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.
Keywords: DNA-binding ligands; G-quadruplex DNA; neomycin; phenanthroline; telomerase inhibition.
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