【作者】 李畅；

【导师】 潘远江；

【作者基本信息】 浙江大学 ， 化学， 2014， 博士

【摘要】 天然芪类化合物是一类以1,2-二苯乙烯为骨架结构的天然多酚类化合物。由于芪类单体白藜芦醇的多种生物活性,上世纪90年代后期以来,针对其进行的研究工作越来越受到重视,白藜芦醇的潜在营养和药用价值也逐渐被科学界及医药工业界所认识与认可。而作为一类重要的白藜芦醇天然衍生物,芪类低聚体由于其在自然界中含量低、难以分离、缺乏有效的合成方法,所以针对其活性的研究很少见诸报道。本论文主要围绕天然芪类化合物展开,对白藜芦醇低聚体的酶促仿生合成与抗氧化活性,以及亚胺类白藜芦醇类似物对Nrf2的激活作用都做了系统性的研究。研究结果主要包括以下几个方面：1.pH调控的辣根过氧化物酶催化白藜芦醇选择性氧化二聚：通过调节反应溶剂体系中水相的pH,可以使得辣根过氧化物酶催化白藜芦醇氧化二聚反应实现精细的选择性。我们实现了pallidol, leachianol F, leachianol G,trans-δ-viniferin和cis-δ-viniferin五种白藜芦醇二聚体的酶催化选择性合成,并衍生合成了另外两个白藜芦醇二聚体parthenocissin A与quadrangularin A,为进一步对其进行生物活性的筛选提供了可能。本论文还对实现该选择性的机制进行了探讨。2.金属-辣根过氧化物酶复合物催化的白藜芦醇氧化反应：本论文筛选了10种不同金属,使其与辣根过氧化物酶作用形成[HRP-M]复合物。[HRP-M]复合物在催化白藜芦醇氧化过程中表现出不同的活性,Ca2+可大幅降低酶的催化活性;[HRP-Mn11]可以92%的产率选择性催化生成二聚体trans-δ-viniferin;[HRP-Cu6]和[HRP-Fe3]则可催化白藜芦醇氧化分解,生成4-羟基苯甲醛与3,5-二羟基苯甲酸。本论文还利用对照实验结合光谱方法对该过程的机制进行了探讨。3.三种白藜芦醇二聚体的抗氧化活性：利用合成的白藜芦醇二聚体样品,本论文考察了pallido、parthenocissin A和quadrangularin A的直接和间接抗氧化能力。三种白藜芦醇二聚体对DPPH均有较强的清除作用,可选择性地清除单线态氧102,其中quadrangularin A是目前己知的最强的天然单线态氧清除剂之一。此外,pallidol还可以激活Keap1-Nrf2-ARE通路,间接起到抗氧化的作用。4.亚胺类白藜芦醇类似物对Nrf2的激活作用：本论文设计合成了34种亚胺类白藜芦醇类似物,并对其Nrf2激活作用进行了筛选。经过构效关系分析,发现6-OH取代的亚胺类白藜芦醇类似物有最强的Nrf2激活作用。在此基础上,本论文设计合成了两个新的类似物,均可实现Nrf2的高效激活。本论文也提出了该类化合物激活Nrf2的分子机制。更多还原

【Abstract】 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.更多还原