Enantioselective S-oxygenation of 2-aryl-1,3-dithiolanes by rabbit lung enzyme preparations

Pulmonary microsomes, highly purified pulmonary flavin-containing monooxygenase, and highly purified pulmonary cytochrome P-450IIB-4 from pregnant female rabbits catalyze the NADPH-dependent S-oxygenation of a series of 2-aryl-1,3-dithiolanes. The S-oxide is the only detectable product formed during the short time period of the enzymatic reactions. Studies on the biochemical mechanism for S-oxygenation of 2-aryl-1,3-dithiolanes suggest that this reaction is catalyzed preferentially by the flavin-containing monooxygenase, although cytochromes P-450 also contribute to S-oxygenation. This conclusion is based on the effects of a cytochrome P-450 inhibitor, aminobenzotriazole, as well as on studies of the stereoselectivity of the reaction. Although both purified rabbit pulmonary cytochrome P-450IIB-4 and purified flavin-containing monooxygenase have identical diastereoselectivity, producing the (trans)-S-oxide, these monooxygenases possess opposite S-oxygenation enantioselectivity. Pulmonary cytochrome P-450IIB-4 S-oxygenates 2-aryl-1,3-dithiolanes almost exclusively at the pro-S-sulfur atom, whereas pulmonary flavin-containing monooxygenase S-oxygenates 2-aryl-1,3-dithiolanes exclusively at the pro-R-sulfur atom. 2-Aryl-1,3-dithiolane S-oxides are S-oxygenated a second time on the S'-sulfide sulfur atom but only by rabbit lung microsomes and pulmonary flavin-containing monooxygenase and not by cytochrome P-450IIB-4. That pulmonary flavin-containing monooxygenase only catalyzes formation of (trans)- and not (cis)-2-aryl-1,3-dithiolane S-oxide formation suggests that the active site of pulmonary flavin-containing monooxygenase exerts great steric limitations on 2-aryl-1,3-dithiolane S-oxygenation.