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-diaminomitose ne (7)) and C(1) nucleophilic (trans-(8) and cis-1-hydroxy-2,7-diamino mitosene (9)) products. The detection of 7 as well as 8 and 9 suggeste d that the aziridine ring-opened quinone methide 4 served as a precurs or to both sets of products. Sodium dithionite-mediated reduction of m itomycin C under conditions furnishing near complete 1a consumption re vealed 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 ge nerated 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 incorpor ating 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 o bserved results are discussed in terms of both the in vivo mitomycin C reductive process and the requirements for the efficient cross-linkin g of complementary strands of DNA by 1a.