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KMID : 0043320120350081413
Archives of Pharmacal Research
2012 Volume.35 No. 8 p.1413 ~ p.1420
Design and synthesis of new mitomycin dimers containing a seven-membered cyclic disulfide and a diol linkers
Kim Jae-Jin

Kim Hyoung-Rae
Arai Hitoshi
Lee Sang-Hyup
Abstract
We report the design and synthesis of two new mitomycin dimers, 7-N,7¡Ç-N¡Ç-(1¡È,2¡È-dithiepanyl-3¡È,7¡È-dimethylenyl)bismitomycin C (8) and 7-N,7¡Ç-N¡Ç-(2¡È,6¡È-dihydroxy-1¡È,7¡È-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.
KEYWORD
Disulfide mitomycin, Diol mitomycin, Mitomycin dimers, 1, 2-Dithiepane, Disulfide formation, Antitumor agent
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