Sequence-specific alkylation of double-strand human telomere repeat sequence by pyrrole-imidazole polyamides with indole linkers.
Sequence-specific alkylation of double-strand human telomere repeat sequence by pyrrole-imidazole polyamides with indole linkers.
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DOI：
10.1021/ja0626584
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发表时间：
2006-08
影响因子：
15
通讯作者：
Shunta Sasaki;T. Bando;Masafumi Minoshima;T. Shimizu;K. Shinohara;Toshiyasu Takaoka;H. Sugiyama
中科院分区：
文献类型：
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作者：
Shunta Sasaki;T. Bando;Masafumi Minoshima;T. Shimizu;K. Shinohara;Toshiyasu Takaoka;H. Sugiyama
我们设计并合成了吡咯（Py）-咪唑（Im）发夹聚酰胺1-（氯甲基）-5-羟基-1，2-二氢-3H-苯并[e]吲哚（seco-CBI）缀合物1和2，其靶向人端粒重复序列5 '-d（TTAGGG）（n）-3'/5 '-d（CCCTAA）（n）-3'的双链区的两条链。高分辨变性聚丙烯酰胺凝胶电泳表明，偶联物1和2分别在5 '-ACCTA-3'和5 '-AGGGTTA-3'的3' A处烷基化DNA。使用39种人癌细胞系评价缀合物1和2的细胞毒性;缀合物1和2的log IC（50）值的平均值分别为-6.96（110 nM）和-7.24（57.5 nM）。偶联物1和2具有作为能够靶向端粒重复序列的抗肿瘤药物的潜力。
We designed and synthesized pyrrole (Py)-imidazole (Im) hairpin polyamide 1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (seco-CBI) conjugates 1 and 2, which target both strands of the double-stranded region of the human telomere repeat sequences, 5'-d(TTAGGG)(n)-3'/5'-d(CCCTAA)(n)-3'. High-resolution denaturing polyacrylamide gel electrophoresis demonstrated that conjugates 1 and 2 alkylated DNA at the 3' A of 5'-ACCCTA-3' and 5'-AGGGTTA-3', respectively. Cytotoxicities of conjugates 1 and 2 were evaluated using 39 human cancer cell lines; averages of log IC(50) values for conjugates 1 and 2 were -6.96 (110 nM) and -7.24 (57.5 nM), respectively. Conjugates 1 and 2 have potential as antitumor drugs capable of targeting telomere repeat sequence.