Canrenone formation via general-base-catalyzed elimination of 7 alpha-(methylthio)spironolactone S-oxide.
The preparation of the two diastereomeric S-oxides of 7 alpha-(methylthio)spironolactone, the major metabolite of spironolactone in humans, is described. When placed in aqueous solution, these diastereomers undergo elimination reactions to give canrenone. The rate of canrenone formation from 7 alpha-(methylthio)spironolactone S-oxide was carefully investigated spectrophotometrically. In weakly acidic media, canrenone formation was found to proceed at significant rates, and the reaction was catalyzed by basic buffer species. At strongly acidic or basic pH only, specific-acid or specific-base catalysis of sulfoxide elimination, respectively, was observed. The observation that formation of canrenone could occur from nonenzymatic elimination of 7 alpha-(methylthio)spironolactone S-oxide may have toxicological significance since it has been determined that canrenone can be metabolized to mutagenic epoxides in vitro. Our studies demonstrate a novel chemical pathway leading from a major metabolite of spironolactone, 7 alpha-(methylthio)spironolactone S-oxide, to canrenone.
Cashman
J R
JR
Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco 94143-0446.
Peña
S
S
D002021:Buffers; D002192:Canrenone / Q000138:chemical synthesis*; D002384:Catalysis; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D013237:Stereoisomerism
D002021:Buffers; D013148:Spironolactone; C072356:7alpha-(methylthio)spironolactone S-oxide; D002192:Canrenone