Synthesis and testing of a triaza-cyclopenta[b]phenanthrene scaffold as a DNA binding agent

A novel DNA binding agent based upon a triaza-cyclopenta[b]phenanthrene scaffold, compound 1, has been synthesized. dsDNA binding analysis of this compound using the ethidium bromide displacement assay indicated a preference for GC-rich sequences. However, equilibrium dialysis experiments against a variety of nucleic acids showed that the target compound bound about 20-fold tighter to G-quartet DNA than to dsDNA under physiological salt concentrations. The binding of 1 to G-quartet DNA was verified by the ability of the compound to promote the formation of the quartet and to compete with TmPyP4 for binding to the quadruplex. Given the importance of G-quartet binding agents in the treatment of cancer and in the understanding of drug-DNA interactions, 1 and its related analogs should find utility as a new class of G-quartet specific agents.