Synthesis and Biological Properties of Sequence-Specific DNA-Alkylating Pyrrole−Imidazole Polyamides

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Abstract
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.