DNA-damaging natural products, despite their promising activity, are often too toxic for clinical use as anti-cancer chemotherapies. Novel strategies to effectively modulate their cytotoxicity could expand the arsenal of usable drugs. Ficellomycin, a cytotoxic, DNA-alkylating antibiotic with a rare and unstable azabicyclo[3.1.0]hexane core, undergoes an intramolecular cyclization to render itself inert outside of a narrow pH range. This bifunctional molecular architecture inspired the design of simplified derivatives containing a DNA-alkylating warhead tethered to a caged nucleophile by a flexible linker. An SAR study was conducted to determine the effect of structural changes on DNA alkylation and intramolecular deactivation kinetics using nitrobenzyl pyridine (NBP) as a model for DNA. The lessons learned from these simplified structures will serve to guide the future development of more complex agents with potential pharmacological applications.

Modulating the cytotoxicity of DNA alkylators through intramolecular deactivation

ACS Spring Meeting 2021

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