Metabolic liabilities frequently cause promising medicinal chemistry leads to be abandoned. We have been interested in hit-to-lead development of isoxazoles in several medicinal chemistry contexts over the years, and a common safe metabolism route for the heterocycle in general is hydroxylation on a methyl adjacent to the heterocycle mediated Cyp3A4. We have recently been optimizing anti-tumor agents in the aryl isoxazole series and have realized sub-micromolar cytotoxicities against brain and breast cancer cell lines. However, one concern has been the potential formation of toxic metabolites via an arene oxide route, akin to the bay area epoxide for polynuclear hydrocarbons. We have recently observed two novel oxidations in the Aim series, characterized by single crystal x-ray diffractometry, which appear to proceed by a common endoperoxide. The structures are highly accurate, and the intramolecular interactions in the unit cells are relevant to the observed anti-tumor activity. Filatov (<i>JACS</i>, <b>2017</b>, 6282) has proposed that anthryl endoperoxide as a promising avenue contributing to anti-tumor activity, and we will continue to explore the synthesis and study of the AIMs, and describe our most recent progress.

Oxidation of anthryl-isoxazoles (AIMs) and implications for metabolism

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.