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 prepared from tyrosol and dihydrolipoic acid in the presence, when appropriate, of sulfur. Compound 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 reduction assay (88–93% reduction vs 68% by Trolox). At 10 μM concentration, all compounds 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 concentration) and cell damage induced by 400 μM tert-butylhydroperoxide. All compounds 1–4 exhibited overall greater antioxidant activity than hydroxytyrosol.