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.
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel. talia.miron@weizmann.ac.il
Talia
T
Miron
Irving
I
Listowsky
Meir
M
Wilchek
D000498:Allyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D004220:Disulfides; D004789:Enzyme Activation / Q000187:drug effects; D005978:Glutathione / Q000737:chemistry; D050536:Glycerol-3-Phosphate Dehydrogenase (NAD+) / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D015394:Molecular Structure; D008970:Molecular Weight; D010206:Papain / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D011817:Rabbits; D013237:Stereoisomerism; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013440:Sulfides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013441:Sulfinic Acids / Q000737:chemistry* / Q000494:pharmacology; D013997:Time Factors
D000498:Allyl Compounds; D004220:Disulfides; D013438:Sulfhydryl Compounds; D013440:Sulfides; D013441:Sulfinic Acids; C006452:allicin; C038491:allyl sulfide; D050536:Glycerol-3-Phosphate Dehydrogenase (NAD+); D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D010206:Papain; D005978:Glutathione