Book of Abstracts: Albany 2005
A Sequence-Specific DNA Alkylating Polyamide, Toward a Tailor-Made Antitumor Agent
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
Department of Chemistry