Development of a Streamlined Synthesis of Aziridinomitosine Analogs

Mitomycin C (MC) is a quinone containing anti-cancer agent that alkylates DNA, forming insterstrand cross-links (ICLs) that prevent the DNA backbone from separating. However, its clinical use is limited by toxicity presumably associated with the requirement for reductive activation. Aziridinomitosenes (AZMs) are structurally similar to MC, but do not need to be reductively activated to become functional, potentially making them less toxic. Additionally, AZMs have been shown to form DNA-protein cross-links (DPCLs) as well as ICLs, which are theorized to increase cytotoxic efficacy. Unfortunately, AZM synthesis is long and inefficient, making them difficult and expensive to produce. A shorter, more flexible, and more convergent route to functional AZMs has been developed that should increase availability, in addition to providing access to additional analogues for the study of the AZM’s biological properties. Starting with tert-butyl-dimethylsilyl protected propargyl alcohol, the streamlined synthesis utilizing 2-phenyloxazole as a model system will be presented