Phenanthroline-2,9-bistriazoles as selective G-quadruplex ligands

• A series of G4 stabilizers based on phenanthroline-2,9-bistriazole was synthesized.
• The compounds were evaluated by SPR, FRET Tm, G4-FID and CD spectroscopy.
• Primary guanidinium functionalized ligands were identified as the most potent G4 stabilizers.
• Diisopropylguanidine ligands exhibited a 13-fold binding selectivity for c-KIT over htelo.

G-quadruplex (G4) ligands are currently receiving considerable attention as potential anticancer therapeutics. A series of phenanthroline-2,9-bistriazoles carrying tethered positive end groups has been synthesized and evaluated as G4 stabilizers. The compounds were efficiently assembled by copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) in CH2Cl2 and water in the presence of a complexing agent. Characterization of the target compounds on telomeric and c-KIT G4 sequences led to the identification of guanidinium-substituted compounds as potent G4 DNA ligands with high selectivity over duplex DNA. The diisopropylguanidium ligands exhibited high selectivity for the proto-oncogenic sequence c-KIT over the human telomeric sequence in the surface plasmon resonance (SPR) assay, whereas the compounds appeared potent on both G4 structures in the FRET melting temperature assay. The phenanthroline-2,9-bistriazole ligands were thus identified as potent G4 ligands with high selectivity over duplex DNA, and preliminary results indicate that the scaffold may form basis for the development of subtype-specific G4 ligands.

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