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Title: Comparative analysis of DNA alkylation by conjugates between pyrrole-imidazole hairpin polyamides and chlorambucil or seco-CBI.
Authors: Minoshima, Masafumi
Bando, Toshikazu  kyouindb  KAKEN_id
Shinohara, Ken-Ichi
Kashiwazaki, Gengo
Nishijima, Shigeki
Sugiyama, Hiroshi  kyouindb  KAKEN_id
Author's alias: 杉山, 弘
Keywords: Alkylating agent
Antitumor agent
DNA alkylation
Minor groove binder
Pyrrole imidazole polyamide
Issue Date: 1-Feb-2010
Publisher: Elsevier
Journal title: Bioorganic & medicinal chemistry
Volume: 18
Issue: 3
Start page: 1236
End page: 1243
Abstract: We investigated sequence-specific DNA alkylation using conjugates between the N-methylpyrrole (Py)-N-methylimidazole (Im) polyamide and the DNA alkylating agent, chlorambucil, or 1-(chloromethyl)-5-hydroxy-1, 2-dihydro-3H-benz[e]indole (seco-CBI). Polyamide-chlorambucil conjugates 1-4 differed in the position at which the DNA alkylating chlorambucil moiety was bound to the Py-Im polyamide. High-resolution denaturing polyacrylamide gel electrophoresis (PAGE) revealed that chlorambucil conjugates 1-4 alkylated DNA at the sequences recognized by the Py-Im polyamide core moiety. Reactivity and sequence specificity were greatly affected by the conjugation position, which reflects the geometry of the alkylating agent in the DNA minor groove. Polyamide-seco-CBI conjugate 5 was synthesized to compare the efficacy of chlorambucil with that of seco-CBI as an alkylating moiety for Py-Im polyamides. Denaturing PAGE analysis revealed that DNA alkylation activity of polyamide-seco-CBI conjugate 5 was similar to that of polyamide-chlorambucil conjugates 1 and 2. In contrast, the cytotoxicity of conjugate 5 was superior to that of conjugates 1-4. These results suggest that the seco-CBI conjugate was distinctly active in cells compared to the chlorambucil conjugates. These results may contribute to the development of more specific and active DNA alkylating agents.
Rights: c 2009 Elsevier Ltd. All rights reserved.
This is not the published version. Please cite only the published version. この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。
URI: http://hdl.handle.net/2433/97888
DOI(Published Version): 10.1016/j.bmc.2009.12.033
PubMed ID: 20074970
Appears in Collections:Journal Articles

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