# Enabling Elucidation of the Biological Activity of Resveratrol Natural Products with Synthesis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $260,590

## Abstract

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.

## Key facts

- **NIH application ID:** 9838233
- **Project number:** 5R01GM121656-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Corey Stephenson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $260,590
- **Award type:** 5
- **Project period:** 2017-02-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838233

## Citation

> US National Institutes of Health, RePORTER application 9838233, Enabling Elucidation of the Biological Activity of Resveratrol Natural Products with Synthesis (5R01GM121656-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9838233. Licensed CC0.

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