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.

项目概要 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，其驱动力是基于流行病学证据的信念： 食用富含抗氧化剂的食物与较低的发病率有关 白藜芦醇对退行性疾病和相应的寿命延长尤其有效。 一个引人注目的例子，其生物活性及其低聚物一直是高度关注的 近 20 年来一直争论不休的话题有重要证据表明白藜芦醇具有 抗癌、抗糖尿病和抗炎作用，以及延长寿命的特性。 白藜芦醇等简单分子的作用机制很难阐明，因为它是 相对混杂的配体，对其靶蛋白的结合亲和力较低。 富电子酚的结果，很容易将其中许多有益的归因于 事实上，这种抗氧化能力的关联。 及其对人类健康的影响使得激进的猝灭实验在世界各地无处不在 尽管对此进行了广泛的研究，但基于白藜芦醇的天然产品的分离论文。 关于抗氧化剂的益处及其在调节中的作用仍然存在争议 特别是，人们对氧化应激的机制缺乏了解。 在分子水平上准确测量抗氧化剂及其代谢物的作用。 白藜芦醇猝灭 ROS（活性氧）的动力学与 了解白藜芦醇作为抗氧化剂的作用及其生物活性。 白藜芦醇这种自由基捕获的动力学表明，它的主要作用不太可能是 是与德里克教授小组合作的生物环境中的抗氧化剂。 Pratt（渥太华大学），我们将：（1）使用持久性开发交叉耦合方法 自由基用于合成含二氢苯并呋喃的白藜芦醇天然产物 (2) 确定动力学 目标1中制备的化合物在有机溶液和水溶液中的过氧自由基捕获， 脂质双层和细胞培养；确定良好的脂质抑制剂的抗铁死亡潜力 细胞质 ROS 形成良好抑制剂的过氧化和抗凋亡潜力； 确定白藜芦醇自氧化的动力学、机制和产物 生理相关条件并将这些研究扩展到白藜芦醇二聚体/寡聚体； 测定白藜芦醇氧化降解产物的亲电势并携带 进行实验以确定其细胞靶标；将这些研究扩展到白藜芦醇； 二聚体/低聚物。