Stereoselective S-oxygenation of 2-aryl-1,3-dithiolanes by the flavin-containing and cytochrome P-450 monooxygenases.
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.
Cashman
J R
JR
Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, 94143-0446.
Olsen
L D
LD
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000378:metabolism*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013454:Sulfoxides / Q000378:metabolism; D013552:Swine
D006571:Heterocyclic Compounds; D013454:Sulfoxides; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)