Secondary DNA structures as molecular targets for cancer therapeutics

DNA sequence information is pivotal to transcription, replication and recombination. DNA structure is dependent upon intracellular conditions such as ion concentration and the presence of proteins that may bind to DNA to facilitate the interconversion between different forms and to stabilize specific secondary structures. Dependent upon the primary DNA sequence, purine- and pyrimidine-rich strands of DNA can adopt four-stranded structures known as G-quadruplexes and i-motifs, respectively. These structures have been proposed to exist in biologically important regions of DNA, e.g. at the end of chromosomes and in the regulatory regions of oncogenes such as c-myc. Proteins such as topoisomerase I and Rap1 can facilitate the formation of G-quadruplex structures, and for transcriptional activation of c-myc, proteins such as NM23–H2 and hnRNP K are required. These proteins bind to the non-duplex forms of the nuclease hypersensitivity element III, of c-myc. The design and synthesis of small molecules that target these secondary DNA structures and the biochemical and biological effects of these compounds are of potential importance in cancer chemotherapy.