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.

Synthesis and investigation of quadruplex-DNA-binding, 9-O-substituted berberine derivatives

“…For example, the aminohexyl-substituted derivative 1b 6 and the phenylpropyl-substituted compound 1d 3 have the highest affinity to G-quadruplex DNA, whereas the deriva-tives with other alkyl chain lengths have a lower affinity [38]. Along the same line, the influence of the length and substituents of the side chains at the G4-DNA ligands have been assessed for quinolinium [43], indoloquinoline [44,45], phenanthroline [46], phenothiazine [47], and thiazole orange [48] derivatives. In these studies, the delicate balance between the hydrophobic effects of the alkyl chain and the thermodynamically favorable interactions on the association of ammonium or pyridinium groups in the grooves and loops was assessed.…”

Targeting G-quadruplex motifs interferes with differentiation of adipose-derived mesenchymal stem cells

“…Several studies addressed G4 motif stabilization by using selective small molecules to induce anticancer effects mainly associated with DNA damage at telomeres, cancer cell senescence, apoptosis, immunogenic cancer cell death [ 3 , 4 ]. G4 structure stabilization blocks telomerase activity [ 5 ] and its access to the G-rich single strand, thus preventing telomere extension and cancer cell immortality. Targeting G4 motifs with specific ligands represents the focus of several clinical investigations in cancer.…”