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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.

Author information

1
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel. talia.miron@weizmann.ac.il

Abstract

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.

PMID:
20133026
DOI:
10.1016/j.ejmech.2010.01.031
[Indexed for MEDLINE]

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