Synthesis of Resveratrol Natural Products and Evaluation of their Antioxidant Properties

Abstract

Numerous reports exist for the biological properties of resveratrol natural products and many clinical trials have been initiated based on promising preliminary evidence that these compounds have promising therapeutic potential. Many of these clinical trials end with inconclusive results and evidence of side effects that may hinder future clinical trials. There is much that is unknown about this class of natural products which underscores the need to develop new methodologies of the synthesis of these compounds in scalable quantities that will fuel future research studies. This dissertation discloses the advancements made for the synthesis of natural products and their analogues as well as the radical trapping antioxidant properties of those synthesized. The syntheses of natural products and analogues will help serve future structure activity relationship (SAR) studies to make unequivocal conclusions regarding the biological properties of resveratrol natural products. Chapter 1 describes the biosynthetic pathway for resveratrol synthesis and the proposed radical-based oligomerization strategy that could produce higher order oligomers. An introduction of radical-based methods in total synthesis as well as the persistent radical effect is provided. The biological properties of resveratrol natural products are also described therein. Chapter 2 describes an electrochemical methodology that was developed for the synthesis of C8 – C8’ bis-quinone methide dimers and tetramers and C3 – C8’ dihydrobenzofuran resveratrol dimers. The results of this methodology created a library of quadrangularin A analogs that were evaluated for the radical trapping antioxidant properties. Chapter 3 presents that the C8 – C8’ bis quinone methide dimers were found to be persistent radicals that were able to undergo intermolecular coupling to produce dihydrobenzofuran motieties found in numerous resveratrol-derived natural products. This synthetic strategy has helped drive the synthesis of resveratrol trimer analogs. Chapter 4 presents the efforts made to evaluate the radical-trapping antioxidant properties of synthesized natural products as well as their synthetic precursors. Through collaboration, these natural products, natural product analogs, and commercially purchased phenols and polyphenols were also evaluated for their radical trapping antioxidant activities. The results from this study are as follows: C8 – C8 bisquinone methide dimers are good antioxidants in organic solutions but fail to inhibit autoxidation in liposomes due to their mechanism of action (via dissociation). The antioxidant potential of phenols is reliant on lipophilicity and substitutions that stabilize the resulting phenoxy radical. The antioxidant potential of resveratrol natural products is also reliant on lipophilicity and alkylated natural product precursors behave as better antioxidants. Surprisingly, analogs containing hindered phenols on substituted dihydrofurans about an unprotected resorcinol have increased radical trapping activities and trap more equivalents than those that lack the sterically encumbering alkylations or have protected resorcinols. Cell studies performed to ascertain the ability of these antioxidants to prevent ferroptosis in cells generated results that were parallel to the liposome studies indicating that the substitutions and structural motifs that permit good activity in liposomes are needed to rescue cells from ferroptosis. Preliminary data shows that hindered phenols can work synergistically with resorcinols in the same way that occurs between vitamin E and vitamin C. These results support that resveratrol antioxidants could work in a similar synergistic manner.