Click and combinatorial approaches to quadruplex ligand discovery

Abstract

The increasing need of therapeutically relevant ligands fuels the demand for developing efficient synthetic methodologies to rapidly construct molecular libraries. The Cu(I) catalyzed Huisgen azide-alkyne cycloaddition, popularly known as “click reaction” represents a facile approach to synthesize simple to complex molecules for biological targets. The click reaction, due to its versatility and biocompatibility, has become a highly sought-after synthetic tool for the synthesis of selective G-quadruplex ligands. DNA and RNA G-quadruplexes have regulatory roles within the cellular system which can be modulated using small molecule ligands. Click ligation between two different chemical entities has generated potent triazole ligands for G-quadruplexes with promising anti-cancer activities. The application of this transformation has evolved from traditional lead discovery to target-templated in situ chemistry in which the G-quadruplex participates in the synthesis of potent binders. In this chapter, we outline click and target-templated combinatorial approaches for the discovery of quadruplex ligands.