G-quadruplex are unique secondary structures of DNA formed from sequences rich in guanine. Such sequences include the TTAGGG repeat in human telomeres (the end of chromosomes) and those within the promoter regions of numerous oncogenes. In telomeres, G-quadruplex presence - and stabilisation - eliminates the activity of telomerase, a DNA polymerase, and restores natural apoptosis. In genes such as c-kit, bcl-2 and, c-myc, G-quadruplex - formed from guanine-rich sequences in their promoter regions - help down-regulate overactive transcription that otherwise causes malignancies such as tumours and cancer.
While the overall topology of G-quadruplex vary, the basic structure is conserved through G-tetrad, composed of four guanines arranged together through Hoogsteen hydrogen bonds. Several planar G-tetrads π-stack on top of each other to give the general G-quadruplex structure. The hydrogen bonding and π-stacking ensures these constructs are relatively stable, however G-quadruplex agents could help induce and stabilise this configuration.
The choice of targeting G-quadruplex for anti-cancer agents is still novel. The most potent G-quadruplex stabilising agent is telomestatin, a natural product with large aromatic surface that is postulated to π-stack to the G-tetrads. Despite its potency for telomerase and G-quadruplex, its natural product extraction or large scale synthesis is expensive. Based on the structure of telomestatin, we want to develop a novel macrocycle series – triazolophanes - that can interact with the large aromatic surfaces of G-tetrads and tether to the grooves of G-quadruplex through positively-charged side groups.