# A Divergent Platform to Chemically Redesign Bioactive 5-8-5 Terpenoids

> **NIH NIH R01** · FLORIDA STATE UNIVERSITY · 2024 · $319,477

## Abstract

PROJECT ABSTRACT
 Natural products continue to have a disproportionate impact on how we understand and treat disease. These
biologically pre-validated therapeutic leads have inspired ~50% of FDA-approved drugs, a fact underscores the
importance of studying biogenic chemotypes with unique activity in cell culture. Inspired by the rich opportunities
for natural products at the interface of chemistry, biology, and medicine, this proposal focuses on a family of
terpenoids distinguished by a fused [5-8-5] carbocyclic molecular framework. The flagship members of this family
possess impactful, albeit divergent, pharmacological profiles. For example, fusicoccin A stabilizes 14-3-3 protein-
protein interactions (PPIs), ophiobolin A is a cytotoxic membrane disruptor, and bipolarolide A inhibits HMG-CoA
reductase. The specificity of these terpenoids for their diverse biological receptors is determined by the identity
and arrangement of substituents surrounding a common 5-8-5 substructure. Given the complex conformational
dynamics of cyclooctanoids, we postulate that the groups flanking the central eight-membered ring modulate the
overall molecular shape. This potentially programmable feature might allow this terpenoid family to interface with
diverse biological receptors. Thus, the [5-8-5] ring system appears to be a privileged scaffold for the design of
novel therapeutics. However, existing approaches to this family of terpenoids rely on convergent, target-specific
chemistry. Viewed through the lens of drug discovery, the lack of chemistry to diversify the [5-8-5] motif is the
main impediment to understanding and advancing the pharmacology of this natural product family.
 During the past grant period, we developed a synthetic platform to prepare and edit the fusicoccin scaffold.
We now seek to extend this chemistry in several directions. In Aim 1, we will exploit our platform to establish the
features of fusicoccin A that impart selectivity for individual 14-3-3 PPIs. In doing so, we bring a unique chemical
perspective to the long-standing problem of selectively modulating the 14-3-3 interactome. In Aim 2, we will
extend our synthetic strategy to capture ophiobolin A and bipolarolide A. These isomeric sesterterpenes feature
peripheral and skeletal modifications to the 5-8-5 scaffold that cannot be addressed by existing chemistry. We
outline an enabling synthetic entry point to these molecules from a common 5-8-5 intermediate. Thus, successful
completion of the proposed research will establish a divergent platform to chemically redesign [5-8-5] terpenoid
chemotypes. It will also establish whether the fusicoccins can be exploited to interrogate specific components of
the 14-3-3 interactome in cell culture. This research will signifyingly broaden access to [5-8-5] terpenoid natural
products with diverse pharmacological profiles and shed light on how to chemically evolve this chemotype toward
a specific functional endpoint.

## Key facts

- **NIH application ID:** 10804653
- **Project number:** 5R01GM125926-07
- **Recipient organization:** FLORIDA STATE UNIVERSITY
- **Principal Investigator:** JAMES H. FREDERICH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $319,477
- **Award type:** 5
- **Project period:** 2017-09-15 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10804653

## Citation

> US National Institutes of Health, RePORTER application 10804653, A Divergent Platform to Chemically Redesign Bioactive 5-8-5 Terpenoids (5R01GM125926-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10804653. Licensed CC0.

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