Synthesis and biological properties of sequence-specific DNA-alkylating pyrrole-imidazole polyamides.
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.
Bando
Toshikazu
T
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto, Japan.
Sugiyama
Hiroshi
H
D000478:Alkylation; D001483:Base Sequence; D004247:DNA / Q000737:chemistry* / Q000235:genetics; D020868:Gene Silencing; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000633:toxicity; D009757:Nylons / Q000138:chemical synthesis* / Q000737:chemistry* / Q000633:toxicity; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000633:toxicity
D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D004247:DNA