G-Quadruplexes are unique non-canonical nucleic acid secondary structures formed by stacking of G-tetrads in the presence of monovalent cations, abundant in replication origins, gene promoters, and ends of the chromosomes. There are more than 370,000 putative G-quadruplex forming sequences in the human genome. High conformational variability is present in the G-quadruplexes depending on the sequence, loop length and bulges. The facilitation in the formation and stabilization of G-quadruplexes by small molecules in the gene promoter regions of oncogenes and ends of the chromosomes can be a promising therapy for cancer remediation. Most of the G-quadruplex (G4) binding ligands contain an extended planar aromatic surface that maximizes the stacking with the end G-tetrad in a G-quadruplex. However, this common feature also reduces the G4 ligands’ ability to bind to different G-quadruplex conformations selectively. Introducing side chains to G4 ligands could be a suitable approach to enhance their binding specificity. In the present work, we synthesized two conjugates by coupling an aminosugar (neomycin) side chain to a known G4 ligand (phenanthroline) with different linker lengths. Results from thermal denaturation monitored by CD suggest that one of the conjugates exhibits a large synergistic effect on the binding affinity to the hybrid-type G-quadruplex conformation. Interestingly, the binding of the conjugates to G4 does not require metal ions such as Ni(II) and Pt(II) for complexation of phenanthroline. The data is consistent with the binding affinity measurements using isothermal titration calorimetry and ESI mass spectrometry. The conjugates inhibited the activity of human telomerase at the submicromolar concentrations. Length of the linker found to a have a profound effect on the binding affinity and conformation selectivity of the conjugates toward G4.

Use of neomycin as a side chain for phenanthroline based G-quadruplex binding ligands and telomerase inhibitors

2019 Fall National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.