Mitomycin C (MC) is a natural product that exhibits therapeutic cancer qualities by forming interstrand crosslinks with DNA in cancer cells, therefore inhibiting replication and cell growth. However, the clinical utility of MC is limited because of adverse side effects. It is hypothesized that MC toxicity arises from the reduction that is required before DNA adducts are formed. Aziridinomitosenes (AZMs), compounds structurally similar to MC, are able to alkylate DNA without reductive activation. Most notably, our synthetic AZMs have been shown to form DNA/protein crosslinks as well as DNA interstrand crosslinks in the absence of added reductant. In order to determine the mechanism by which these adducts form, several analogs with varying substitution at four separate electrophilic centers are being prepared. Synthetic efforts toward a C7-alkyl substituted AZM propagates testing that may potentially create more potent and less toxic anti-cancer agents. These and related studies will be presented.
Dr. Don Warner