A two-pronged attack on DNA: Targeting guanine quadruplexes with nonplanar porphyrins and DNA-binding small molecules

Abstract

Cancer therapy requires the identification and selective targeting of cancer‐specific effectors. DNA is considered to be a chemotherapeutic target for cancer because of its involvement in cellular proliferation. In addition to the well‐known double‐stranded structures (A, B, Z‐DNA), DNA can form a number of multi‐stranded structures (triplexes, quadruplexes, i‐motifs) that have distinct biological relevance. In particular, guanine quadruplexes (GQs) are four‐stranded nucleic acid structures formed by guanine‐rich sequences that fold into non‐canonical secondary structures [1]. They consist of two or more G‐tetrads which form when four guanine residues connected by hydrogen bonds are held in a planar arrangement and stabilized further by cations such as Na+ and K+. Although GQs can take numerous conformations, there are common features among the GQ structures that may be harnessed to develop small‐molecules that bind to them [2]. GQs are present in biologically important regions, such as at the end of telomeres as well as in the regulatory regions of oncogenes (c‐MYC, c‐KIT, RET, KRAS) [3]. Formation of GQs in gene promoters results in the suppression of transcription; therefore, ligands that stabilize GQs in such gene promoters will inhibit transcriptional activation.