Stereoselective S-oxygenation of 2-aryl-1,3-dithiolanes by the flavin- containing and cytochrome P-450 monooxygenases

JR Cashman and LD Olsen

Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, 94143-0446.

The reaction of NalO4, highly purified flavin-containing monooxygenase (EC 1.14.13.8), and microsomes from hog liver with 2-aryl-1,3- dithiolanes and 2-aryl-1,3-dithiolane S-oxides was investigated. The initial rates determined for the microsome- and purified flavin- containing monooxygenase-catalyzed rate of S-oxidation of para- substituted 2-aryl-1,3-dithiolanes were similar, demonstrating that S- oxidation of these substrates occurred with similar velocities at saturating concentrations of substrate and, at least for the first S- oxidation, the reaction was insensitive to the nature of the para- substituent. The diastereoselectivity of S-oxygenation of 2-aryl-1,3- dithiolanes was determined and, in general, a marked preference for addition of oxygen to the sulfide sulfur atom was observed to occur trans to the aryl groups. In all cases examined, enantioselective enzymatic S-oxidation was observed. For S-oxide formation in microsomes, the data provided evidence for a minor role of cytochrome P- 450 in S-oxide formation, but the flavin-containing monooxygenase was mainly responsible for production of S-oxide. In contrast to previous reports, the enantioselectivity of S-oxidation catalyzed by highly purified cytochrome P-450IIB-1 and cytochrome P-450IIB-10 was not always opposite to that catalyzed by hog liver flavin-containing monooxygenase activity. 2-Aryl-1,3-dithiolane S-oxides were also oxidized a second time by NalO4, microsomes, or highly purified flavin- containing monooxygenase from hog liver but not cytochrome P-450IIB-1 or P-450IIB-10. The rate of the second oxidation was 10-15-fold slower than the corresponding first S-oxidation and S,S'-dioxide formation was markedly dependent on the electronic nature of the para-substituent (Hammett correlation rho value of -1.3 and -1.1 for microsomes and highly purified flavin-containing monooxygenase from hog liver, respectively). The large dependence of the rate of S,S'-dioxide formation on the nature of the para-substituent demonstrates that velocity values at saturating concentrations of S-oxide were not the same for all 2-aryl-1,3-dithiolane S-oxides and suggests that the chemical nature of the 2-aryl-1,3-dithiolane S-oxide contributes to the rate-determining step of this enzymatic reaction.

Volume 38, Issue 4, pp. 573-585, 10/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics