Sequence specificity, reactivity, and antitumor activity of DNA-alkylating pyrrole-imidazole diamides.
Sequence specificity, reactivity, and antitumor activity of DNA-alkylating pyrrole-imidazole diamides.
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DOI：
10.1016/s1074-5521(03)00160-1
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发表时间：
2003-08
影响因子：
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通讯作者：
T. Bando;H. Iida;Z. Tao;A. Narita;N. Fukuda;T. Yamori;H. Sugiyama
中科院分区：
文献类型：
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作者：
T. Bando;H. Iida;Z. Tao;A. Narita;N. Fukuda;T. Yamori;H. Sugiyama
合成了咪唑(Im)-吡咯（Py）二胺缀合物和多卡霉素a衍生的dna烷基化片段，并对它们的序列特异性、反应性和抗肿瘤活性进行了比较研究。测序凝胶分析表明，ImPyDu(1)在微摩尔浓度下能使富含at序列的DNA 3 '端烷基化。ImPyDu86(2)与DNA在富含at的位点以及微摩尔浓度的二烷基位点发生反应。ImPyLDu86(3)在纳摩尔浓度下有效地将二烷基化位点烷基化。log ic50对39个肿瘤细胞系1-3的平均值分别为- 4.59,- 5.95和- 8.25。1 ~ 3种不同的生长抑制模式各不相同，相关系数相对较低。在人肺癌细胞系中进行了3基因的阵列表达监测。参与DNA损伤反应、转录和信号转导的基因表达显著下调。
Three conjugates of imidazole (Im)-pyrrole (Py) diamide and a DNA-alkylating moiety derived from the antibiotic duocarmycin A were synthesized, and their sequence specificity, reactivity, and antitumor activity comparatively examined. Sequencing gel analysis indicated that ImPyDu (1) alkylates DNA at the 3′ end of AT-rich sequences at micromolar concentration. ImPyDu86 (2) reacts with DNA at AT-rich sites together with dialkylation sites at micromolar concentration. ImPyLDu86 (3) efficiently alkylates dialkylation sites at nanomolar concentration. Average values of log IC50against a 39 cancer cell line panel of 1–3 were −4.59, −5.95, and −8.25, respectively. The differential growth inhibition pattern of 1–3 varied with relatively low correlation coefficients. Array-based gene expression monitoring was performed for 3 in a human lung cancer cell line. Substantial downregulation of expression was seen for genes involved in DNA damage response, transcription, and signal transduction.