SYNTHESIS, SAR AND BIOLOGICAL STUDIES OF NATURAL AND NATURE-INSPIRED POLYPHENOLS

Polyphenols represent a wide class of diverse natural products, largely present in our diet, which have attracted the interest of several scientists in the last decades because of their beneficial effects on human health. Despite of intensive research efforts, the mechanisms of action of these compounds are still largely mysterious. This is partially due to the lack of a systematic investigation of single pure compounds with respect to several studies on complex mixtures from plant extracts. In addition, polyphenols are well known to undergo extensive hepatic and intestinal metabolism, which is of particular interest since metabolites can be responsible for both beneficial and toxic effects of dietary polyphenols. In this scenario, the purpose of this PhD thesis was to develop synthetic strategies to obtain pure natural polyphenols and their analogues for systematic studies on their biological activity and to investigate the metabolites of this class of compounds. The first part of this PhD thesis focused on resveratrol-derivatives, known as stilbenoids, a class of phytoalexins, produced by plants as means of defence against pathogens invasion and stress factors. In spite of the huge number of scientific reports on resveratrol, systematic studies on resveratrol-derived compounds are quite scarce. This derives from the difficulty to isolate and purify these compounds by extraction procedures from natural sources. In order to address this issue, we aimed at developing efficient and versatile biocatalytic and synthetic approaches to obtain natural-resveratrol derivatives in substantial amounts for their biological evaluation. Moreover, design and synthesis of new stilbenoid analogues were carried out for structure-activity-relationship (SAR) studies in order to identify the molecular features of the most active compounds involved in the interaction with biological targets. In addition, the synthetic strategies developed would allow to obtain new chemical entities with improved pharmacodynamic and pharmacokinetic characteristics with respect to the natural precursors. In particular, the compounds were tested as antimicrobials and as inhibitors of α-amylase, fundamental enzyme in glucose metabolism. The second part of this PhD thesis dealt with xanthohumol, the main prenylflavonoid found in hops and beer, endowed with several bioactivities. By LC-MS/MS, we identified and quantified xanthohumol metabolites in humans, which could be responsible for both beneficial and toxic effects of the natural precursor. The investigation of differences in xanthohumol metabolism in humans would reflect inter-individual differences in microbiota composition, and consequently in metabolic profiles. In addition, the last chapter described the development of a synthetic strategy to build a chemical probe of xanthohumol for the identification of its biological targets. In particular, efforts were made to selectively functionalize the prenyl chain of xanthohumol, without affecting the other parts of the molecule, which were supposed to be relevant to the interaction with the target.