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.

项目总结 目前公众对抗氧化剂补充剂的健康益处的关注程度是 值得注意的是，根据流行病学证据，人们相信 食用富含抗氧化剂的食物与较低的发病率有关 退化性疾病和相应的寿命延长。白藜芦醇是一种特殊的 一个引人注目的例子，它的生物活性和它的低聚物一直是一个高度 争论了近20年的话题。有重要证据表明，白藜芦醇对 具有抗癌、抗糖尿病、消炎、延年益寿等功效。这个 白藜芦醇这样的简单分子的作用机制很难阐明，因为它是 一种相对混杂的配基，与其目标蛋白的结合亲和力较低。作为一名 富含电子的酚类的结果，人们很容易将这些有益的东西归因于 其作为抗氧化剂的能力。事实上，这种抗氧化能力的联系 它对人类健康的影响使得激进的猝灭实验在 白藜芦醇类天然产物分离试纸。尽管在这一领域进行了广泛的研究 Arena，关于抗氧化剂的好处及其在调控中的作用仍存在争议 氧化应激。特别是，人们对这种模式缺乏机械性的理解。 抗氧化剂及其代谢产物在分子水平上的作用。精确的测量结果 白藜芦醇猝灭ROS(活性氧物种)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。事实上， 白藜芦醇捕获自由基的动力学表明，它的主要作用是 是一种生物环境中的抗氧化剂。与德里克教授的小组合作 PRATT(渥太华大学)，我们将：(1)使用持久的 二氢苯并呋喃类白藜芦醇天然产物合成中的自由基 并广泛评价这些化合物的生物活性；以及(2)测定动力学 在有机和水溶液中捕获在目标1中制备的化合物的过氧基自由基， 脂类双层和细胞培养.测定良好的脂类抑制剂的抗铁上链能力 胞质ROS形成的良好抑制剂的过氧化和抗凋亡潜力； 白藜芦醇自氧化反应动力学、机理及产物的测定 生理相关条件，并将这些研究扩展到白藜芦醇二聚体/低聚物； 测定白藜芦醇氧化降解产物和载体的亲电电位 开展实验以确定其细胞靶点；将这些研究扩展到白藜芦醇 二聚体/低聚物。