# Chemical synthesis to access rare heterocycles and tool compounds to probe bacterial polysaccharide metabolism

> **NIH NIH R35** · CLEMSON UNIVERSITY · 2024 · $361,107

## Abstract

Abstract
Two emphasis areas are proposed which are underpinned by synthetic organic chemistry. First, new synthetic
methodology to access exceptionally rare nitrogen-rich compounds will be developed to expand the availability
of medicinally relevant, densely functionalized heterocycles. We pioneered new methodology to synthesize the
rare diazacyclobutene (DCB) heterocycle. Less than ten examples of stable DCBs where previously known. The
dearth of examples has prevented their application in any biological or synthetic context. Nevertheless,
preliminary biological investigations show that some DCBs exhibit potent anti-parasitic activity, suggesting that
further development of the scaffold may unlock additional biological activity relevant to human disease.
Accessing new examples of DCBs will enable biological evaluation and expansion of the synthetic utility of the
heterocycle. Exploiting new reactivity of DCBs and related intermediates will provide new methods to synthesize
a large variety of medicinally relevant, richly functionalized heterocycles through the development of cascade
reactions of labile monocyclic DCB intermediates. Similarly, the intentional diversion of key reactive
intermediates with Lewis Acids will access additional rare heterocycles through novel mechanisms. The second
emphasis area will develop new non-microbicidal tool compounds to interrogate the polysaccharide metabolism
of gut bacteria of the Bacteroides genus. The enzymatic machinery deployed by the Bacteroides genus serves
as a model system to understand glycan foraging strategies deployed by the entire Bacteroidetes phylum, which
represents over half of the constituents of a normal healthy microbiota). Presently, our lab has uncovered the
only known chemical probes to interrogate this fundamental system governing carbohydrate utilization by
prominent gut microbes. Additionally, Bacteroides spp. are associated with common anaerobic bacterial
infections affecting multiple organ systems, sepsis, gut inflammatory and autoimmune diseases, and colorectal
cancer. Building on our prior discovery that the natural product acarbose shuts down the Starch Utilization
System (Sus) of Bacteroides spp., we will synthesize useful chemical probes to interrogate this fundamental
metabolic pathway deployed by prominent gut microbes for eventual therapeutic gain. Thus, we will provide tools
to clarify the mechanism of action of acarbose-induced arrest of bacterial starch metabolism by deploying
synthetic analogs bearing fluorophores and photoaffinity tags. This will also provide key fundamental knowledge
about the promiscuity of the probe with other Sus-like constructs. We will uncover potential downstream effects
on virulence factors (i.e. biofilm formation, antibiotic resistance, and toxin production) in the organisms upon
acarbose-mediated shutdown of the Sus. This work will lay important groundwork toward providing versatile tools
to understand gut microbial metabolism as it pertains...

## Key facts

- **NIH application ID:** 10841815
- **Project number:** 1R35GM153221-01
- **Recipient organization:** CLEMSON UNIVERSITY
- **Principal Investigator:** Daniel Charles Whitehead
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $361,107
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841815

## Citation

> US National Institutes of Health, RePORTER application 10841815, Chemical synthesis to access rare heterocycles and tool compounds to probe bacterial polysaccharide metabolism (1R35GM153221-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10841815. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*