# Synthetic approaches to complex amines that inhibit protein synthesis by impacting the ribosome

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $265,514

## Abstract

Project Summary/Abstract:
 Our work in the previous funding period was inspired by synthetic challenges inherent in molecules that
directly bind to the ribosome or indirectly impact its function. Structure-activity relationship studies are difficult
in these classes of molecules, due to lack of flexible synthetic methods to enable flexible changes to the
positioning, stereochemistry and steric environments of key amine and alcohol groups that engage in H-
bonding or electrostatic interactions with the binding site; the same is true for altering alkyl and aryl groups that
participate in hydrophobic or π-π interactions. Our versatile methods streamline syntheses of stereochemically
complex amine 'triads' present in natural products that inhibit protein synthesis, including aminocyclitols,
anthracyclines, and tetracyclines. This enables us to construct 'unnatural products' inspired by bioactive natural
products, where diversity can be achieved in: 1) heteroatoms installed in the amine 'triad' building blocks, 2)
stereochemical relationships amongst the three contiguous, heteroatom-bearing sp3 carbon centers of the
triad, and 3) densely functionalized carbo- and heterocyclic scaffolds. A library of >1000 unique compounds in
novel amine chemical space displaying significant stereochemical complexity has shown promising activities
against drug-resistant malaria and tuberculosis, Chaga's disease, hepatocellular carcinoma, and other
biological targets.
 This renewal builds on our expertise in securing complex, densely functionalized amine motifs to investigate
structure-activity relationships in molecules that impact protein synthesis, primarily through interactions with the
ribosome. Analogs of the potent antimalarial natural product jogyamycin will be prepared to probe how binding
to the ribosome is impacted; these studies are key to the design of simpler synthetic amine scaffolds that show
similar bioactivity, but better selectivity for parasitic vs. eukaryotic mitochondrial ribosomes, lowered toxicity,
and less propensity to develop resistance. In the same manner, our expertise in complex amine synthesis will
be applied to the design of 'hybrid' anthracyclines that mitigate the toxicity and multi-drug resistance seen in
the widely-used antitumor drug doxorubicin (DOX) and other related drugs of significance to the treatment of
cancer. We have secured the aid of several collaborators to assess the biological activities of our compounds
and provide insight into the design of 2nd-generation libraries, including the Eli Lilly Open Innovation program,
GSK (in progress), Corteva Agrisciences, several academic colleagues (Prof. Taifo Mahmud, Prof. Dev Arya,
Prof. Silvia Cavagnero, Dr. Desiree Bates), and the University of Wisconsin Medicinal Chemistry Center.

## Key facts

- **NIH application ID:** 10470244
- **Project number:** 5R01GM111412-09
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Jennifer Marie Schomaker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $265,514
- **Award type:** 5
- **Project period:** 2014-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470244

## Citation

> US National Institutes of Health, RePORTER application 10470244, Synthetic approaches to complex amines that inhibit protein synthesis by impacting the ribosome (5R01GM111412-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10470244. Licensed CC0.

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