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. Exploration of ficellomycin’s natural capacity for self-regulation may present a novel strategy for modulation of cytotoxicity more generally. Toward this end, we have synthesized a protected ficellomycin precursor in four steps and 6% overall yield. Key steps in the sequence include Sharpless asymmetric epoxidation, sodium azide based ring-opening, and Staudinger reduction.

Faculty Mentor/Advisor

Herman Nikolayevskiy

Available for download on Sunday, May 01, 2022

Included in

Chemistry Commons

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May 1st, 12:00 AM

A Ficellomycin Inspired Platform: Modulating Cytotoxicity by Tuning the Instability of Substituted Azabicyclo[3.1.0]hexanes

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. Exploration of ficellomycin’s natural capacity for self-regulation may present a novel strategy for modulation of cytotoxicity more generally. Toward this end, we have synthesized a protected ficellomycin precursor in four steps and 6% overall yield. Key steps in the sequence include Sharpless asymmetric epoxidation, sodium azide based ring-opening, and Staudinger reduction.