Home About us Contact
|
Home About us Contact | ||
|
|
||
Good Inhibitors (good + inhibitor)
Selected AbstractsThermal analysis of polymer,water interactions and their relation to gas hydrate inhibitionJOURNAL OF APPLIED POLYMER SCIENCE, Issue 4 2007Manika Varma-Nair Abstract Gas hydrates formed in oil production pipelines are crystalline solids where hydrocarbon gas molecules such as methane, propane, and their mixtures are trapped in a cagelike structure by hydrogen-bonded water molecules to form undesirable plugs. Methanol and glycol are currently used to prevent these plugs via thermodynamic inhibition. Small amounts of water-soluble polymers may provide an alternate approach for preventing gas hydrates. In this study, we expand the fundamental understanding of water,polymer systems with differential scanning calorimetry. Nonfreezable bound water was used to quantify polymer,water interactions and relate them to the chemical structure for a series of polymers, including acrylamides, cyclic lactams, and n -vinyl amides. For good interactions, the water structure needs to be stabilized through hydrophobic interactions. An increased hydrophobicity of the pendant group also appears to favor polymer performance as a gas hydrate inhibitor. Good inhibitors, such as poly(diethyl acrylamide) and poly(N -vinyl caprolactam), also show higher heat capacities, which indicate higher hydrophobicity, than poor performers such as polyzwitterions, in which hydrophilicity dominated. The phase behavior and thermodynamic properties of dilute polymer solutions were also evaluated through measurements of the heat of demixing and lower critical solution temperature. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 2642,2653, 2007 [source] Norbornane Mimics of Distorted , - D -Glucopyranosides , Inhibitors of , - D -Glucopyranosidases?HELVETICA CHIMICA ACTA, Issue 4 2006Stephan Buser Abstract The racemic gluco -configured norbornanes 4 and 16 were prepared and tested as inhibitors of ,- glucosidases. The known alcohol 5 was deprotected to provide the triol 6. Silylation (,,7), monobenzoylation (,,8/9), and oxidation provided the regioisomeric ketones 10 and 11. Reduction of 10 gave the desired endo -alcohol 13, albeit in low yield, while reduction of the isomeric ketone 11 provided mostly the altro -configured endo -alcohol 12. The alcohol 13 was desilylated to 14. Debenzoylation to 15 followed by hydrogenolytic deprotection gave the amino triol 4 that was reductively aminated to the benzylamine 16. The amino triols 4 and 16 proved weak inhibitors of the , -glucosidase from Caldocellum saccharolyticum (4: IC50,=,5.6,mm; 16:IC50,=,3.3,mm) and from sweet,almonds (16:IC50,=,5.5,mm). A comparison of 4 with the manno -configured norbornane 3 shows that 3 is a better inhibitor of snail , -mannosidase than 4 is of ,- glucosidases, in keeping with earlier results suggesting that these , -glycosidases enforce a different conformational itinerary. [source] Polyethylene glycol and polyvinyl alcohol as corrosion inhibitors for aluminium in acidic mediumJOURNAL OF APPLIED POLYMER SCIENCE, Issue 6 2007S. A. Umoren Abstract The corrosion inhibition of aluminum in H2SO4 in the presence of polyethylene glycol (PEG) and polyvinyl alcohol (PVA) as inhibitors at 30,60 °C was studied using gravimetric, gasometric, and thermometric techniques. The inhibition efficiency (%I) increased with increase in concentration of the inhibitors. Increase in temperature increased the corrosion rate in the absence and presence of inhibitors but decreased the inhibition efficiency. Both PEG and PVA were found to obey Temkin adsorption isotherm at all concentrations and temperatures studied. Phenomenon of physical adsorption is proposed from the activation parameters obtained. Thermodynamic parameters reveal that the adsorption process is spontaneous. PEG was found to be a better inhibitor than PVA. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2007 [source] Structure,function relationship of novel X4 HIV-1 entry inhibitors , L- and D-arginine peptide-aminoglycoside conjugatesFEBS JOURNAL, Issue 24 2007Ravi Hegde We present the design, synthesis, anti-HIV-1 and mode of action of neomycin and neamine conjugated at specific sites to arginine 6- and 9-mers d - and l -arginine peptides (APACs). The d -APACs inhibit the infectivity of X4 HIV-1 strains by one or two orders of magnitude more potently than their respective l -APACs. d -arginine conjugates exhibit significantly higher affinity towards CXC chemokine receptor type 4 (CXCR4) than their l -arginine analogs, as determined by their inhibition of monoclonal anti-CXCR4 mAb 12G5 binding to cells and of stromal cell-derived factor 1, (SDF-1,)/CXCL12 induced cell migration. These results indicate that APACs inhibit X4 HIV-1 cell entry by interacting with CXCR4 residues common to glycoprotein 120 and monoclonal anti-CXCR4 mAb 12G5 binding. d -APACs readily concentrate in the nucleus, whereas the l -APACs do not. 9-mer- d -arginine analogues are more efficient inhibitors than the 6-mer- d -arginine conjugates and the neomycin- d -polymers are better inhibitors than their respective neamine conjugates. This and further structure,function studies of APACs may provide new target(s) and lead compound(s) of more potent HIV-1 cell entry inhibitors. [source] Syntheses of cyclodextrin,3,-azido-3,-deoxythymidine conjugates and their sulfates with improved anti-HIV activitiesJOURNAL OF POLYMER SCIENCE (IN TWO SECTIONS), Issue 1 2006Ildoo Chung Abstract New anti-HIV agents, cyclodextrin,3,-azido-3,-deoxythymidine (CD,AZT) conjugates, were synthesized and characterized. A succinate diester spacer was used to covalently couple 3,-azido-3,-deoxythymidine (AZT) onto cyclodextrin. In addition, their sulfates were prepared by the reaction of CD,AZT conjugates and a sulfur trioxide/pyridine complex at 80 °C. The degree of AZT substitution of the synthesized conjugates and the sulfur contents of their sulfates were calculated from elemental analysis and ranged from 1.3 to 4.7 and from 8.4 to 12.1, respectively. These resulting sulfated conjugates were expected to have a synergistic effect against HIV because of the two anti-HIV active agents (sulfate group and AZT) by the inhibition of virus attachment to cells and that of reverse transcriptase. The in vitro antiviral activity of these conjugates was determined and used to evaluate the potential applications in anti-AIDS drugs. The in vitro anti-HIV activities indicated that the synthesized conjugates and their sulfates against HIV-1 and HIV-2 strains were much better inhibitors than AZT. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 295,303, 2006 [source] Hepatic microsomal cytochrome P450 enzyme activity in relation to in vitro metabolism/inhibition of polychlorinated biphenyls and testosterone in Baltic grey seal (Halichoerus grypus)ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 3 2003Hongxia Li Abstract Among other factors, cytochrome P450 (CYP) enzyme activity determines polychlorinated biphenyl (PCB) bioaccu-mulation, biotransformation, and toxicity in exposed species. We measured the oxidative metabolism in vitro of 12 PCB congeners, representing structural groups based on the number and position of the chlorine atoms, by the hepatic microsomes of one Baltic grey seal (Halichoerus grypus). Microsomal metabolism was observed for several PCBs with vicinal H atoms exclusively in the ortho and meta positions and without any ortho -Cl substituents (CB-15 [4,4,-Cl2] and CB-77 [3,3,,4,4,-Cl4]), vicinal meta and para -H atoms (CB-52 [2,2,,5,5,-Cl4], and ,101 [2,2,,4,5,5,-Cl5]) or with both characteristics in combination with either only one ortho -Cl (CB-26 [2,3,,5-Cl3], CB-31 [2,4,,5-Cl3]) or two ortho -Cl substituents (CB-44 [2,2,,3,5,-Cl4]). To allocate PCB biotransformation to specific CYPs, the inhibitive effect of compounds with known CYP-specific inhibition properties was assessed on in vitro PCB metabolism and on regio- and stereospecific testosterone hydroxylase activities. Metabolic inhibition was considered relevant at concentrations ,1.0 ,M because these inhibitors became decreasingly selective at higher concentrations. At <1.0 ,M, ellipticine (CYP1A1/2 inhibitor) selectively inhibited CB-15, ,26, ,31, and ,77 metabolism, with no significant inhibition of CB-44, ,52, and ,101 metabolism. Inhibition of CB-52 and ,101 metabolism by chloramphenicol (CYP2B inhibitor) started at 1.0 ,M and maximized at about 100% at 10 ,M. Ketoconazole (CYP3A inhibitor) appeared to selectively inhibit CB-26, ,31, and ,44 metabolism relative to CB-15, ,77, and ,52 at concentrations ,1.0 ,M. Major testosterone metabolites formed in vitro were 2,-(CYP3A), 6,- (CYP3A, CYP1A), and 16,- (CYP2B) hydroxytestosterone and androstenedione (CYP2B, CYP2C11). The CYP forms indicated are associated with the specific metabolism of testosterone in laboratory animals. Inhibition of 2,- and 6,-hydroxytestosterone formation at ellipticine and ketoconazole concentrations ,1.0,M suggested that both inhibitors were good substrates of CYP3A-like enzymes in grey seal. Chloramphenicol (model for CYP2B) is apparently not a good inhibitor of CYP1A and CYP3A activities in grey seal because the chemical did not inhibit any metabolic route of testosterone at concentrations from 0.1 to 10 ,M. Our findings demonstrated that at least CYP1A- and CYP3A-like enzymes in the liver of grey seals are capable of metabolizing PCBs with ortho - meta and/or meta - para vicinal hydrogens. A CYP2B form might also be involved, but this could not be proven by the results of our experiments. Defining the profiles of CYP enzymes that are responsible for PCB biotransformation is necessary to fully understand the bioaccumulation, toxicokinetics, and risk of PCB exposure in seals and other free-ranging marine mammals. [source] 7-Methyl Trimethoprim Analogues as Inhibitors of the Folate Metabolizing Enzymes,JOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 3 2003Aleem Gangjee A series of 5-(1-phenylethyl)pyrimidines 2,10 (Table I) were designed and synthesized as potent and selective inhibitors of Pneumocystis carinii (P. carinii), Toxoplasma gondii (T. gondii) and Mycobacterium avium (M. avium) dihydrofolate reductases (DHFR). The structure of 2,10 incorporates a 7-methyl group to increase the potency of monocyclic trimethoprim (TMP). The target compounds were synthesized by an acid catalyzed condensation of ethyl cyanoacetate and appropriately substituted benzaldehydes followed by a Michael addition using methyl copper-lithium. The resulting adduct was cyclocondensed with guanidine to afford 2,6-diamino-4-hydroxy-5-(1-phenylethyl)pyrimidines 2,7. Both amino moieties of 2,4 were protected with pivaloyl groups and their 4-hydroxy group chlorinated with phosphorus oxychloride. The resulting intermediates were subjected to hydrogenation and deprotection to afford 8,10. Compound 7 was a good inhibitor of DHFR, however the other compounds were poor inhibitors of P. carinii, T. gondii and M. avium DHFR. [source] Novel diadenosine polyphosphate analogs with oxymethylene bridges replacing oxygen in the polyphosphate chainFEBS JOURNAL, Issue 6 2009Potential substrates and/or inhibitors of Ap4A hydrolases Dinucleoside polyphosphates (NpnN,s; where N and N, are nucleosides and n = 3,6 phosphate residues) are naturally occurring compounds that may act as signaling molecules. One of the most successful approaches to understand their biological functions has been through the use of NpnN, analogs. Here, we present the results of studies using novel diadenosine polyphosphate analogs, with an oxymethylene group replacing one or two bridging oxygen(s) in the polyphosphate chain. These have been tested as potential substrates and/or inhibitors of the symmetrically acting Ap4A hydrolase [bis(5,-nucleosyl)-tetraphosphatase (symmetrical); EC 3.6.1.41] from E. coli and of two asymmetrically acting Ap4A hydrolases [bis(5,-nucleosyl)-tetraphosphatase (asymmetrical); EC 3.6.1.17] from humans and narrow-leaved lupin. The six chemically synthesized analogs were: ApCH2OpOCH2pA (1), ApOCH2pCH2OpA (2), ApOpCH2OpOpA (3), ApCH2OpOpOCH2pA (4), ApOCH2pOpCH2OpA (5) and ApOpOCH2pCH2OpOpA (6). The eukaryotic asymmetrical Ap4A hydrolases degrade two compounds, 3 and 5, as anticipated in their design. Analog 3 was cleaved to AMP (pA) and ,,,-methyleneoxy-ATP (pOCH2pOpA), whereas hydrolysis of analog 5 gave two molecules of ,,,-oxymethylene ADP (pCH2OpA). The relative rates of hydrolysis of these analogs were estimated. Some of the novel nucleotides were moderately good inhibitors of the asymmetrical hydrolases, having Ki values within the range of the Km for Ap4A. By contrast, none of the six analogs were good substrates or inhibitors of the bacterial symmetrical Ap4A hydrolase. [source] Hybrid ,/,3 -peptides with proteinogenic side chains. monosubstituted analogues of the chemotactic tripeptide For-Met-Leu-Phe-OMeJOURNAL OF PEPTIDE SCIENCE, Issue 8 2004Cesare Giordano Abstract The ,/,3 -mixed tripeptides R-CO-,3 -HMet-Leu-Phe-OMe (1a,b), R-CO-Met-,3 -HLeu-Phe-OMe (2a,b) and R-CO-Met-Leu-,3 -HPhe-OMe (3a,b) (a, R = tert -butyloxy-; b, R = H,), analogues of the potent chemoattractant For-Met-Leu-Phe-OMe, have been synthesized by classical solution methods and fully characterized. The activities of the new analogues as chemoattractants, superoxide anion producers and lysozyme releasers have been determined on human neutrophils. Whereas all of the three N -formyl derivatives are significantly less active than the parent tripeptide as chemoattractants, compound 1b has been found to be highly active as a superoxide anion producer and 3b as a lysozyme releaser. The results show that the replacement of the native Leu residue at the central position is, in each of the examined cases, the least favourable modification. The three N -Boc derivatives are, as expected, devoid of activity as agonists, but they are all good inhibitors of chemotaxis. Information on the solution conformation has been obtained by examining the involvement of the NH groups in intramolecular H-bonds using 1H NMR. The conformation of the N -Boc analogue 1a has also been determined in the crystal state by x-ray diffraction analysis. The molecule is extended at the ,3 -HMet residue (,1 = ,87°;,1 = 172°;,1 = 126° ) and no intramolecular H-bond is present. Copyright © 2004 European Peptide Society and John Wiley & Sons, Ltd. [source] Identification of a novel set of scaffolding residues that are instrumental for the inhibitory property of Kunitz (STI) inhibitorsPROTEIN SCIENCE, Issue 3 2010Susmita Khamrui Abstract For canonical serine protease inhibitors (SPIs), scaffolding spacer residue Asn or Arg religates cleaved scissile peptide bond to offer efficient inhibition. However, several designed "mini-proteins," containing the inhibitory loop and the spacer(s) with trimmed scaffold behave like substrates, indicating that scaffolding region beyond the spacer is also important in the inhibitory process. To understand the loop-scaffold compatibility, we prepared three chimeric proteins ECIL -WCIS, ETIL -WCIS, and STIL -WCIS, where the inhibitory loop of ECI, ETI, and STI is placed on the scaffold of their homolog WCI. Results show that although ECIL -WCIS and STIL -WCIS behave like good inhibitors, ETIL -WCIS behaves like a substrate. That means a set of loop residues (SRLRSAFI), offering strong trypsin inhibition in ETI, act as a substrate when they seat on the scaffold of WCI. Crystal structure of ETIL -WCIS shows that the inhibitory loop is of noncanonical conformation. We identified three novel scaffolding residues Trp88, Arg74, and Tyr113 in ETI that act as barrier to confine the inhibitory loop to canonical conformation. Absence of this barrier in the scaffold of WCI makes the inhibitory loop flexible in ETIL -WCIS leading to a loss of canonical conformation, explaining its substrate-like behavior. Incorporation of this barrier back in ETIL -WCIS through mutations increases its inhibitory power, supporting our proposition. Our study provides structural evidence for the contribution of remote scaffolding residues in the inhibitory process of canonical SPIs. Additionally, we rationalize why the loop-scaffold swapping is not permitted even among the members of highly homologous inhibitors, which might be important in the light of inhibitor design. [source] | |||||||||||||