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

T Bando, H Sugiyama - Accounts of chemical research, 2006 - ACS Publications
T Bando, H Sugiyama
Accounts of chemical research, 2006ACS Publications
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 …
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.
ACS Publications