Mitomycin C (MC) is a naturally occurring anti-cancer therapy that has historically seen extensive use as a treatment for a wide variety of cancer types. However, MC’s utility has been greatly diminished as a result of severe side effects, such as delayed myelosuppression. We have prepared and studied structurally similar compounds, called aziridinomitosenes (AZMs), that have similar anticancer activity but may be operating by a mechanism different than that of MC. Both MC and AZMs alkylate DNA to form interstrand cross-links (ICLs) that inhibit DNA replication and lead to cell death. In contrast to MC, the AZMs contain electrophilic centers at the C6 and/or C7 positions that are thought to play a role in the observed increased cytotoxicity in a number of cancer cell types. The present study aims to investigate the importance of these sites by preparing analogs that have methyl, ethyl, butyl, phenyl, or benzyl groups at one or both of these positions. The synthesis of each target molecule relies upon the preparation of a 2,5-disubstituted oxazole that is converted to the AZM tetracyclic core via an oxazolium salt/azomethine ylide cycloaddition sequence. To prepare the cycloaddition precursors, readily available 1,2-diols or butyrolactones are converted over a one to three step sequence that generates appropriately substituted esters or lactones. These are subsequently treated with lithiated methyl isocyanide to facilitate oxazole formation. Assembling the remainder of the cycloaddition precursors involves addition to a serine-derived aldehyde, which forms an amino alcohol that is closed to form the required aziridine ring. After this, a lithiated propargyl alcohol is used to install the tethered dipolarophile, which is subjected to the oxazolium salt/azomethine ylide cycloaddition sequence that leads to the final tetracyclic core. Following cycloaddition, oxidation state manipulation and carbamate addition result in the desired AZM analogs. Herein, we will report on our progress to date on all substrates, including steps that have focused on optimization of reactions to form the early stage esters/lactones, intermediate stage cycloadditions, and late stage carbamate installations.

Synthesis of aziridinomitosene anticancer analogs that vary at the C6/C7 positions

249th National Meeting (2015)

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