Reductive activation of mytomycin C (MC), a clinically used anticancer agent, results in the formation of DNA interstrand crosslinks (ICLs) that facilitate to cell apoptosis. However, the activation is also thought to cause many of MC's adverse side effects. Certain synthetic aziridinomitosenes (AZMs) are structurally similar to MC, but are able, without activation, to not only alkylate DNA but also form DNA/protein crosslinks. The AZM has four electrophilic sites:  C1, C6, C7, and C10.  It is hypothesized that the C6 and C7 sites on the quinone ring are responsible for the formation of the DNA/protein adducts.  To test this, variations of the AZM, in which a methyl group is used to block either C6 or C7, are being prepared using a thirteen step sythesis in order to evaluate their propensity to covalently bind proteins to DNA.  Details and relevant studies will be presented.

Investigating the role of aziridinomitosene quinone substitution on DNA crosslinking

243rd National Meeting (2012)

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