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 目前公众对抗氧化剂补充剂的健康益处的兴趣程度是 值得注意的是，这是由信念驱动的-根据流行病学证据- 食用富含抗氧化剂的食物与低发病率有关。 退行性疾病和相应的寿命增加。白藜芦醇是一种 一个引人注目的例子，它的生物活性及其低聚物一直受到高度关注 这是一个争论了近20年的话题。有明显的证据表明，白藜芦醇 抗癌、抗糖尿病和抗炎作用，以及延长寿命的特性。的 一个简单分子如白藜芦醇的作用机制很难阐明，因为它 一种相对混杂的配体，对其靶蛋白具有低结合亲和力。作为 由于富含电子的酚类，很容易将许多这些有益的 它作为抗氧化剂的能力。事实上，这种抗氧化能力 及其对人类健康的影响，使得自由基淬灭实验在世界上无处不在。 基于白藜芦醇的天然产物的分离纸。尽管在这方面进行了广泛的研究， 在竞技场上，抗氧化剂的益处及其在调节 氧化应激特别是，缺乏机械的理解模式， 抗氧化剂及其代谢物在分子水平上的作用。精确测量 白藜芦醇对ROS（活性氧）淬灭的动力学更相关于 了解白藜芦醇作为抗氧化剂的作用及其生物活性。实际上 白藜芦醇捕获自由基的动力学表明，其主要作用 是一种抗氧化剂在生物环境中的作用。与德里克教授的团队一起 Pratt（渥太华大学），我们将：（1）开发交叉耦合方法，使用持久 用于合成含二氢苯并呋喃的白藜芦醇天然产物的自由基 并对这些化合物的生物活性进行了广泛的评价;（2）测定了这些化合物的动力学 在有机溶液和水溶液中捕获在AIM 1中制备的化合物的过氧自由基， 脂质双层和细胞培养;确定良好的脂质抑制剂的抗铁中毒潜力 过氧化和细胞溶质ROS形成的良好抑制剂的抗凋亡潜力; 确定白藜芦醇自氧化的动力学，机制和产品， 生理相关的条件，并将这些研究扩展到白藜芦醇二聚体/低聚体; 测定白藜芦醇氧化降解产物的亲电电位， 进行实验以确定它们的细胞靶点;将这些研究扩展到白藜芦醇 二聚物/低聚物。