Synthesis and Bioactivity Profile of 5-S-Lipoylhydroxytyrosol-Based Multidefense Antioxidants with a Sizeable (Poly)sulfide Chain

Novel polyfunctionalized antioxidants, 5-S-lipoylhydroxytyrosol (1) and its disulfide 2, trisulfide 3, and tetrasulfide 4, were prepd. from tyrosol and dihydrolipoic acid in the presence, when appropriate, of sulfur. Compd. 1 exhibited significant activity in the ferric reducing/antioxidant power (FRAP) assay (1.60 Trolox equiv), whereas polysulfides 2-4 were more efficient in the DPPH redn. assay (88-93% redn. vs 68% by Trolox). At 10 μM concn., all compds. 1-4 proved to be efficient hydroxyl radical scavengers (56-69% inhibition) in a Fenton reaction assay. When administered to human HepG2 cells, 1-4 proved to be nontoxic and exhibited marked protective effects against reactive oxygen species (ROS) generation (60-84% inhibition at 1 μM concn.) and cell damage induced by 400 μM tert-butylhydroperoxide. All compds. 1-4 exhibited overall greater antioxidant activity than hydroxytyrosol.