Chemistry and bioactivity of natural polyphenols

Natural polyphenols exhibit several beneficial effects most notably protection against oxidative stress and degenerative diseases, which can be ascribed largely to their intrinsic capabilities to act as antioxidant or antinitrosating agents. This work has led to definition of the reaction pathways of a number of polyphenols, with special reference to their transformations when acting as antioxidant or antinitrosating agents under conditions of physiological relevance. The H2O2-dependent oxidative pathway of hydroxytyrosol, the well known antioxidant from extra virgin olive oil, was defined evidencing the marked nucleophilic character of hydroxylated compounds generated by addition of hydrogen peroxide to the ortho-quinone of hydroxytyrosol. The reactions of stilbene resveratrol and piceatannol, occurring in red wines and grapes, toward acidic nitrite showed the tendency of these compounds to undergo nitration at the stilbene double bond and their susceptibility to oxidative cleavage under mild conditions. The nitrite scavenging effects of the dietary catechols caffeic acid, chlorogenic acid, piceatannol, hydroxytyrosol and their S-glutathionyl conjugates were assessed by the 2,3-diaminonaphthalene (DAN) nitrosation and tyrosine nitration assays. In the DAN assay the 5-S-glutathionylpiceatannol was found to be the most active, while in the tyrosine assay chlorogenic acid was the best inhibitor, suggesting that the antinitrosating properties do not correlate straightforwardly with the antioxidant activity for these compounds. The antioxidant properties of a new derivative of hydroxytyrosol with dihydrolipoic acid, 5-S-lipoylhydroxytyrosol, were also evaluated showing a higher radical scavenging activity with respect to the parent compound. In a related study the reactivity of menthofuran, a naturally occurring furan derivative found in mint oils, with nitric acid and nitrous acid was comparatively investigated. In the presence of sulfuric acid, nitric acid induced mainly fragmentation/dimerization reactions to give bis-furanyl adducts. By contrast, exposure to nitrous acid led to a complex pattern of products, including an unusual dimer with three different nitrogen functionalities. Among polyphenol metabolites of mammals cysteinyldopas, viz. the 5S and 2S isomers, the biosynthetic precursors of epidermal pheomelanins, characteristic of red-haired individuals have attracted particular interest. In this study the first direct synthesis of 2-S-cysteinyldopa by a three-step procedure with an overall 30% yield was developed which allows preparation of the compound on gram-scale for reactivity studies in the field. A detailed analysis of the chemical and spectrophotometric features of the main intermediates derived from cysteinyldopas in the build up of the pheomelanin chromophore allowed also to dissect the contribution of different structural units disproving the axiom that pheomelanin chromophore is determined only by benzothiazine systems.