Apr 20th, 1:00 PM - 4:00 PM


Synthesis of Quinone-Substituted Aziridinomitosenes to Further Investigate the DNA-Binding Mechanism of Potential Anticancer Drugs

Faculty Sponsor

Dr. Don L. Warner


Aziridinomitosenes (AZMs) are compounds related to the clinically used anticancer agent mitomycin C (MC). MC elicits its cancer fighting properties by cross-linking DNA under reductive conditions. Cross-linking inhibits DNA replication which, in turn, prevents the proliferation of rapidly dividing cancer cells. While MC has a role in the treatment of certain cancers, its clinical use is limited due to significant host toxicity. Previously, we have shown that AZM analogs can form DNA adducts under non-reductive conditions. More specifically, quinone-unsubstituted AZMs can induce interstand cross-links (ICLs) and DNA/protein cross-links (DPCLs) via a novel and currently unknown mechanism. We propose a mechanism by which these cross-links occur, and where substitution at the quinone carbons plays an important role. If our proposed mechanism is correct, ICLs and DPCLs cannot form with quinonesubstituted AZMs. We aim to further evaluate our proposed mechanism by preparing quinonesubstituted AZMs via diastereoselective enolate alkylation of a chiral β-methyl ester or β-methyl lactone. We believe these quinone-substituted AZM analogs will be unable to form DNA crosslinks. The results of these and related studies will serve to increase understanding of the DNA-binding mechanism by synthetic AZMs. This will, in turn, potentially lead to the development of compounds that are more potent and less toxic.