DNA Alkylation by Pyrrole-Imidazole seco-CBI Conjugates with an Indole Linker: Sequence-Specific DNA Alkylation with 10-Base-Pair Recognition through Heterodimer Formation

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• 作者：Masafumi Minoshima ; Toshikazu Bando ; Shunta Sasaki ; Ken-ichi Shinohara ; Tatsuhiko Shimizu ; Jun Fujimoto ; Hiroshi Sugiyama
• 刊名：Journal of the American Chemical Society
• 出版年：2007
• 出版时间：May 2, 2007
• 年：2007
• 卷：129
• 期：17
• 页码：5384 - 5390
• 全文大小：5353K
• 年卷期：v.129,no.17(May 2, 2007)
• ISSN：1520-5126

文摘

The sequence-specific DNA alkylation by conjugates 4 and 5, which consist of N-methylpyrrole(Py)-N-methylimidazole (Im) polyamides and 1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole(seco-CBI) linked with an indole linker, was investigated in the absence or presence of partner Py-Impolyamide 6. High-resolution denaturing polyacrylamide gel electrophoresis revealed that conjugate 4alkylates DNA at the sequences 5'-(A/T)GCCTA-3' through hairpin formation, and alkylates 5'-GGAAAGAAAA-3' through an extended binding mode. However, in the presence of partner Py-Im polyamide 6,conjugate 4 alkylates DNA at a completely different sequence, 5'-AGGTTGTCCA-3'. Alkylation of 4 in thepresence of 6 was effectively inhibited by a competitor 7. Surface plasmon resonance (SPR) results indicatedthat conjugate 4 does not bind to 5'-AGGTTGTCCA-3', whereas 6 binds tightly to this sequence. Theresults suggest that alkylation proceeds through heterodimer formation, indicating that this is a generalway to expand the recognition sequence for DNA alkylation by Py-Im seco-CBI conjugates.