STUDIES ON THE REACTIVITY OF REDUCTIVELY ACTIVATED MITOMYCIN-C

Mitomycin C (1a), a clinically significant antineoplastic antiobiotic, is considered to be the prototype of bioreductive alkylating agents. It has been reported that, in the absence of DNA, reductive activation of 1a furnished both solvolytic C(1) electrophilic (2,7-diaminomitosene (7)) and C(1) nucleophilic (trans-(8) and cis-1-hydroxy-2,7-diaminomitosene (9)) products. The detection of 7 as well as 8 and 9 suggested that the aziridine ring-opened quinone methide 4 served as a precursor to both sets of products. Sodium dithionite-mediated reduction of mitomycin C under conditions furnishing near complete 1a consumption revealed that proton capture to give 7 was the dominant process (77.2-87.8%) between pH 5.5 and 8.5. Earlier observations that 8 and 9 were generated in mildly basic solutions have now been largely attributed to secondary transformations proceeding from 7-aminoaziridinomitosene (21). The propensity of reductively activated mitomycin C to undergo C(1) electrophilic substitution processes was further assessed by incorporating aniline in the reaction mixture. In moderately basic solutions, C(1) electrophilic transformations predominated, whereas in mild acid, appreciable amounts of C(1) nucleophilic adducts were detected. The observed results are discussed in terms of both the in vivo mitomycin C reductive process and the requirements for the efficient cross-linking of complementary strands of DNA by 1a.