Synthesis and Study of Anticancer Agents (AZM) Related to the Natural Product Mitomycin C

Mitomycin C (MC) is a naturally occurring antitumor agent isolated from soil bacterium. MC is effective against solid hypoxic tumors that respond poorly to radiotherapy, such as colorectal, gastric, and lung tumors. MC creates interstrand crosslinks in the DNA of tumor cells, which ultimately leads to apoptosis. MC requires a reductive activation that produces reactive oxygen species (ROS) and leads to adverse side effects, such as myelosuppression. Aziridinomitosenes (AZMs) are structurally related to MC and are believed to form during in vivo reduction of MC. AZMS, however, do not require the reduction step to alkylate DNA. We aim to synthesize and study different analogs of AZMs with varying alkyl groups at two electrophilic sites. The synthetic route starts with commercially available reagents to form an oxazole, followed by the addition of the protected aldehyde that is converted to the required aziridine ring via a Mitsunobu reaction. Currently we are working to synthesize the C6/C7-dimethyl AZM analog and all results are reported herein.