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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

基本信息

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
项目类别：
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

项目摘要

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