Synthesis and activity profile of novel sulfur and seleno derivatives of hydroxytyrosol and resveratrol

Hydroxytyrosol and resveratrol occupy a prominent position among natural polyphenols because of their antioxidant potency and the wide range of biological properties. Several efforts have been directed toward the preparation of novel derivatives of these compounds with improved antioxidant and pharmacological activities. In pursuing a research program on the design and synthesis of novel bioinspired antioxidant agents, we recently became interested in exploring the potential of sulphur/selenium-containing conjugates of natural polyphenols as prototypes of novel multifunctional compounds combining diverse scavenging and inhibitory activities against oxidative stress inducing species and systems. S/Se alkyl substituted phenols are efficient scavengers of hydroperoxides and have recently been shown to display efficient chain-breaking activity.1,2 Along this line 5-S-lipoylhydroxytyrosol (1) and its polysulfides 2-4 were prepared by conjugation of hydroxytyrosol with dihydrolipoic acid. 3 Compound 1 exhibited significant activity in the ferric reducing/antioxidant power (FRAP) assay (1.60 Trolox equivalents), while polysulfides 2-4 were more efficient in the DPPH reduction assay (88-93% reduction vs. 68% by Trolox). At 10 \uf06dM 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 non-toxic and exhibited marked protective effects against reactive oxygen species (ROS) generation (60-84% inhibition at 1 \uf06dM concentration) and cell damage induced by 400 \uf06dM tert-butylhydroperoxide. All compounds 1-4 exhibited overall greater antioxidant activity than hydroxytyrosol. Benzo[b]selenophene and diselenide derivatives of resveratrol (5-8) were also prepared and they proved to be more potent than the parent compound in the DPPH assay. The diselenide derivative 8 was also found to act as an efficient glutathione peroxidase mimic in preliminary experiments. The new hydroxytyrosol and resveratrol derivatives represent promising lead structures for the development of innovative antioxidants inspired to natural products