Title of Research Project
Modulating the Cytotoxicity of DNA Alkylators through Intramolecular Deactivation
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
audio
NathanielGarrison_IntramolecularDeactivation_chemistry_poster.pptx (1257 kB)
PowerPoint
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.
