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At least 217 records · Page 12Linked to original sources
PubMed2003

Hydride-exchange reactions between NADH and NAD+ model compounds under non-steady-state conditions. Apparent and real kinetic isotope effects.

The kinetics of the hydride exchange reaction between NADH model compound 10-methyl-9,10-dihydroacridine (MAH) and 1-benzyl-3-cyanoquinolinium (BQCN+) ion in acetonitrile were studied at temperatures ranging from 291 to 325 K. The extent of reaction-time profiles during the first half-lives are compared with theoretical data for the simple single-step mechanism and a 2-step mechanism involving initial donor/acceptor complex formation followed by unimolecular hydride transfer. The profiles for the reactions of MAH deviate significantly from those expected for the simple single-step mechanism with the deviation increasing with increasing temperature. The deviation from simple mechanism behavior is much less pronounced for the reactions of 10-methyl-9,10-dihydroacridine-10,10-d2 (MAD) which gives rise to extent of reaction dependent apparent kinetic isotope effects (KIEapp). Excellent fits of the experimental extent of reaction-time profiles with theoretical data for the 2-step mechanism, in the pre-steady-state time period, were observed in all cases. Resolution of the kinetics of the hydride exchange reaction into the microscopic rate constants over the entire temperature range resulted in real kinetic isotope effects for the hydride transfer step ranging from 40 (291 K) to 8.2 (325 K). That the reaction involves significant hydride tunnelling was verified by the magnitudes of the Arrhenius parameters; Ea D - EaH = 8.7 kcal mol-1 and AD/AH = 8 x 10(4). An electron donor acceptor complex (lambda max = 526 nm) was observed to be a reaction intermediate. Theoretical extent of reaction-time profile data are discussed for the case where a reaction intermediate is formed in a non-productive side equilibrium as compared to the case where it is a real intermediate on the reaction coordinate between reactants and products. The common assumption that the two cases are kinetically indistinguishable is shown to be incorrect.

Acridines↗
PubMed2000

Stereochemistry of halopyridyl and thiazolyl thiourea compounds is a major determinant of their potency as nonnucleoside inhibitors of HIV-1 reverse transcriptase.

Chiral derivatives of two cyclohexylethyl halopyridyl thiourea compounds (HI-509 and HI-510), two alpha-methyl benzyl halopyridyl compounds (HI-511 and HI-512), and a cyclohexyl ethyl thiazolyl thiourea compound (HI-513) were synthesized as nonnucleoside inhibitors (NNI) of human immunodeficiency virus (HIV) reverse transcriptase (RT). The R stereoisomers of all five compounds inhibited the recombinant RT in vitro with 100-fold lower IC50 values. HI-509R, HI-510R, HI-511R, HI-512R and HI-513R were active anti-HIV agents and inhibited HIV-1 replication in human peripheral blood mononuclear cells at nanomolar concentrations, whereas their enantiomers were inactive. Each of these five compounds was also active against NNI-resistant HIV-1 strains, with HI-511R being the most active agent. When tested against the NNI-resistant HIV-1 strain A17 with a Y181C mutation in RT, HI-511R was found to be 10,000-times more active than nevirapine, 5000-times more active than delavirdine, and 50-times more active than trovirdine. HI-511 R inhibited the HIV-strain A17 variant, containing RT mutations Y181C plus K103N, with an IC50 value of 2.7 microM, whereas the IC50 values of nevirapine, delavirdine, and trovirdine against this highly NNI-resistant HIV-1 strain were >100 microM.

Anti-HIV Agents↗
PubMed1993

Cysteine, a chelating moiety for synthesis of technetium-99m radiopharmaceuticals--Part IV. Benzyl cysteine and derivatives.

To explore the possibility of utilizing cysteine derivatives for technetium-99m radiopharmaceutical preparation with clinical potential, we synthesized two benzyl substituted cysteine compounds, namely, S-benzyl cysteine 1 and cysteine benzyl ester 3. It was expected, from our previous studies on benzoyl cysteines, that the above two ligands after chelation with 99mTc would be excreted by the hepatobiliary pathway. Although for 99mTc-3 the above expectation was realized, 99mTc-1 behaved in a most unexpected way by affixing itself with kidney and selecting the renal tubular secretory pathway for its excretion. It is anticipated that the affinity of 99mTc-1 for kidney is due to its interaction with the kidney sulphhydryl group and it also formed an adduct with other sulphydryl containing compounds like thiophenol. In terms of the kidney-to-background ratio, 99mTc-1 showed some superiority over other kidney structure agents, like 99mTc-dimercaptosuccinic acid and 99mTc-glucoheptanoic acid and, therefore, the chelate (99mTc-1) may have the potential to replace the above two radiopharmaceuticals in clinical use.

Animals↗
PubMed1985

Preparation and analysis of deuterium-labeled aspirin: application to pharmacokinetic studies.

Inhibition of endogenous prostacyclin and thromboxane biosynthesis by aspirin is critically dose-dependent in humans. Gastrointestinal and hepatic hydrolysis may limit systemic availability of aspirin, especially in low doses, perhaps contributing to the biochemical selectivity of aspirin. Existing analytical methods do not permit determination of systemic bioavailability when low (less than 100 mg) doses of aspirin are administered. Deuterium-labeled aspirin (2-acetoxy[3,4,5,6-2H4]benzoic acid) was synthesized from salicylic acid by catalytic exchange and subsequent acetylation. Analysis of the compounds as benzyl esters by GC-MS followed extractive alkylation from plasma. Heptadeuterated compounds were used as internal standards. Simultaneous administration of tetradeuterated aspirin intravenously with native aspirin orally to anesthetized dogs permitted kinetic studies of both aspirin and salicylic acid. The sensitivity of the method is superior to published methods using HPLC and, thus, more applicable to studies of low dose aspirin. Pulse administration of stable isotope-labeled aspirin permits detailed and repeated studies of dose-related aspirin pharmacokinetics in humans.

Animals↗
PubMed1977

The nature of the rate-limiting step in aniline hydroxylation involving cytochrome p-450 rat liver microsomes.

The kinetics of aniline hydroxylation was studied with: (1) rat liver microsomes involving NADPH and O2 (system 1), (2) hepatic microsomes and tert-butylhydroperoxide (system 2) and (3) microsomes and cumyl hydroperoxide (system 3) at 15--37 degrees C. The reactions were characterized by the values of the aniline oxidation rate constants, k2 = V/E0, where E0 is the initial concentration of cytochrome P-450: K 1/2 = 1.60 - 10(8) EXP (-13 400/RT) sec-1, k 2/2 = 1.66 - 10(9) exp (-14 500/RT) sec-1, k 3/2 = 6.83 - 10(9) exp (-15 300/RT) sec-1. The values of delta H0 and delta S0, were calculated and compared for the three systems. The evidence suggests that oxygen insertion into the substrate molecule is the rate-limiting step in the reaction of aniline oxidation for the mentioned systems. The nature of aniline binding to cytochrome P-450 and that of the hydroxylating agent have been discussed.

Aniline Compounds↗
PubMedDate not supplied

Synthesis of two photoreactive heterobifunctional reagents derived from hexanoic acid.

The synthesis of two photoreactive heterobifunctional reagents derived from hexanoic acid is described. The compounds are succinimido 6-N-(4-azidobenzoyl)aminohexanoate (1c) and succinimido 6-mercapto-S-(4-azidothiophenyl)hexanoate (2c). Compound 1c was synthesized from benzyloxycarbonyl 4-aminobenzoic acid and 6-aminohexanoic acid benzyl ester. Compound 2c was obtained by disulfide exchange of dithiobis-4-aminobenzene with 6-mercaptohexanoic acid. The azido function was introduced by displacement of the corresponding diazonium salt and the active ester, by the mixed anhydride method. Both compounds were decomposed by ultraviolet irradiation. Phytohemagglutinin was modified by reaction with reagent 1c or 2c. Irradiation afforded polymeric lectin derivatives resulting from intermolecular cross-linking. Sodium dodecyl sulfate--polyacrylamide gel electrophoresis analyses revealed the presence of Coomasie-positive bands of molecular weight 33000, 67000, 120000, 144000, and higher. Polymeric structures resulting from irradiation of phytohemagglutinin modified with compound 2c were cleaved by reduction with 2-mercaptoethanol or with dithiothreitol. Phytohemagglutinin modified by reaction with compound 1c or 2c retained its ability to stimulate pig spleen lymphocytes in vitro. Whereas the lectin treated with reagent 2c was active as the unmodified protein, the lectin treated with compound 1c was more active than unmodified lectin at nearly all the concentrations tested.

Animals↗