Quantitative structure-activity relationship (QSAR) and three-dimensional QSAR analysis of a series of xanthates as inhibitors and inactivators of cytochrome P450 2B1

1. Various xanthates (R-OCS2) were found to be mechanism-based inactivators of cytochrome P450 2B1 (CYP2B1) and CYP2B6 via formation of reactive metabolites. 2. In the present study, quantitative structure-activity relationships (QSARs) were derived with inhibitory and inactivation potencies of 15 xanthates (R = two to 20 methylene groups, allyl, cyclohexyl or O -tricyclo[5.2.1.0 2,6] dec-9-yl (D609)) against purified, reconstituted rat liver CYP2B1. Factor, regression and comparative molecular field analyses (CoMFA) were used. 3. The compounds formed two groups whose activities depended on different structural features: the first group consisted of compounds with ethyl, propyl, allyl, cyclohexyl and D609 substituents; the second involved compounds with eight to 20 methylene groups. 4. High correlation between the molecular volume and inhibitory potency of the xanthates of the second group was found. The inactivation potency in the first group correlated with the charge of the first carbon atom of R, identifying this atom as a potential target for metabolic attack. A decrease in the inactivation potency with an increase in the size of R was observed in the second group. This finding could be explained by a decreased rate of metabolism of the long alkyl chain compounds and/or by difficulty in binding of the resulting metabolite(s) to the enzyme molecule.

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