COMPARATIVE REACTIVITIES OF MITOMYCIN-C, 7-(N-PIPERIDINO)MITOMYCIN, AND MITOMYCIN-A - THE ROLE OF THE C(7) SUBSTITUENT

Mitomycin C (1a) is considered to be the protypical bioreductive alkylating agent. Enzymatic reduction leads to activation of the two DNA-bonding sites (C(1) and C(10) in 1a, permitting the formation of intrahelical interstrand DNA-mitomycin C cross-link adducts. Drug discovery programs have uncovered several C(7) mitomycin analogues that display a superior profile versus 1a when assayed against a battery of tumor models. The chemical properties of these and related C(7)-substituted mitomycins have not been extensively explored. We have compared the reactivity of mitomycin C (1a) with the two C(7)-substituted mitomycins, 7-(N-piperidino)mitomycin (1b) and mitomycin A (1c), under reductive conditions in tetrahydrofuran-water mixtures (''pH'' 5.5, 6.5). Key observations included (1) enhanced levels of drug utilization in proceeding from 1a to 1b and 1c, (2) increased percentages in the activation of the C(1) and C(10) bonding sites in 1b, c versus 1a, and (3) increased amounts of C(1) nucleophilic and C(10) nucleophilic products for 1b, c versus 1a. The results of these findings are discussed in light of previous studies, the role of the C(7) substituent in the mode of mitomycin action, and the design of future mitomycin analogues.