De Novo Design of Selective Quadruplex–Duplex Junction Ligands and Structural Characterisation of Their Binding Mode: Targeting the G4 Hot‐Spot

Targeting the interface between DNA quadruplex and duplex regions by small molecules holds significant promise in both therapeutics nanotechnology. Herein, a new pharmacophore is reported, which selectively binds with high affinity to quadruplex–duplex junctions, while presenting poorer for G-quadruplex or alone. Ligands complying reported exhibit selectivity including one observed HIV-1 LTR-III sequence. The structure of complex junction ligand this family has been determined NMR methods. According these data, remarkable structural motif junctions achieved through an unprecedented interaction mode so far unexploited medicinal biological chemistry: insertion benzylic ammonium moiety into centre partially exposed G-tetrad at duplex. Further decoration described scaffolds additional fragments opens up road development selective ligands G-quadruplex-forming genome.