# Synthetic and translational studies of antitumor and antimicrobial natural products

> **NIH NIH R35** · YALE UNIVERSITY · 2020 · $581,228

## Abstract

PROJECT SUMMARY/ABSTRACT:
Our research program seeks to elucidate the mechanism of action and structure–function relationships of bio-
active natural products, toward treatments for drug-resistant bacterial infections and cancer. The development
of syntheses that enable precise manipulation of each class of molecules, with correlated insights into mecha-
nism, are the unifying goals of each project. A major effort involves discovering new pleuromutilin antibiotics to
treat drug-resistant Gram-negative infections. Pleuromutilins are bivalent molecules with a glycolic ester resi-
due and a tricyclic skeleton that bind the P and A sites of the bacterial ribosome, respectively. While the gly-
colic acid ester has been extensively optimized, limitations in chemistry have historically prevented exploitation
of the tricyclic core. We developed semisynthetic and fully synthetic approaches to core-modified pleuromu-
tilins; we have thereby synthesized derivatives with potencies exceeding the natural product. We will further
develop this chemistry toward agents to treat carbapenem-resistant Enterobacteriaceae, pathogens for which
few existing antibiotics are effective. Resistance to pleuromutilins is slow to develop; a long-term goal involves
understanding the molecular basis of this durability. A second area of focus is the pimarane diterpenes known
as the myrocins. Myrocins exhibit antiproliferative effects in murine models of adenocarcinoma. The structure
of the active form of myrocins, their biological target, and their mechanism of action, are unknown. We have
developed a powerful annulation strategy that allows us to prepare myrocins in nine steps from commercial
reagents. We will use this chemistry to elucidate their target and mechanism of action, and thereby access
optimized derivatives for preclinical evaluation. In a third project we seek to complete a total chemical synthe-
sis of lomaiviticin A, a glycosylated bacterial metabolite that inhibits cancer cell growth at pM concentrations.
We established that the cytotoxicity of lomaiviticin derives from induction of double-strand breaks in DNA; elu-
cidated its mode of DNA binding; and determined the mechanism of cleavage. We have recently neared com-
pletion of a total chemical synthesis of lomaiviticin; using this synthesis as a springboard, we will prepare car-
bohydrate-modified derivatives with increased DNA affinity, sequence selectivity, and increased stability. Two
new reactions discovered en route to lomaiviticin – an interrupted Barton vinyl iodide synthesis and a method
for the stereocontrolled construction of attached rings – will be further developed. Finally, we will advance our
studies of gukulenin A, a pseudodimeric α-tropolone natural product with nM activity against colorectal cancer.
We will complete the synthesis of gukulenin, elucidate its structure-function relationships, and identify its bio-
logical target. Two new methods for the synthesis of highly-substituted α-tropolone...

## Key facts

- **NIH application ID:** 9922967
- **Project number:** 5R35GM131913-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Seth B. Herzon
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $581,228
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9922967

## Citation

> US National Institutes of Health, RePORTER application 9922967, Synthetic and translational studies of antitumor and antimicrobial natural products (5R35GM131913-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9922967. Licensed CC0.

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