G-quadruplexes (G4s) are guanine rich and i-motifs are cytosine rich non-canonical fourstrandedDNA secondary structures present throughout the genome. Their presence in important regulatoryregions of the genome marks their significance in biology. This perspective discusses the importance of bothG-quadruplex and i-motif structures and highlights their discovery, structural uniqueness, prevalence, androle in the biological system. Herein, we discuss the ligands developed in our laboratory that targetG-quadruplexes and i-motifs and modulate gene expression in cancer cells. We also shed light on some recenttechniques developed by us to simplify the synthesis and screening of G4 and i-motif specific ligands andtheir importance in anti-cancer therapeutics.

Synopsis: G-quadruplexes and i-motifs are non-canonical DNA secondary structures prevalent in the telomeric region as well as in the regulatory regions of proto-oncogenes. We have described selective targeting of DNA secondary structures by small molecules and their functional role in the regulation of gene expression.