Design and synthesis of new mitomycin dimers containing a seven-membered cyclic disulfide and a diol linkers

Abstract

We report the design and synthesis of two new mitomycin dimers, 7-N,7'-N'-(1″,2″-dithiepanyl-3″,7″-dimethylenyl)bismitomycin C (8) and 7-N,7'-N'-(2″,6″-dihydroxy-1″,7″-heptanediyl)bismitomycin C (9). Mitomycins 8 and 9 are dimers connected by a seven-membered cyclic disulfide (a 1,2-dithiepane) and a 2,6-dihydroxyheptane linkers, respectively. Mitomycin 8 was designed to undergo efficient nucleophilic activation and following alkylation to give DNA adducts such as DNA interstrand cross-link (DNA ISC) adducts. The key moiety in 8 is a seven-membered cyclic disulfide linker that can generate two thiol groups in a molecule through disulfide cleavage. The two thiols can serve as probes to activate two mitomycin rings by intramolecular cyclization to quinone rings. The mitomycin 8 was synthesized using mitomycin A (1) and the key intermediate, cyclic disulfide 11 that was prepared through a nine-step synthetic sequence from 1,6-heptadiene (12). The diol mitomycin 9 was also synthesized from 1 and diamine salt 15.