Enabling Elucidation of the Biological Activity of Resveratrol Natural Products with Synthesis

通过合成阐明白藜芦醇天然产物的生物活性

• 批准号: 9219786
• 负责人: Corey Stephenson
• 金额: $ 27.11万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9219786
• 关键词: Acids; Affinity; Aging; Anti-Inflammatory Agents; Anti-inflammatory; Antidiabetic Drugs; Antioxidants; Apoptotic; Architecture; Belief; Binding; Biological; Biological Process; Biological Products; Biomimetics; Cell Culture Techniques; Characteristics; Chemicals; Chemistry; Collaborations; Collection; Communities; Complex; Consumption; Coupling; Degenerative Disorder; Development; Dimerization; Electrons; Employee Strikes; Epidemiology; Evaluation; Free Radicals; Gene Expression; Gene Expression Regulation; Genomics; Health; Health Benefit; Homeostasis; Human; In Vitro; Incidence; Industry; Investigation; Kinetics; Laboratories; Letters; Libraries; Life Extension; Ligands; Lipid Bilayers; Longevity; Measurement; Measures; Methodology; Methods; Molecular; Molecular Probes; Natural Products; Organic Synthesis; Oxidation-Reduction; Oxidative Stress; Paper; Phenols; Physiological; Preparation; Property; Proteins; Reactive Oxygen Species; Reporting; Research; Response Elements; Resveratrol; Role; Route; Series; Signal Transduction; Supplementation; Universities; aqueous; base; cellular targeting; dimer; epidemiology study; experimental study; food consumption; high throughput screening; indoline; inhibitor/antagonist; interest; lipid peroxidation inhibitor; oxidation; perhydroxyl radical; professor; prophylactic; quinone methide; red wine; screening

PROJECT SUMMARY The current level of public interest concerning the health benefits of antioxidant supplements is remarkable and is driven by the belief – on the basis of epidemiological evidence – that the consumption of foods that are rich in antioxidants is associated with lower incidence of degenerative disease and corresponding increase in longevity. Resveratrol is a particularly striking example, and one where its biological activity and its oligomers has been a highly contentious topic of debate for nearly 20 years. There is significant evidence that resveratrol has anticancer, antidiabetic, and anti-inflammatory action, as well as life extension properties. The mechanism of action for a simple molecule such as resveratrol is difficult to elucidate, since it is a relatively promiscuous ligand that has low binding affinity towards its target proteins. As a consequence of electron rich phenols, it is tempting to attribute many of these beneficial properties to its ability to act as an antioxidant. Indeed, this association of antioxidant capacity and its implications for human health has made radical quenching experiments ubiquitous in the isolation papers of resveratrol based natural products. Despite extensive research within this arena, there remains controversy over the benefits of antioxidants and their role in regulating oxidative stress. In particular, there is a paucity of mechanistic understanding of the mode of action of antioxidants and their metabolites at a molecular level. Accurate measurements of the kinetics of ROS (reactive oxygen species) quenching by resveratrol are much more relevant to understanding the role of resveratrol as an antioxidant and its biological activity. In fact, the kinetics of this radical trapping by resveratrol suggest that it is highly unlikely that its primary role is that of an antioxidant in a biological setting. In conjunction with the group of Professor Derek Pratt (University of Ottawa), we will: (1) Develop cross-coupling methodologies using persistent radicals for the synthesis of dihydrobenzofuran-containing resveratrol natural products andbroadly evaluate the biological activity of these compounds; and (2) Determine the kinetics of peroxyl radical-trapping of the compounds prepared in aim 1 in organic and aqueous solution, lipid bilayers and cell culture; determine the anti-ferroptotic potential of good inhibitors of lipid peroxidation and the anti-apoptotic potential of good inhibitors of cytosolic ROS formation; determine the kinetics, mechanisms and products of resveratrol autoxidation under physiologically-relevant conditions and extend these studies to resveratrol dimers/oligomers; determine the electrophilic potential of resveratrol’s oxidative degradation products and carry out experiments to identify their cellular targets; extend these studies to resveratrol dimers/oligomers.

项目摘要 有关抗氧化剂补充剂健康益处的当前公共利益水平是 杰出的，并由这种信念（在流行病学证据的基础上）驱动 消费富含抗氧化剂的食物与较低的事件有关 退化性疾病和相应的寿命增加。白藜芦醇特别是 引人注目的例子，以及其生物活性及其低聚物的一个高度 有争议的辩论主题已有近20年。有大量证据表明白藜芦醇有 抗癌，抗糖尿病和抗炎作用以及生命延长特性。 简单分子（例如白藜芦醇）的作用机理很难阐明，因为它是 一种相对滥交的配体对其靶蛋白的结合亲和力较低。作为 富含电子酚的结果，很容易归因其中许多有益的 其具有抗氧化剂的能力的特性。确实，这种抗氧化能力的关联 它对人类健康的影响使根本的淬火实验无处不在 白藜芦醇天然产物的隔离论文。尽管有广泛的研究 竞技场，关于抗氧化剂的好处及其在调节中的作用仍然存在争议 氧化应激。特别是，对模式的机械理解很少 抗氧化剂及其代谢产物在分子水平上的作用。准确的测量 白藜芦醇淬灭ROS（活性氧）的动力学（活性氧）与 了解白藜芦醇作为抗氧化剂及其生物学活性的作用。实际上， 白藜芦醇的这种根本捕获的动力学表明，其主要作用极不可能 是在生物环境中的抗氧化剂。与德里克教授一起结合 普拉特（渥太华大学），我们将：（1）使用持久性开发交叉耦合方法 用于合成含二氢呋喃的白藜芦醇天然产物的自由基 并在路口评估这些化合物的生物学活性； （2）确定动力学 在有机和水溶液中AIM 1中制备的化合物的过氧基自由基捕获 脂质双层和细胞培养；确定脂质良好抑制剂的抗凋亡潜力 胞质ROS形成良好抑制剂的过氧化和抗凋亡潜力； 确定白藜芦醇自动氧化的动力学，机制和产物 与物理相关的条件，并将这些研究扩展到白藜芦醇二聚体/低聚物； 确定白藜芦醇氧化物降解产物的亲电潜力并携带 消除实验以鉴定其细胞靶标；将这些研究扩展到白藜芦醇 二聚体/低聚物。