title: Design, synthesis, and mode of action studies of a mitomycin tetramer inducing double activations with a single probe.
abstract: We report design, synthesis, and mechanistic studies of a new mitomycin tetramer 9 along with a new mitomycin dimer 10. Mitomycin 9 is a tetramer connected by the disulfide linker 11, and easily undergoes disulfide cleavage to provide two dimeric structures 9r that each contains a single thiol probe for activations. So, tetramer 9 as a precursor of 9r was specifically targeted to undergo double activations with a single probe. A tetramer 9 was synthesized using 1 and key intermediate 11, and a dimer 10 was synthesized from 1 and diamine 12. Activation studies revealed that 9 underwent effective double activations with a single probe by nucleophiles while the reference 10 did not. Evaluations of DNA ISC formations showed that 9 generated substantial levels of DNA ISC by nucleophilic activation while the references 10 and 2 did not. The effectiveness of 9 in activation and formation of DNA ISC per probe was verified by comparing with dimers 5-8 of double activations with two probes. These findings highlighted the role of a single thiol in 9r and demonstrated the intended double activations with a single probe, which marks the first case in mitomycin studies.
authors.affiliation: College of Pharmacy and Innovative Drug Center, 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.affiliation: College of Pharmacy and Innovative Drug Center, Duksung Women's University, 419 Ssangmun-dong, Dobong-gu, Seoul 132-714, Republic of Korea.
authors.forename: Yeon Kyeong
authors.initials: YK
authors.lastname: Park
authors.affiliation: College of Pharmacy and Innovative Drug Center, Duksung Women's University, 419 Ssangmun-dong, Dobong-gu, Seoul 132-714, Republic of Korea. Electronic address: sanghyup@duksung.ac.kr.
authors.forename: Sang Hyup
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000477:Alkylating Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry; D018736:DNA Adducts / Q000737:chemistry*; D019281:Dimerization; D004220:Disulfides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016685:Mitomycin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000477:Alkylating Agents; D018736:DNA Adducts; D004220:Disulfides; D007364:Intercalating Agents; D016685:Mitomycin; D004247:DNA
keywords: DNA alkylation; DNA interstrand cross-link; Disulfide cleavage; Double activations; Mitomycin tetramer