Organic Synthesis of Aziridinomitosenes for Investigation of the Role of C6 and C7 in Halting Cell Replication
Don L. Warner
DNA replication is essential for cell life and division. In cancerous tumors, replication has increased out of the normal constraints of the cell making the mechanism for replication a viable target for chemotherapy agents. Mitomycin C (MC) is one such agent that functions by alkylating DNA so that transcription is hindered. However, the positive effects of MC are belied by the negative side effects of its use that are hypothesized to come from its need for reductive activation and subsequent release of reactive oxygen species. Aziridinomitosenes (AZMs) share structural and mechanistic homologies with MC, however, they differ slightly in mechanism; they do not require reductive activation in the cell to be effective. Additionally, AZMs have been shown to create not just DNA interstrand crosslinks, but also DNA-protein crosslinks that the cell is less capable of repairing. This latter effect is thought to be related to two potential active sites: C6 and C7 on the opposite side of the molecule from where the initial DNA adduct forms. AZM analogs with varied substitution at the hypothesized active sites have been synthesized to show that C6 and C7 are mechanistically important for AZM potency and effectiveness. My goal has been to synthesize AZM analogs with methyl groups at either C6 or C7. Thus far, synthesis has progressed through 16 and 17 main reaction steps for the C6 and C7 analogs respectively. This leaves quinone ring formation and installation of the carbamate group on each AZM to be completed. These and related studies will be presented.
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