Major

Chemistry

Research Abstract

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.

Faculty Mentor/Advisor

Herman Nikolayevskiy

Available for download on Sunday, January 01, 2040

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Chemistry Commons

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May 7th, 12:00 AM May 10th, 12:00 AM

Modulating the Cytotoxicity of DNA Alkylators through Intramolecular Deactivation

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.