Isohelical Analysis of DNA Groove-Binding Drugs

Many antitumor drugs, and many carcinogens, act by binding within the minor groove of double-helical DNA, interfering with both replication and transcription. Several of these, including netropsin and distamycin, are quite base specific, recognizing and binding only to certain base sequences. The repeating pyrrole-amide unit of netropsin, and the repeated benzimidazole unit of the DNA stain and carcinogen Hoechst 33258, both are approximately 20% too long for synchronous meshing with base pairs along the floor of the minor groove in B DNA. We have carried out a systematic computer search for possible repeating drug backbones that are isohelical with DNA and that also provide chemical groups capable of reading and differentiating between A·T and G·C base pairs. These isohelical se-quence-reading drug polymers or “isolexins” should offer the possibility of targeting synthetic drug analogues specifically against one region of a genome rather than another, or against neoplastic cells in preference to normal cells.