title: Studies on synthesis and activation mechanism of mitomycin dimers connected by 1,2-dithiolane and diol linkers.
abstract: We report the synthetic and mechanistic studies on a new cyclic disulfide mitomycin dimer, 7-N,7'-N'-(1″,2″-dithiolanyl-3″,5″-dimethylenyl)bismitomycin C (8), and a diol mitomycin dimer, 7-N,7'-N'-(2″,4″-dihydroxy-1″,5″-pentanediyl)bismitomycin C (9). Mitomycin 8 is a dimer connected by a 1,2-dithiolane (a five-membered cyclic disulfide) linker, and was specifically designed to undergo nucleophilic activation and double DNA alkylations leading to efficient production of DNA interstrand cross-link (DNA ISC) adducts. Disulfide cleavage in 8 would generate two thiol groups that could serve as probes to activate two mitomycin rings. At first, the target mitomycin 8 was synthesized using mitomycin A (1) and the key intermediate, cyclic disulfide (10), which was prepared through a seven-step synthetic sequence. Diol mitomycin 9 was also synthesized from 1 and diamine salt 13. Next, kinetic studies using solvolysis reaction revealed that the activation rates of 8 were much higher than those of 9 and mitomycin C (2) under nucleophilic conditions provided by Et(3)P presumably due to the presence of a cyclic disulfide unit in 8. These findings led us to propose a nucleophilic activation pathway for 8. Then, DNA ISC experiments further revealed that the levels of DNA ISC caused by 8 in the presence of Et(3)P were much higher (97%) than those by 9 (5%) and 2 (4%). More importantly, mitomycin 8 underwent much faster activation and produced slightly higher levels of DNA ISC than the previously reported mitomycins 5-7. Overall, we concluded that 8 was highly efficient for both nucleophilic activation and corresponding DNA ISC formation, and that this differentiation came from the crucial function of the cyclic disulfide unit in 8.
authors.affiliation: College of Pharmacy, Duksung Women's University, 419 Ssangmun-dong, Dobong-gu, Seoul 132-714, Republic of Korea.
authors.forename: Hyoung Rae
authors.initials: HR
authors.lastname: Kim
authors.forename: Jae Jin
authors.initials: JJ
authors.lastname: Kim
authors.forename: Jung Jae
authors.initials: JJ
authors.lastname: Park
authors.forename: Sang Hyup
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000477:Alkylating Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry*; D019281:Dimerization; D016685:Mitomycin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C448825:1,2-dithiolane; D000477:Alkylating Agents; D003432:Cross-Linking Reagents; D016685:Mitomycin; D008063:Thioctic Acid; D004247:DNA