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Eur J Med Chem. 2010 May;45(5):1912-8. doi: 10.1016/j.ejmech.2010.01.031. Epub 2010 Jan 21.

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

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Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.


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.

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