DNA Interstrand Crosslinks by H-pin Polyamide (S)-seco-CBI Conjugates

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• 作者：Chuanxin Guo ; Sefan Asamitsu ; Dr. Gengo Kashiwazaki ; Shinsuke Sato ; Dr. Toshikazu Bando and Prof. Dr. Hiroshi Sugiyama
• 刊名：ChemBioChem
• 出版年：2017
• 出版时间：January 17, 2017
• 年：2017
• 卷：18
• 期：2
• 页码：166-170
• 全文大小：1227K
• ISSN：1439-7633

文摘

Although DNA interstrand crosslinking (ICL) agents are widely used as antitumor drugs, DNA sequence-specific ICL agents are quite rare. In this study, H-pin imidazole-pyrrole polyamide 1-(chloromethyl)-2,3-dihydro-1H-benzo[e]indol-5-ol (seco-CBI) conjugates that produce sequence-specific DNA ICLs were designed and synthesized. Conjugates with H-pin polyamide and seco-CBI moieties were constructed to recognize a 7 bp DNA sequence, and their reactivity and selectivity in DNA alkylation were evaluated by using high-resolution denaturing gel electrophoresis and sequence-specific plasmid cleavage. One conjugate (6), which contained a chiral (S)-seco-CBI, exhibited greater sequence-specific ICL activity toward the target DNA sequence and was cytotoxic to a cancer cell line. Molecular modeling studies indicated that the greater activity of 6 resulted from the relative orientation of the cyclopropane group in the (S)-CBI unit.