# Pharmacophore-Directed  Retrosynthesis Applied to Bioactive Natural Products Informing Mechanism of Action Studies

> **NIH NIH R35** · BAYLOR UNIVERSITY · 2020 · $273,570

## Abstract

Project Summary/Abstract
 While ‘diversity-oriented,’ ‘biology-oriented,’ and ‘analogue-oriented’ syntheses have contributed to
Wender’s call for ‘function-oriented synthesis,’ the simultaneous alignment of total synthesis efforts with structure
activity relationship (SAR) studies has not been fully realized. This is particularly true with natural products where
little to no SAR information exists. Bringing hypotheses regarding a targeted natural product's pharmacophore
into the retrosynthetic planning stages of a total synthesis effort would dramatically accelerate the identification
of simplified, bioactive derivatives as lead compounds for therapeutic intervention.
 Our chemical and biological studies of natural products possessing a broad range of cellular effects will
be guided by the following inquiry: Can total synthesis efforts, in particular with limited SAR and unknown cellular
targets, be more closely aligned to biological studies by targeting designed derivatives possessing a
hypothesized pharmacophore during the retrosynthetic planning stages to enable SAR studies to be conducted
en route to the natural product? Our study will develop a type of innovative retrosynthetic analysis that more
closely aligns total synthesis efforts with concurrent biological studies. We term this strategy ‘pharmacophore-
directed retrosynthesis’ (PDR) to emphasize the importance of considering hypothesized pharmacophores at
the retrosynthetic planning stage of a total synthesis effort. This approach will importantly lead to the identification
of simplified versions of the natural product with similar potency or potentially new functions in route to the natural
product. While this approach increases the challenges of natural product total synthesis beyond important,
contemporary goals, including atom-economy, step and redox efficiency, and protecting group avoidance,
significantly it will greatly accelerate harvesting of the vast information content of natural products for basic cell
biology and medicine. This strategy begins with a hypothesized pharmacophore for a bioactive natural product
which informs and directs the retrosynthetic strategy. Stepwise, methodical introduction of complexity to the
hypothesized pharmacophore enables concurrent SAR data collection which in turn informs cellular probe
synthesis. A fruitful group of ongoing collaborators, including molecular, cell, and cancer biologists and chemical
biologists will utilize our natural product-based probes to contribute to fundamental advances in cell biology.
Overall, our proposed synthetic studies, combined with collaborative biological studies, will both open new
avenues for novel therapeutics, and contribute to a greater understanding of basic cellular mechanisms involved
in human disease including bacterial infection, inflammation, cardiovascular, Alzheimer’s disease, and cancer.
 The proposed research will demonstrate the importance of closely engaging total synthesis efforts with
biolog...

## Key facts

- **NIH application ID:** 9851517
- **Project number:** 1R35GM134910-01
- **Recipient organization:** BAYLOR UNIVERSITY
- **Principal Investigator:** DANIEL ROMO
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $273,570
- **Award type:** 1
- **Project period:** 2020-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851517

## Citation

> US National Institutes of Health, RePORTER application 9851517, Pharmacophore-Directed  Retrosynthesis Applied to Bioactive Natural Products Informing Mechanism of Action Studies (1R35GM134910-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9851517. Licensed CC0.

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