Synthesis and biological properties of sequence-specific DNA-alkylating pyrrole-imidazole polyamides

被引:176
作者
Bando, Toshikazu [1 ]
Sugiyama, Hiroshi [1 ]
机构
[1] Kyoto Univ, Dept Chem, Grad Sch Sci, Kyoto 6068502, Japan
关键词
D O I
10.1021/ar030287f
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
In recent years, many diseases including cancer and hereditary and viral diseases have been understood at the DNA sequence level. Direct control of the expression level of a specific gene would provide a promising approach for knowledge-based therapy. N-Methylpyrrole (Py) and N-methylimidazole (Im) polyamides are a new type of small compound that precisely bind to the minor groove of the DNA duplex in a sequence-specific fashion and recruit alkylating agents to the target sequence. We designed and synthesized a series of sequence-specific alkylating Py-Im polyamide conjugates that selectively alkylate predetermined DNA sequences. We have demonstrated that sequence-specific alkylating agents possess gene-silencing activities and a promising potency against human cancer cell lines as well as against xenografts of human cancer cell lines. In this Account, we focus on recent progress in alkylating Py-Im polyamides with regard to sequence specificity and biological activities and the future direction of rational molecular design of genetic switches in the postgenome era is described.
引用
收藏
页码:935 / 944
页数:10
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