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The mechanism generally admitted for the bioactivation of the antithrombotic prodrug, clopidogrel, is its two-step enzymatic conversion into a biologically active thiol metabolite. The first step is a classical cytochrome P450 (P450)-dependent monooxygenation of its thiophene ring leading to 2-oxo-clopidogrel, a thiolactone metabolite. The second step was(More)
Metabolic cleavage of the CO-S bond of some thioesters RCOSR' with the formation of RCOOH requires a monooxygenase-dependent oxidative activation of this bond. The nature of the S-containing product(s) resulting from this cleavage remains unclear in most cases. This communication provides the first evidence for the formation of sulfenic acid intermediates(More)
Oxidation of 2-phenylthiophene (2PT) by rat liver microsomes, in the presence of NADPH and glutathione (GSH), led to three kinds of metabolites whose structures were established by 1H NMR and mass spectrometry. The first ones were 2PT-S-oxide dimers formed by Diels-Alder type dimerization of 2PT-S-oxide, while the second ones were GSH adducts derived from(More)
The mechanism generally admitted for the bioactivation of the antithrombotic prodrug, prasugrel, 1c, is its two-step enzymatic conversion into a biologically active thiol metabolite. The first step is an esterase-catalyzed hydrolysis of its acetate function leading to a thiolactone metabolite 2c. The second step was described as a cytochrome P450(More)
Metabolic activation of the tetrahydro-thienopyridine antithrombotic prodrug, prasugrel, involves two steps: an esterase-dependent hydrolysis of its acetate function leading to thiolactone 6 and a cytochrome P450 (P450)-catalyzed oxidative cleavage of this thiolactone. This article shows that this second step involves the intermediate formation of a(More)
Microsomal Incubations: Human microsomes (pool, 10 mg protein/mL) were obtained from BD-Gentest (Le Pont de Claix, France). Typical incubations were performed in potassium phosphate buffer (0.1M, pH 7.4) containing 2 mM CaCl2, 100 mM KF, microsomes (1 mg protein/mL), 2-oxo-clopidogrel (100 μM) and a reducing agent (20 mM ascorbic acid, or 0.5 mM(More)
The conformational conversion of the nonpathogenic "cellular" prion isoform into a pathogenic "scrapie" protease-resistant isoform is a fundamental event in the onset of transmissible spongiform encephalopathies (TSE). During this pathogenic conversion, helix H1 and its two flanking loops of the normal prion protein are thought to undergo a conformational(More)
Conformational study of methylated derivatives of macrolide antibiotics roxithromycin (6-OMe-roxithromycin and 6,11-OMe-roxithromycin) has been achieved by NMR in solution and molecular dynamics (MD) simulations and compared to 6-OMe-erythromycin (clarithromycin). A complete conformational study by NMR has been led by determination of homonuclear coupling(More)
A new structurally distinct class of 14-membered-ring macrolides is characterized by a keto-function instead of the cladinose sugar, well-known for its fragility even in weakly acidic media. This new class called ketolides is endowed with remarkable antibacterial activity against macrolide-resistant strains. A complete assignment of the 1H and 13C NMR(More)
The study of macrolide-ribosome interactions has been investigated using two-dimensional transferred nuclear Overhauser effect spectroscopy (TRNOESY). A new medically important macrolide antibiotic, roxithromycin, with the replacement of the 9-keto group in erythromycin by a 9-oxime chain, was studied in the complex state with the bacterial ribosome.(More)