Source:http://linkedlifedata.com/resource/pubmed/id/21658959
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
13
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pubmed:dateCreated |
2011-6-24
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pubmed:abstractText |
Dimeric DNA alkylating agents have drawn significant interest because these compounds are expected to provide at least two reactive sites and as a result, generate enhanced levels of DNA interstrand cross-link (DNA ISC) adducts compared to their monomeric agents. We report the synthesis and mechanistic studies of a novel mitomycin dimer, 7-N,7'-N'-(1?,2?-dithiocanyl-3?,8?-dimethylenyl)bismitomycin C (8) connected by an eight-membered cyclic disulfide. Mitomycins require prior activation (i.e., transformation to a good electrophile) for DNA adduction and therefore, 8 was aimed to undergo facile nucleophilic activation and produce enhanced levels of DNA ISC. At the core of this function lies a cyclic disulfide in 8. It was expected that disulfide cleavage by an appropriate nucleophile would successively produce two thiols that may trigger activation of two mitomycin rings in a dimer through intramolecular cyclization to quinine rings. Compound 8 was synthesized from mitomycin A (1) and the key intermediate, cyclic disulfide (11), along with the reference diol mitomycin 7-N,7'-N'-(2?,7?-dihydroxy-1?,8?-octanediyl)bismitomycin C (23) which does not contain the disulfide unit. We found that 8 underwent significantly enhanced nucleophilic activation in the presence of Et(3)P compared with 23, and that the disulfide unit in 8 played a key role for the nucleophilic activation. Based on these findings, we proposed a mechanism for nucleophilic activation of 8. We further demonstrated that 8 generated much higher levels of DNA ISC (94%) compared with 23 (4%) and 2 (3%) in the presence of Et(3)P (and L-DTT) leading to the conclusion that 8 is more efficient for DNA ISC processes than 23 and 2 due to the role of disulfide unit.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Alkylating Agents,
http://linkedlifedata.com/resource/pubmed/chemical/DNA,
http://linkedlifedata.com/resource/pubmed/chemical/Disulfides,
http://linkedlifedata.com/resource/pubmed/chemical/Mitomycin,
http://linkedlifedata.com/resource/pubmed/chemical/Mitomycins
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
1464-3391
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pubmed:author | |
pubmed:copyrightInfo |
Copyright © 2011 Elsevier Ltd. All rights reserved.
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pubmed:issnType |
Electronic
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pubmed:day |
1
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pubmed:volume |
19
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4004-13
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pubmed:meshHeading | |
pubmed:year |
2011
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pubmed:articleTitle |
Synthesis and mechanistic studies of a mitomycin dimer containing an eight-membered cyclic disulfide.
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pubmed:affiliation |
College of Pharmacy, Duksung Women's University, Seoul, Republic of Korea.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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