# Synthesis of a Bridged Bicyclic Natural Product Using Allenyl Esters

> **NIH NIH R15** · FLORIDA ATLANTIC UNIVERSITY · 2020 · $448,418

## Abstract

In this renewal application we propose to continue the development of new organic reactions for the facilitated
synthesis of natural product inspired bicyclic compounds (resveramorphs) that we have recently shown to
protect neuronal cells from oxidative stress. Specifically, several of our resveramorphs protect synaptic
transmission from acute oxidative stress in a fruit fly model (at the larval neuromuscular junction) at doses as
low as 100 pM. To our knowledge, this level of neuroprotective activity is unprecedented for a small molecule.
Moving forward, we seek to continue our focus on the chemistry of unique building blocks (allenoates), using
them to prepare these neuroprotective compounds as tools to characterize a potentially new cellular target for
neuroprotection against oxidative stress. Our chemical synthesis routes will make possible the compounds
needed to narrow down and identify the biological target, as well as to characterize small-molecule interactions
with that target. More specifically, we have recently discovered a new addition reaction of carbon nucleophiles
to unactivated carbon-carbon triple bonds that takes place in the absence of transition metals. We propose to
explore the synthetic potential of this reaction, elucidate its mechanism, and use it to more efficiently prepare
resveramorphs. In another aim, we seek an asymmetric route to resveramorph analogs by taking advantage of
the axial chirality properties of our allenoate building blocks. Ultimately, this organic reaction development is
expected to enhance accessibility to resveramorphs, which, based on our current studies, are beginning to
exhibit a structure/activity relationship (SAR). With the additional synthetic tools being proposed as part of this
renewal application, we propose to expand this SAR study to define those elements in the molecule important
for binding (pharmacophore) and ultimately identify an even more potent “tool compound” for biological study.
In this regard, our preliminary data indicate that resveramorphs act by stabilizing the resting membrane
potential and prolonging synaptic transmission. From this and other data, we hypothesize that resveramorphs
may be modulating potassium channels directly. Through a collaboration with a member of our Biology
Department (and coPI), the neuroprotective activity of resveramorphs will be examined. In this phase of the
project, genetic manipulations targeting potassium channels in two invertebrate models, Drosophila
melanogaster and Caenorhabditis elegans, are proposed to identify the biological target of our active analogs.
Ultimately, these studies are expected to provide a firm footing for future medicinal chemistry investigations to
identify novel agents against diseases such as Parkinson’s and Alzheimer’s.

## Key facts

- **NIH application ID:** 10046244
- **Project number:** 2R15GM110651-03
- **Recipient organization:** FLORIDA ATLANTIC UNIVERSITY
- **Principal Investigator:** SALVATORE D LEPORE
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $448,418
- **Award type:** 2
- **Project period:** 2014-04-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10046244

## Citation

> US National Institutes of Health, RePORTER application 10046244, Synthesis of a Bridged Bicyclic Natural Product Using Allenyl Esters (2R15GM110651-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10046244. Licensed CC0.

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