Use of neomycin as a structured amino‐containing side chain motif for phenanthroline‐based G‐quadruplex ligands and telomerase inhibitors

Abstract In this paper, we report the synthesis of a phenanthroline and neomycin conjugate ( 7 ). Compound 7 binds to a human telomeric G‐quadruplex ( G1 ) with a higher affinity compared with its parent compounds (phenanthroline and neomycin), which is determined by several biophysical studies. Compound 7 shows good selectivity for G‐quadruplex (G4) DNA over duplex DNA. The binding of 7 with G1 is predominantly enthalpy‐driven, and the binding stoichiometry of 7 with G1 is one for the tight‐binding event as determined by ESI mass spectrometry. A plausible binding mode is a synergistic effect of end‐stacking and groove interactions, as indicated by docking studies. Compound 7 can inhibit human telomerase activity at low micromolar concentrations, which is more potent than previously reported 5‐substituted phenanthroline derivatives.