The medicinal thiosulfinates from garlic and Petiveria are not radical-trapping antioxidants in liposomes and cells, but lipophilic analogs are.

The radical-trapping antioxidant (RTA) activities of allicin and petivericin, thiosulfinates widely believed responsible for the medicinal properties of garlic and Petiveria, were determined in phosphatidylcholine lipid bilayers. The results indicate that both compounds are surprisingly ineffective, in sharp contrast with previous studies in organic solution which showed that they undergo facile Cope elimination to produce sulfenic acids - potent radical-trapping agents. In an effort to understand the medium dependence of this activity, a more lipophilic (hexylated) analog of petivericin was synthesized and shown to be among the most effective RTAs known, but only in the presence of a hydrophilic thiol (e.g. N-acetylcysteine). Additional symmetric and unsymmetric thiosulfinates were synthesized to shed light on the structural features that underlie this reactivity. These studies reveal that amphiphilic thiosulfinates which undergo S-thiolation with a hydrophilic thiol to give lipophilic sulfenic acids are required, and that an activated methylene group - key to promote Cope elimination - is not. Interestingly, the added thiol was also found to regenerate the sulfenic acid following its reaction with peroxyl radicals. This activity was diminished at more acidic pH, suggesting that it occurs by electron transfer from the thiolate. Allicin, petivericin and hexylated petivericin were assayed as inhibitors of lipid peroxidation in human TF1a erythroblasts and HEK-293 kidney cells, revealing similar efficacies in the low μM range - the same range in which allicin and petivericin were found to induce cell death concomitant with, or as a result of, glutathione (GSH) depletion. In contrast, hexylated petivericin was not cytotoxic throughout the concentration range assayed, and had no effect on GSH levels. Taken together, the results in lipid bilayers and in cell culture suggest that the greater lipophilicity of hexylated petivericin enables it to partition to membranous cell compartments where it forms a lipid-soluble sulfenic acid that traps peroxyl radicals, whereas allicin and petivericin partition to the cytosol where they deplete GSH and induce cell death.