Synthesis Research And Activity Evaluation Based On Natural Stilbenoids

Natural stilbenoids, constructed based on1,2-stilbene backbone, is a kind of natural polyphenols. Because of the diverse bioactivities of resveratrol, a stilbene monomer, related research works have attracted much attention since late1990s. The nutritional and pharmaceutical values of resveratrol have long been recognized and accepted by scientific community and pharmaceutical industry. However, as an important kind of natural resveratrol derivatives, stilbene oligomers are not well studied due to their low contents in natural resources, difficulty in isolation and systhesis. Focusing on natural stilbenoids, in this dissertation we developed some biomimetic enzymatic methodology of resveratrol oligomers, evaluated their antioxidant activities and systematically studied the Nrf2inducing activities of imine resveratrol analogs. The results include,1. pH-switched Horseradish Peroxidase (HRP) catalyzed selective oxidative dimerization of resveratrol. In dimerization process of resveratrol catalyzed by HRP, subtle chemoselectivity was achieved by concisely adjusting the aqueous pH of the solvent system. Five resveratrol dimers, pallidol, leachianol F, leachianol G, trans-δ-viniferin and cis-δ-viniferin were selectively synthesized using this strategy. And two other resveratrol dimers, parthenocissin A and quadrangularin A, were further obtained derivatively. This strategy made it possible to further investigate the activities of these resveratrol dimers. The mechanism of this selective process was also discussed.2. Metal-HRP complex catalyzed oxidation of resveratrol. Ten different metal ions were used to incorporate with HRP to form [HRP-M] complexes, and the formed complexes were screened in their catalytic capacity in oxidation of resveratrol. Among them, Ca2+could decrease the catalytic activity of HRP;[HRP-Mn11] can selectively catalyze the dimerization of resveratrol, obtaining trans-δ-viniferin in92%yield; while [HRP-Cu6] or [HRP-Fe3] catalyzed oxidative decomposition of resveratrol, forming4-hydroxylbenzaylaldehyde and3,5-dihydroxylbenzylacid. The mechanism was also discussed with the help of control experiments and spectroscopic methods.3. Antioxidant activities of three resveratrol dimers. The direct and indirect antioxidant activities of three resveratrol dimers, pallidol, parthenocissin A and quadrangularin A were evaluated, which were obtained using the enzymatic methods provided in the first two chapters. All three resveratrol dimers are strong DPPH scavengers, and they can selectively quench singlet oxygen (1O2). Quadrangularin A was found among the most effective natural singlet oxygen scavengers. Besides, pallidol can activate the Keap1-Nrf2-ARE in cells, and achieve the antioxidant activity indirectly.4. Nrf2inducing activities of imine resveratrol analogs (IRAs).34IRAs were designed and their Nrf2inducing activities were scavenged. It is found that6-OH IRAs have the strongest inducing activities towards Nrf2based on preliminary and quantitative SAR studies. Two novel analogs were then designed and further proved to be strong Nrf2inducers. The molecular mechanism of the Nrf2activating process of IRAs was also proposed.