Sequence-specific DNA alkylations have been a topic of much current interest due to their significant potential in molecular biology and human medicine. Minor-groove-binding polyamides that contain N-methylimidazole (Im)-N-methylpyrrole (Py), which uniquely recognize each of the four Watson-Crick base pairs, can be used as novel recognition components of sequence-specific DNA alkylating agents. We have demonstrated that hybrid molecules constructed from segment A of duocarmycin A and Py-Im diamides or hairpin polyamides specifically alkylate predetermined nucleotide sequences (1). We demonstrated that alkylating Py-Im polyamides that recognized specific sites on the template strand effectively inhibit transcription in an in vitro transcription system (2) and induced sequence-specific gene silencing in human cell lines (3). More recently, we found that alkylating Py-Im polyamides that differ only in that the C-H bond is substituted by an N atom in the second ring showed significantly different cytotoxicities in 39 human cancer cell lines (4).

References and Footonotes

1. Tao, Z.-F., Fujiwara, T., Saito, I., and Sugiyama, H. J. Am. Chem. Soc. 121, 4961 (1999).
2. Oyoshi, T., Kawakami, W., Narita, A., Bando, T., and Sugiyama, H. J. Am. Chem. Soc. 125, 4752 (2003).
3. Shinohara, K., Narita, A., Oyoshi, T., Bando, T., Teraoka, H., and Sugiyama, H. J. Am. Chem. Soc. 126, 5113 (2004).
4. Bando, T., Narita, A., Iwai, A., Kihara, K., and Sugiyama, H. J. Am. Chem. Soc. 126, 3406 (2004).