Design, synthesis, and characterization of polyintercalating ligands

This chapter attempts to extend interactions beyond bisintercalation to significantly improve binding affinities. Functionalized DNA polyintercalators that bind to DNA in a sequence-selective manner represent, at least in principle, an attractive strategy for targeting cellular DNA. As such, polyintercalation could be considered an alternative to approaches such as triple helix-forming oligonucleotides, minor groove-binding molecules, peptide nucleic acids, and modified zinc fingers/Indeed, the idea of connecting several intercalating groups via appropriate linkages to create DNA binding agents with high affinity is certainly not new. Synthetic trisintercalators have been reported, most notably a polyamine-linked trisacridine compound synthesized by Laugaa et al., that binds to DNA with an affinity near 1014 M-1. There are potential difficulties associated with the design of polyintercalators. Linking multiple intercalating moieties together does not necessarily result in a corresponding increase in binding constant or even in full intercalation. The pursuit of predictable sequence specificity in a high-affinity polyintercalating system will require a detailed structural understanding, but unfortunately the characterization of DNA-bound structure is complicated in the case of polyintercalators.