# Pharmacophore Directed Retrosynthesis Toward the Anti-Inflammatory Agent Rameswaralide and Anti-Cancer Agent Ineleganolide

> **NIH NIH F31** · BAYLOR UNIVERSITY · 2020 · $42,372

## Abstract

Project Summary. The study of natural products has impacted drug discovery dramatically from the standpoint
of identifying novel therapeutic targets and drug leads. Herein, we propose to apply our group’s ‘Pharmacophore-
Directed Retrosynthesis (PDR) concept to the synthesis and biological studies of two structurally, and biologically
intriguing natural products, rameswaralide and ineleganolide, having anti-inflammatory and anticancer activity,
respectively. Due to the complex structure of many natural products, their use as therapeutics can be limited if
an adequate supply is not available through, for example, fermentation or from a renewable source. With this in
mind, we will pursue a total synthesis of these natural products guided by PDR to enable the identification of
simplified equipotent lead molecules in route to the natural products. The pharmacophore of these natural
products is hypothesized to be the common 5,5,7 tricyclic core. The core will be accessed in a concise manner
through an organocatalyzed, Diels-Alder-Lactonization (DAL) cascade involving a kinetic resolution developed
in our laboratory followed by a ring expansion. We propose that the disparate biological activity of these natural
products is derived from the structural variations beyond the common 5,5,7-tricyclic core. Systematic annulation
onto this tricyclic core of (i) a substituted cyclohexanone in the case of rameswaralide and (ii) both a substituted
cyclohexanone and tetrahydrofuran through intramolecular oxa-Michael addition in the case of ineleganolide,
will provide extensive SAR data. Over the course of our synthetic endeavors, Prof. Jun Liu’s group (Johns
Hopkins) will assay synthetic intermediates leading up to rameswaralide and ineleganolide for anti-inflammatory
and anti-cancer activity, respectively. These data will further refine the synthesis of proposed alkynylated cellular
probes for subsequent cellular target identification in collaboration with Prof. Jun Liu’s Laboratory (Johns Hopkins
University). The proposed research seeks to identify an equipotent, simplified derivative of these natural products
as potential anti-inflammatory and anticancer drug leads while also potentially revealing novel cellular targets for
therapeutic intervention of human disease. A caveat to our hypothesis is that the fully or almost fully
functionalized natural product may be required for the observed bioactivity; however, application of a PDR
approach has the potential to identify simpler derivatives prior to completion of a total synthesis.
Hypothesis. We hypothesize that the common 5,5,7 core tricycle of rameswaralide and ineleganolide is the
pharmacophore of these bioactive natural products. We further hypothesize that the selectivity and disparate
bioactivity, namely anti-inflammatory and anticancer activity, observed for these structurally related natural
products arises from a substituted cyclohexanone in the case of rameswaralide and both a substituted
cyclohexanone...

## Key facts

- **NIH application ID:** 9899090
- **Project number:** 5F31CA239560-02
- **Recipient organization:** BAYLOR UNIVERSITY
- **Principal Investigator:** Nathanyal J Truax
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $42,372
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899090

## Citation

> US National Institutes of Health, RePORTER application 9899090, Pharmacophore Directed Retrosynthesis Toward the Anti-Inflammatory Agent Rameswaralide and Anti-Cancer Agent Ineleganolide (5F31CA239560-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9899090. Licensed CC0.

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