Studies on activation mechanism of a mitomycin dimer, 7-N,7′-N′-(1″,2″-dithiepanyl-3″,7″-dimethylenyl)bismitomycin C

Abstract

We report the studies on nucleophilic activation and DNA alkylation of a cyclic disulfide mitomycin dimer, 7-N,7'-N'-(1″,2″-dithiepanyl-3″,7″-dimethylenyl)bismitomycin C (6) along with a diol mitomycin dimer, 7-N,7'-N'-(2″,6″-dihydroxy-1″,7″-heptanediyl)bismitomycin C (7). We wished to see if disulfide mitomycin 6 undergoes efficient nucleophilic activation and corresponding formation of DNA interstrand cross-link (DNA ISC) products compared to diol mitomycin 7. Mitomycin 6 is a dimer connected by a seven-membered cyclic disulfide (a 1,2-dithiepane) linker, and mitomycin 7 is also a dimer containing 2,6-dihydroxyheptane linker that was employed as a reference one to identify the effect of disulfide unit in 6. Through kinetic studies using solvolysis reaction, we found that 6 underwent much faster nucleophilic activation by Et3P compared to 7, and that the enhanced activation rates were induced by the disulfide unit in 6. These findings led us to propose a nucleophilic activation mechanism for 6. We further demonstrated that 6 produced much higher levels of DNA ISC (86%) by the action of Et3P compared with 7 (5%) and 1 (4%). Therefore, we have concluded that 6 was highly efficient for nucleophilic activation and DNA ISC formation due to the key role of cyclic disulfide unit in 6.