Synthesis and pH-dependent stability of purine-6-sulfenic acid, a putative reactive metabolite of 6-thiopurine.
Previous studies have shown that 6-thiopurine is metabolically activated by hepatic cytochrome P-450 to an intermediate capable of binding to proteins by a mixed disulfide linkage. The identity of the active metabolite was postulated to be purine-6-sulfenic acid. In the present report, we describe the synthesis of the sulfenic acid derivatives of 6-thiopurine and two structurally similar compounds, 9-methyl-6-thiopurine and 4-mercapto-1H-pyrazolo[3,4-d]-pyrimidine. The unusual pH-dependent stability profiles of these compounds in buffered aqueous media are presented and explained on the basis of a disproportionation mechanism of sulfenic acid decomposition. Studies with radiolabeled purine-6-sulfenic acid demonstrate that this species binds directly to hepatic microsomal protein. These results support the proposed involvement of purine-6-sulfenic acid in the metabolic activation and tissue binding of 6-thiopurine.
D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D015122:Mercaptopurine / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D011687:Purines / Q000138:chemical synthesis* / Q000378:metabolism; D051381:Rats; D013056:Spectrophotometry, Ultraviolet
D011687:Purines; C039369:purine-6-sulfenic acid; D003577:Cytochrome P-450 Enzyme System; D015122:Mercaptopurine