMICA ACTA, Issue 12 2005Narinder Mohal The fusion-isomeric cellobinoimidazole 2, a potential inhibitor of the syn -protonating , -glycosidase Cel7A, was synthesised by Koenigs,Knorr glycosylation of the ,- D -arabinopyranoside 32, followed by selective hydrolysis. Glycosylation of 32 with acetobromoglucose 6 proceeded with poor diastereoselectivity, giving the desired 1,3-linked , - d- disaccharide 35 as minor product, besides the major 1,3-linked ,- d- disaccharide 36. Hg2+ -Promoted glycosylation of 32 led predominantly to the 1,2-ortho ester 33. Sequential removal of the silyl, acetyl, and allyl groups of 35 led to a 45,:,55 equilibrium mixture 2 and the manno -configured isomer 39. Similarly, deprotection of 36 gave a mixture of the maltonoimidazole 42 and the manno -configured isomer 43. According to a known protocol, the glycosyl acceptor 32 was synthesised in eleven steps and an overall yield of 8,13% from D -lyxose. The silylated arabinopyranosyl moiety of the ,- d- glucosides 13,19, 33, 34, and 36 adopts a 4C1 conformation, while the arabinopyranosyl moiety of the , - d- glucosides 17 and 35 exists as a 1,:,3,mixture of 4C1 and 1C4 conformers, as a result of the combined preferred axial orientation of bulky vicinal substituents and the anomeric effect. MM3* Modelling evidences a preferred 4C1 conformation of 35 and 36, and stronger steric interactions between the pyranosyl moieties of 35. The equilibrium mixture 2/39 proved a poor inhibitor of Cel7A with an IC50 value of ca. 4,mM. [source] Radiosynthesis of [123I]N -(3-iodoprop-(2E)-enyl)-2,-(imino-methyl)-3,-(3,,4,-dichlorophenyl) nortropane as a potential SPET tracer for dopamine transporterJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 12 2002Meixiang Yu Abstract The radiosynthesis of a novel tropane derivative [123I]KUC-25019, [[123I];N -(3-iodoprop-(2E)-enyl)-2,-(imino-methyl)-3,-(3,,4,-dichlorophenyl)nortropane], a potential inhibitor of the dopamine transporter is reported. The synthetic routes include the preparation of standard reference, the stannyl precursor and the 123I-labeling synthesis. The no-carrier-added 123I-labeling has about 20% yield, the specific activity of [123I]KUC-25019 is > 107 GBq/µmol and the radiochemical purity of [123I] KUC-25019 is >95%. Copyright © 2002 John Wiley & Sons, Ltd. [source] 6,-Azido-7,-hydroxy-17-oxo-5,-androstan-3,-yl acetateACTA CRYSTALLOGRAPHICA SECTION C, Issue 9 2004J. I. F. Paixăo In the title compound, C21H31N3O4, a potential inhibitor of aromatase, all rings are fused trans. Rings A, B and C have chair conformations which are slightly flattened. Ring D has a 14,-envelope conformation. The steroid nucleus has a small twist, as shown by the C19,C10,C13,C18 torsion angle of 6.6,(2)°. Ab initio calculations of the equilibrium geometry of the molecule reproduce this small twist, which appears to be due to the steric effect of the 6,-azide substituent rather than to packing effects. [source] Glycerol and Glycerol Glycol GlycodendrimersEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 22 2003Mike M. K. Boysen Abstract Non-covalent interactions between structural parts of complex oligosaccharides and saccharide-recognising proteins are of crucial importance for many cell communication phenomena. Specificity of such interactions and stability of these ligand-receptor complexes are achieved through multivalent interactions between multiple copies of a saccharide ligand and a corresponding number of protein receptors. Substances presenting multiple copies of the saccharide ligand on easily accessible scaffold molecules therefore appear to be promising tools for study of multivalent interactions and their possible inhibition. Such multivalent glycomimetics can be prepared by attachment of saccharide residues to the surface functional groups of dendrimers. In the course of our work, we have prepared novel glycodendrimers with glycerol and glycerol glycol polyether scaffolds. Isopropylidene-protected hydroxyethyl mannoside was chosen as the carbohydrate component, with the construction of the dendritic structures proceeding by a convergent approach featuring iterative Williamson etherification and ozonolysis/hydride reduction steps. Deprotected representatives of such structures are potential inhibitors of mannose-binding lectins of E. coli. Three representative compounds were deprotected and their anti-adhesive properties were examined. The route to these glycodendrimers was also evaluated in terms of synthetic chemistry. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003) [source] Interaction of ribosome recycling factor and elongation factor EF-G with E. coli ribosomes studied by the surface plasmon resonance techniqueGENES TO CELLS, Issue 12 2000Tetsuya Ishino Ribosome recycling factor (RRF), in concert with elongation factor EF-G, is required for disassembly of the post-termination complex of a ribosome after the release of polypeptides. How RRF dissociates the complex has long been puzzling. Crystal structures of RRF molecules have been solved recently and shown to mimic a transfer RNA (tRNA) shape, which prompted us to examine whether RRF binds to the ribosome as tRNA does. The formation of ribosome complexes on the surface-coupled RRF and elongation factor EF-G of Escherichia coli was monitored in real time with a BIACORE 2000 instrument based on the surface plasmon resonance technique. RRF interacted with 70S ribosomes as well as 50S and 30S subunits, although it interacted preferentially with 50S subunits, which was clearly seen under high but physiological ionic conditions. This 50S interaction was diminished by a single amino acid substitutions for Arg132 of RRF, which did not appreciably affect the protein folding but nullified the activity in vivo and in vitro. Moreover, a set of antibiotics that inhibited the RRF,50S interaction were also inhibitory to the polysome breakdown activity of RRF in vitro. The BIACORE technique also worked very well in demonstrating the action of the antibiotics thiostrepton and fusidic acid, which are inhibitory to the RRF function by freezing the pre- and post-translocation intermediates catalysed by EF-G. These results suggest that the preferential interplay of RRF with the 50S subunit may be of biological significance, probably reflecting the mode of RRF action. The BIACORE technique proved useful for real-time monitoring of the interaction between the ribosome and translation factors, as well as for screening of potential inhibitors for ribosome recycling factor. [source] Characterization of Arginine Transport in Helicobacter pyloriHELICOBACTER, Issue 4 2003George L. Mendz ABSTRACT Background. The amino acid L-arginine is an essential requirement for growth of Helicobacter pylori. Several physiological roles of this amino acid have been identified in the bacterium, but very little is known about the transport of L-arginine and of other amino acids into H. pylori. Methods. Radioactive tracer techniques using L-(U- 14C) arginine and the centrifugation through oil method were employed to measure the kinetic parameters, temperature dependence, substrate specificity, and effects of analogues and inhibitors on L-arginine transport. Results. The transport of arginine at millimolar concentrations was saturable with a Km of 2.4 ± 0.3 mM and Vmax of 1.3 ± 0.2 pmole min,1 (µl cell water),1 or 31 ± 3 nmole per minute (mg protein),1 at 20°C, depended on temperature between 4 and 40°C, and was susceptible to inhibitors. These characteristics suggested the presence of one or more arginine carriers. The substrate specificity of the transport system was studied by measuring the effects of L-arginine analogues and amino acids on the rates of transport of L-arginine. The absence of inhibition in competition experiments with L-lysine and L-ornithine indicated that the transport system was not of the Lysine-Arginine-Ornithine or Arginine-Ornithine types. The presence of different monovalent cations did not affect the transport rates. Several properties of L-arginine transport were elucidated by investigating the effects of potential inhibitors. Conclusions. The results provided evidence that the transport of L-arginine into H. pylori cells was carrier-mediated transport with the driving force supplied by the chemical gradient of the amino acid. [source] Discovery and design of novel inhibitors of botulinus neurotoxin A: targeted ,hinge' peptide librariesJOURNAL OF APPLIED TOXICOLOGY, Issue 1 2003J. Hayden Abstract Intoxication by the zinc protease botulinus neurotoxin A (BoNT-A) results from cleavage of a single Q,R bond in the neuronal protein SNAP-25, which disables the docking mechanism required for neurotransmitter release. In the present study, potential inhibitors of BoNT-A were assessed from their effects on the BoNT-A cleavage of a synthetic 17-mer peptide (SNAP-25, residues 187,203) spanning the Q,R cleavage site. Compounds that inhibited BoNT-A included thiols (zinc chelators) such as dithiothreitol, dimercaptopropanesulfonic acid, mercaptosuccinic acid and captopril. In addition, compounds containing multiple acidic functions, such as the SNARE motif V2 (ELDDRADALQ), the tripeptide Glu-Glu-Glu and the steroid glycoside glycyrrhizic acid, were effective inhibitors. ,Hinge' peptide mini-libraries (PMLs) having the structure acetyl-X1 -X2 -linker-X3 -X4 -NH2 or X1 -X2 -linker-X3, where X1,X4 were mixtures of selected amino acids and the flexible linker was 4-aminobutyric acid, also provided effective inhibition. Targeted PMLs containing the acidic amino acids Asp and Glu, the scissile-bond amino acids Gln and Arg and the zinc chelators His and Cys produced pronounced inhibition of BoNT-A. Deconvolution of these libraries will provide novel ligands with improved inhibitory potency as leads in the design of peptide mimetics to treat BoNT poisoning. Copyright ? 2003 Crown in the right of Canada. Published by John Wiley and Sons, Ltd. [source] Fusion core structure of the severe acute respiratory syndrome coronavirus (SARS-CoV): In search of potent SARS-CoV entry inhibitorsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2008Ling-Hon Matthew Chu Abstract Severe acute respiratory coronavirus (SARS-CoV) spike (S) glycoprotein fusion core consists of a six-helix bundle with the three C-terminal heptad repeat (HR2) helices packed against a central coiled-coil of the other three N-terminal heptad repeat (HR1) helices. Each of the three peripheral HR2 helices shows prominent contacts with the hydrophobic surface of the central HR1 coiled-coil. The concerted protein,protein interactions among the HR helices are responsible for the fusion event that leads to the release of the SARS-CoV nucleocapsid into the target host-cell. In this investigation, we applied recombinant protein and synthetic peptide-based biophysical assays to characterize the biological activities of the HR helices. In a parallel experiment, we employed a HIV-luc/SARS pseudotyped virus entry inhibition assay to screen for potent inhibitory activities on HR peptides derived from the SARS-CoV S protein HR regions and a series of other small-molecule drugs. Three HR peptides and five small-molecule drugs were identified as potential inhibitors. ADS-J1, which has been used to interfere with the fusogenesis of HIV-1 onto CD4+ cells, demonstrated the highest HIV-luc/SARS pseudotyped virus-entry inhibition activity among the other small-molecule drugs. Molecular modeling analysis suggested that ADS-J1 may bind to the deep pocket of the hydrophobic groove on the surface of the central coiled-coil of SARS-CoV S HR protein and prevent the entrance of the SARS-CoV into the host cells. J. Cell. Biochem. 104: 2335,2347, 2008. © 2008 Wiley-Liss, Inc. [source] Object-oriented approach to drug design enabled by NMR SOLVE: First real-time structural tool for characterizing protein,ligand interactionsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue S37 2001Daniel S. Sem Abstract As a result of genomics efforts, the number of protein drug targets is expected to increase by an order of magnitude. Functional genomics efforts are identifying these targets, while structural genomics efforts are determining structures for many of them. However, there is a significant gap in going from structural information for a protein target to a high affinity (Kd,<,100 nM) inhibitor, and the problem is multiplied by the sheer number of new targets now available. nature frequently designs proteins in classes that are related by the reuse, through gene duplication events, of cofactor binding domains. This reuse of functional domains is an efficient way to build related proteins in that it is object-oriented. There is a growing realization that the most efficient drug design strategies for attacking the mass of targets coming from genomics efforts will be systems-based approaches that attack groups of related proteins in parallel. We propose that the most effective drug design strategy will be one that parallels the object-oriented manner by which nature designed the gene families themselves. IOPE (Integrated Object-Oriented PharmacoEngineering) is such an approach. It is a three-step technology to build focused combinatorial libraries of potential inhibitors for major families and sub-families of enzymes, using cogent NMR data derived from representatives of these protein families. The NMR SOLVE (Structurally Oriented Library Valency Engineering) data used to design these libraries are gathered in days, and data can be obtained for large proteins (>,170 kDa). Furthermore, the process is fully object-oriented in that once a given bi-ligand is identified for a target, potency is retained if different cofactor mimics are swapped. This gives the drug design process maximum flexibility, allowing for the more facile transition from in vitro potency to in vivo efficacy. J. Cell. Biochem. Suppl. 37: 99,105, 2001. © 2002 Wiley-Liss, Inc. [source] Synthesis of 2,6-diamino-5-[(2-substituted phenylamino)ethyl]pyrimidin-4(3h)-one as inhibitors of folate metabolizing enzymes,,JOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 6 2006Aleem Gangjee A series of eleven novel 2,6-diamino-5-[(2-substituted phenylamino)ethyl]pyrimidin-4(3H)-one derivatives were synthesized as potential inhibitors of dihydrofolate reductase (DHFR) and thymidylate synthase (TS). The synthesis of analogues 2a-f, 3a and 3e was achieved via an improved method. Commercially available anilines 12a-f were used as starting materials which on reaction with chloroacetaldehyde followed by cyanoacetate and cyclocondensation with guanidine afforded 2,6-diamino-5-[(2-substituted phenylamino)ethyl]pyrimidin-4(3H)-one 2a-f in three steps. The N-methyl analogues 3a-3e were prepared by reductive methylation. These compounds were evaluated against dihydrofolate reductase from Escherichia coli, Toxoplasma gondii, Pneumocystis carinii, human, and rat liver. Few compounds were marginally active against dihydrofolate reductase. The most potent inhibitor, (2c) which has a 1-naphthyl substituent on the side chain, has an IC50 = 150 ,M and 9.1 ,M against Escherichia coli and Toxoplasma gondii DHFR, respectively. [source] Effects of furocoumarins from Cachrys trifida on some macrophage functionsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2001M. J. Abad Phytochemical and biological studies aimed at the discovery and development of novel antiinflammatory agents from natural sources have been conducted in our laboratory for a number of years. In this communication, three naturally occurring furocoumarins (imperatorin, isoimperatorin and prantschimgin) were evaluated as potential inhibitors of some macrophage functions involved in the inflammatory process. These furocoumarins have been tested in two experimental systems: ionophore-stimulated mouse peritoneal macrophages serve as a source of cyclooxygenase-1 and 5-lipoxygenase, and mouse peritoneal macrophages stimulated with E. coli lipopolysaccharide are the means of testing for anti-cyclooxygenase-2 and nitric-oxide-synthase activity. All above-mentioned furocoumarins showed significant effect on 5-lipoxygenase (leukotriene C4) with IC50 values of < 15 ,M. Imperatorin and isoimperatorin exhibited strong-to-medium inhibition on cyclooxygenase-1- and cyclooxygenase-2-catalysed prostaglandin E2 release, with inhibition percentages similar to those of the reference drugs, indometacin and nimesulide, respectively. Of the three furocoumarins, only imperatorin caused a significant reduction of nitric oxide generation. Imperatorin and isoimperatorin can be classified as dual inhibitors, since it was evident that both cyclooxygenase and lipoxygenase pathways of arachidonate metabolism were inhibited by these compounds. However, selective inhibition of the 5-lipoxygenase pathway is suggested to be the primary target of action of prantschimgin. [source] Design of translactam HCMV protease inhibitors as potent antiviralsMEDICINAL RESEARCH REVIEWS, Issue 4 2005Alan D. Borthwick Abstract Human cytomegalovirus (HCMV) is an important pathogen for which there is a significant unmet medical need. New HCMV antivirals, active against novel molecular targets, are undoubtedly needed as the currently available drugs ganciclovir, cidofovir, and foscarnet, which are all viral DNA inhibitors, suffer from limited effectiveness, mainly due to the development of drug resistance, poor bioavailability, and toxicity. One of the newer molecular targets that has been exploited in the search for better drug candidates is HCMV protease. Our ,Ala HCMV protease (wild type variant with the internal cleavage site deleted) was cloned and expressed in E. coli. This viral enzyme was used to develop HCMV protease assays to evaluate potential inhibitors. The chirally pure (SRS)-,-methyl pyrrolidine-5,5- trans -lactam template was synthesized, which together with the natural substrate requirements of HCMV protease and detailed SAR, was used to design potent and selective mechanism based inhibitors of HCMV protease. The mechanism of action of these inhibitors of HCMV protease was investigated by ESI/MS, and the X-ray crystal structure of the HCMV protease was used to refine our selective viral enzyme inhibitors to obtain plasma stable antivirals. A novel ELISA antiviral assay was developed which, together with a cytotoxicity assay, enabled us to discover anti-HCMV drug candidates equivalent in potency to ganciclovir that had good pharmacokinetics in the dog and good brain and ocular penetration in the guinea pig. © 2005 Wiley Periodicals, Inc. Med Res Rev. [source] Anti-snake venom properties of Schizolobium parahyba (Caesalpinoideae) aqueous leaves extractPHYTOTHERAPY RESEARCH, Issue 7 2008Mirian M. Mendes Abstract Many medicinal plants have been recommended for the treatment of snakebites. The aqueous extracts prepared from the leaves of Schizolobium parahyba (a plant found in Mata Atlantica in Southeastern Brazil) were assayed for their ability to inhibit some enzymatic and biological activities induced by Bothrops pauloensis and Crotalus durissus terrificus venoms as well as by their isolated toxins neuwiedase (metalloproteinase), BnSP-7 (basic Lys49 PLA2) and CB (PLA2 from crotoxin complex). Phospholipase A2, coagulant, fibrinogenolytic, hemorrhagic and myotoxic activities induced by B. pauloensis and C. d. terrificus venoms, as well as by their isolated toxins were significantly inhibited when different amounts of S. parahyba were incubated previously with these venoms and toxins before assays. However, when S. parahyba was administered at the same route as the venoms or toxins injections, the tissue local damage, such as hemorrhage and myotoxicity was only partially inhibited. The study also evaluated the inhibitory effect of S. parahyba upon the spreading of venom proteins from the injected area into the systemic circulation. The neutralization of systemic alterations induced by i.m. injection of B. pauloensis venom was evaluated by measuring platelet and plasma fibrinogen levels which were significantly maintained when S. parahyba extract inoculation occurred at the same route after B. pauloensis venom injection. In conclusion, the observations confirmed that the aqueous extract of S. parahyba possesses potent snake venom neutralizing properties. It may be used as an alternative treatment to serum therapy and as a rich source of potential inhibitors of toxins involved in several physiopathological human and animal diseases. Copyright © 2008 John Wiley & Sons, Ltd. [source] Structures of S. aureus thymidylate kinase reveal an atypical active site configuration and an intermediate conformational state upon substrate bindingPROTEIN SCIENCE, Issue 4 2006Masayo Kotaka Abstract Methicillin-resistant Staphylococcus aureus (MRSA) poses a major threat to human health, particularly through hospital acquired infection. The spread of MRSA means that novel targets are required to develop potential inhibitors to combat infections caused by such drug-resistant bacteria. Thymidylate kinase (TMK) is attractive as an antibacterial target as it is essential for providing components for DNA synthesis. Here, we report crystal structures of unliganded and thymidylate-bound forms of S. aureus thymidylate kinase (SaTMK). His-tagged and untagged SaTMK crystallize with differing lattice packing and show variations in conformational states for unliganded and thymidylate (TMP) bound forms. In addition to open and closed forms of SaTMK, an intermediate conformation in TMP binding is observed, in which the site is partially closed. Analysis of these structures indicates a sequence of events upon TMP binding, with helix ,3 shifting position initially, followed by movement of ,2 to close the substrate site. In addition, we observe significant conformational differences in the TMP-binding site in SaTMK as compared to available TMK structures from other bacterial species, Escherichia coli and Mycobacterium tuberculosis as well as human TMK. In SaTMK, Arg 48 is situated at the base of the TMP-binding site, close to the thymine ring, whereas a cis -proline occupies the equivalent position in other TMKs. The observed TMK structural differences mean that design of compounds highly specific for the S. aureus enzyme looks possible; such inhibitors could minimize the transfer of drug resistance between different bacterial species. [source] High-performance liquid chromatographic determination of creatine kinase activity influenced by methylglyoxalBIOMEDICAL CHROMATOGRAPHY, Issue 2 2009Xiaofang Peng Abstract Protein glycation has been implicated in the development of diabetic complications and other health disorders, which mainly arise from accumulation of advanced glycation endproducts (AGEs) in vivo. Methylglyoxal (MGO), a typical reactive intermediate carbonyl formed in early glycation process, can react non-enzymatically with N -terminal amino groups on proteins, leading to their inactivation and generation of detrimental AGEs. Recently, it was reported that activity of creatine kinase (CK, EC 2.7.3.2) could be reduced or even eliminated completely after incubation with MGO in vitro. CK activity is usually determined by conventional colorimetric assays. However, these methods are not appropriate for monitoring the influence of MGO on CK activity since MGO can also directly react with creatine, a substrate of CK. In this study, an efficient and much more accurate HPLC approach was established to investigate the effect of MGO on CK activity. Aminoguanidine was utilized to eliminate interference from the undesirable reaction between residual MGO and creatine. It was found that higher concentrations of MGO and longer incubation time for CK and MGO caused more pronounced reduction in CK activity. This HPLC method greatly facilitates acquisition of kinetic data about CK reaction and through further improvement it may be adopted to rapidly screen potential inhibitors of MGO-induced glycation. Copyright © 2008 John Wiley & Sons, Ltd. [source] Berry anthocyanins and anthocyanidins exhibit distinct affinities for the efflux transporters BCRP and MDR1BRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2009A Dreiseitel Background and purpose:, Dietary anthocyanins hold great promise in the prevention of chronic disease but factors affecting their bioavailability remain poorly defined. Specifically, the role played by transport mechanisms at the intestinal and blood,brain barriers (BBB) is currently unknown. Experimental approach:, In the present study, 16 anthocyanins and anthocyanidins were exposed to the human efflux transporters multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), using dye efflux, ATPase and, for BCRP, vesicular transport assays. Key results:, All test compounds interacted with the BCRP transporter in vitro. Of these, seven emerged as potential BCRP substrates (malvidin, petunidin, malvidin-3-galactoside, malvidin-3,5-diglucoside, cyanidin-3-galactoside, peonidin-3-glucoside, cyanidin-3-glucoside) and 12 as potential inhibitors of BCRP (cyanidin, peonidin, cyanidin-3,5-diglucoside, malvidin, pelargonidin, delphinidin, petunidin, delphinidin-3-glucoside, cyanidin-3-rutinoside, malvidin-3-glucoside, pelargonidin-3,5-diglucoside, malvidin-3-galactoside). Malvidin, malvidin-3-galactoside and petunidin exhibited bimodal activities serving as BCRP substrates at low concentrations and, at higher concentrations, as BCRP inhibitors. Effects on MDR1, in contrast, were weak. Only aglycones exerted mild inhibitory activity. Conclusions and implications:, Although the anthocyanidins under study may alter pharmacokinetics of drugs that are BCRP substrates, they are less likely to interfere with activities of MDR1 substrates. The present data suggest that several anthocyanins and anthocyanidins may be actively transported out of intestinal tissues and endothelia, limiting their bioavailability in plasma and brain. [source] Novel azapeptide inhibitors of cathepsins B and K. Structural background to increased specificity for cathepsin BCHEMICAL BIOLOGY & DRUG DESIGN, Issue 2005E. Wieczerzak Abstract:, We have designed and synthesized a new series of azapeptides which act as potential inhibitors of cathepsin B and/or cathepsin K. Their structures are based upon the inhibitory sites of natural cysteine protease inhibitors, cystatins. For the synthesized azapeptides, the equilibrium constants for dissociation of inhibitor,enzyme complex, Ki, were determined. Comparison of these values indicated that all of the azainhibitors act much stronger toward cathepsin B. Z-Arg-Leu-His-Agly-Ile-Val-OMe (7) proved to be approximately 500 times more potent for cathepsin B than for cathepsin K. To be able to explain the obtained experimental values we used the molecular dynamics procedures to analyze the interactions between cathepsin B and compound 7. We also determined the structure of the most potent and selective cathepsin B azainhibitor by means of NMR studies and theoretical calculations. In this report, we describe SAR studies of azapeptide inhibitors indicating the influence of the conformational flexibility of the examined compounds on inhibition of cathepsins B and K. [source] Biosynthesis of New Indigoid Inhibitors of Protein Kinases Using Recombinant Cytochrome P450 2A6CHEMISTRY & BIODIVERSITY, Issue 1 2005Zhongliu-Liu Wu Glycogen synthase kinase-3 (GSK-3) is a potential drug target for a number of human diseases. Some indigoids have been found to be potent inhibitors of GSK-3, and individual compounds with better activity, specificity, and solubility are desired. In this work, a new disubstituted indigoid generation system was developed with a tryptophanase-deficient Escherichia coli strain as a host to express the human cytochrome P450 2A6 mutant L240C/N297Q, which catalyzes the oxidation of indole to isatin and indoxyl, which in turn react to generate indigoids. Forty-five substituted 1H -indoles from commercial sources were used as substrates in the system, and indigoid mixtures were tested as potential inhibitors of GSK-3. After preliminary screening, cell extracts with high inhibitory activity towards GSK-3,/, were fractionated, and the IC50 values of twelve individual indigoids were measured for GSK-3,/, as well as the protein kinases CDK1/cyclinB and CDK5/p25. Several indigoids, including an indigo, showed stronger inhibition than found in previous work. The most potent towards GSK-3,/,, dimethyl indirubin 5,5,-dicarboxylate (IC50 of 51,nM), was modified by chemical reactions. One product, indirubin 5,5,-dicarboxylic acid 5-methyl ester, inhibited GSK-3,/, with an IC50 of 14,nM and selectivity nearly 40-fold over CDK1 and CDK5. Indirubin-5-5,-dicarbonitrile was also modified to the corresponding 3,-oxime, which had low specificity but showed very high inhibition of all three kinases with IC50 values of 5, 13, and 10,nM towards GSK-3,/,, CDK1, and CDK5, respectively. Thus, this system has the potential to generate new indigoids with therapeutic potential. [source] | ||||||||||||||||||||||||||||