# Enzymatic Fluoroalkylation using Te-Adenosyl-Telluromethionine Analogs and Late-Stage Diversification of Natural Products Exhibiting Antibacterial Behavior

> **NIH NIH R21** · PENNSYLVANIA STATE UNIVERSITY, THE · 2021 · $189,000

## Abstract

Project Summary
 Methyl groups are an important structural modification in natural products and are often essential for the
effectiveness of natural products as antibacterial and/or antitumor agents. In nature, these methyl groups are
most often appended by S-adenosylmethionine (SAM)-dependent methyltransferases (MTs) in a regioselective
and stereoselective manner. This proposal focuses on transferring fluoromethyl and other fluorine-containing
alkyl groups to natural products, because fluorine atoms have been shown to enhance the pharmacological
effects of many drugs. In fact, about 20-30% of all drugs contain at least one fluorine atom. Strategies for
introducing fluorine into biomolecules are therefore at the forefront of organic and medicinal chemistry. In this
proposal, the the synthesis of novel fluoromethyl and difluoromethyl donors that have biological relevance is
described. Indeed, we show that these fluorine-containing analogs of SAM, Te-adenosyl-(fluoromethyl)-
telluromethionine (FMeTeSAM) and Te-adenosyl-(difluoromethyl)-telluromethionine (F2MeTeSAM) are acted
upon by SAM-dependent MTs to transfer fluoroalkyl groups to target substrates, including catechol-O-
methyltransferase-catalyzed O-fluoromethylation on dihydroxybenzoic acid and O-difluoromethylation on
norepinephrine; nicotinamide N-methyltransferase-catalyzed N-fluoromethylation on nicotinamide; NovO-
catalyzed C-fluoromethylation on coumarin; and 6-mercaptopurine methyltransferase-catalyzed S-
difluoromethylation on 6-mercaptopurine. Ideally, this ability will be leveraged to modify methyl-containing
natural products of clinical value (e.g. novobiocin and oxaline) with fluoromethyl groups in a facile manner at a
late stage in their biosynthetic pathways, and to assess whether their pharmacological effects are improved.
Other aims will focus on the enzymatic synthesis of β-fluoromethyl amino acids, which are found in a number
of important antibiotics, as well as the addition of fluoromethyl groups to completely unactivated carbon
centers via radical mechanisms.

## Key facts

- **NIH application ID:** 10196336
- **Project number:** 1R21AI160172-01
- **Recipient organization:** PENNSYLVANIA STATE UNIVERSITY, THE
- **Principal Investigator:** SQUIRE J. BOOKER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $189,000
- **Award type:** 1
- **Project period:** 2021-03-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10196336

## Citation

> US National Institutes of Health, RePORTER application 10196336, Enzymatic Fluoroalkylation using Te-Adenosyl-Telluromethionine Analogs and Late-Stage Diversification of Natural Products Exhibiting Antibacterial Behavior (1R21AI160172-01). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10196336. Licensed CC0.

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