Reaction mechanisms of allicin and allyl-mixed disulfides with proteins and small thiol molecules

Allylsulfides from garlic are chemopreventive agents. Entering cells they are expected to initially interact with glutathione. Accordingly, reaction mechanisms of the product, S-allylthio-glutathione, with model proteins and thiols were analyzed in cell free systems. With glutathionyl, cysteinyl or captopril representing S-allyl aliphatic adducts, the reaction with sulfhydryl groups resulted in mixed disulfide mixtures, formed by both, S-allyl and aliphatic moieties. To improve conventional prodrug treatment of blood pressure, cancer and intestinal inflammation S-allylthio prodrugs, such as S-allylthio-6-mercaptopurine and S-allylthio-captopril were synthesized. Synergistic activities of the 2 constituents, as well as increased cell permeability allow for efficient in vivo activity. Upon reaction of these derivatives with glutathione, S-allylthio-glutathione is formed, while 6-mercaptopurine is the leaving group. Excess cellular glutathione enables several cycles of sulfhydryl-disulfide exchange reactions to occur, extending the hybrid drug's pharmacodynamics. (C) 2010 Elsevier Masson SAS. All rights reserved.