Natural polyphenols as lead compounds in the synthesis of antitumor agents and other useful products

Abstract

NATURAL POLYPHENOLS AS LEAD COMPOUNDS IN THE SYNTHESIS OF ANTITUMOR AGENTS AND OTHER USEFUL PRODUCTS Abstract Some polyphenol dimers, such as lignans, neolignans and stilbenoid lignans, because of their biological properties as well as their structural variety, are an attractive target for chemical synthesis or modification. These polyphenols may be considered lead compounds to obtain products with useful properties, for instance as possible antitumor agents. Thus, this three year research work has been oriented to the synthesis of new dimers, obtained by biomimetic oxidative coupling of natural polyphenols belonging to the stilbenoid and phenylpropanoid families, namely resveratrol or caffeic acid analogues. To this purpose we employed both chemical and enzymatic methods; in particular, metal-mediated reactions were used for the synthesis of nitrogenated lignans with a benxanthene core, whereas stilbenolignans were also obtained with laccase-mediated reactions. During this work, an unexpected enzymatic reaction afforded an hydantoin-related product and this result is also reported herein. The results of this research are discussed mainly in chapter 2, where three sections are reported: 1) Biomimetic synthesis of stilbenolignans 2) Biomimetic synthesis of benzo[k,l]xanthene lignanamides 3) Enzymatic synthesis of hydantoin-related compounds In each section, we have reported in detail the synthesis, structural determination, and mechanism of the formation of the products. The final goal of our project was to obtain a library of bioactive compounds to be addressed to biological evaluation with the aim to establish structure-activity relationships for a future optimization of the most promising products. The biological evaluation has been completed for the stilbenolignan group and it is in progress for the other compounds.