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首页> 外文期刊>Chemistry: A European journal >Sequence-Specific DNA Alkylation Targeting for Kras Codon 13 Mutation by Pyrrole–Imidazole Polyamide seco-CBI Conjugates
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Sequence-Specific DNA Alkylation Targeting for Kras Codon 13 Mutation by Pyrrole–Imidazole Polyamide seco-CBI Conjugates

机译：吡咯-咪唑聚酰胺seco-CBI共轭物靶向Kras密码子13突变的序列特异性DNA烷基化。

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摘要

Hairpin N-methylpyrrole-N-methylimidazole polyamide seco-CBI conjugates 2–6 were designed for synthesis by Fmoc solid-phase synthesis, and their DNA-alkylating activities against the Kras codon 13 mutation were compared by high-resolution denaturing gel electrophoresis with 225 base pair (bp) DNA fragments. Conjugate 5 had high reactivity towards the Kras codon 13 mutation site, with alkylation occurring at the A of the sequence 5'-ACGTCACCA-3' (site 2), including minor 1 bp-mismatch alkylation against wild type 5'-ACGCCACCA-3' (site 3). Conjugate 6, which differs from conjugate 5 by exchanging one Py unit with a b unit, showed high selectivity but only weakly alkylated the A of 5'-ACGTCACCA-3' (site 2). The hairpin polyamide seco-CBI conjugate 5 thus alkylates according to Dervan's pairing rule with the pairing recognition which b/b pair targets T–A and A–T pairs. SPR and a computer-minimized model suggest that 5 binds to the target sequence with high affinity in a hairpin conformation, allowing for efficient DNA alkylation.
机译：设计发夹状N-甲基吡咯-N-甲基咪唑聚酰胺seco-CBI共轭物2-6，通过Fmoc固相合成进行合成，并通过高分辨率变性凝胶电泳与225比较其对Kras密码子13突变的DNA-烷基化活性。碱基对（bp）DNA片段。缀合物5对Kras密码子13突变位点具有高反应活性，烷基化发生在序列5'-ACGTCACCA-3'（位点2）的A处，包括针对野生型5'-ACGCCACCA-3的次要1 bp错配烷基化'（网站3）。缀合物6与缀合物5的区别在于通过将一个Py单元交换为b单元而显示出高选择性，但仅弱烷基化了5'-ACGTCACCA-3'的A（位点2）。发夹式聚酰胺seco-CBI共轭物5因此根据Dervan的配对规则烷基化，并具有配对识别，即b / b对靶向T–A和A–T对。 SPR和计算机最小化模型表明，5在发夹构象中以高亲和力与靶序列结合，从而实现了有效的DNA烷基化。

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