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.

Public Health Relevance

Reactive oxygen species (ROS) have been implicated in an enormous number of biological processes, including cell signaling, homeostasis, gene regulation, aging, and the onset of degenerative diseases. Despite extensive research within this arena, there remains controversy over the benefits of antioxidants in human health. Given the widespread public interest in resveratrol supplementation as a prophylactic measure (an industry earning $30 million per annum in the U.S. alone), it is critically important that we understand the biological mode of action of this compound and its various metabolites and their impact on human health. The concise biomimetic synthesis of the natural products in this proposal will enable the elucidation of biological mechanism of action of resveratrol derived antioxidants.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM121656-03
Application #
9610652
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2017-02-01
Project End
2020-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Romero, Kevin J; Galliher, Matthew S; Pratt, Derek A et al. (2018) Radicals in natural product synthesis. Chem Soc Rev 47:7851-7866
Romero, Kevin J; Galliher, Matthew S; Raycroft, Mark A R et al. (2018) Electrochemical Dimerization of Phenylpropenoids and the Surprising Antioxidant Activity of the Resultant Quinone Methide Dimers. Angew Chem Int Ed Engl 57:17125-17129