Rational Design of Acridine-Based Ligands with Selectivity for Human Telomeric Quadruplexes

Abstract

Structure-based modeling methods have been used to design a series of disubstituted triazole-linked acridine compounds with selectivity for human telomeric quadruplex DNAs. A focused library of these compounds was prepared using click chemistry and the selectivity concept was validated against two promoter quadruplexes from the c-kit gene with known molecular structures, as well as with duplex DNA using a FRET-based melting method. Lead compounds were found to have reduced effects on the thermal stability of the c-kit quadruplexes and duplex DNA structures. These effects were further explored with a series of competition experiments, which confirmed that binding to duplex DNA is very low even at high duplex:telomeric quadruplex ratios. Selectivity to the c-kit quadruplexes is more complex, with some evidence of their stabilization at increasing excess over human telomeric quadruplex DNA. Selectivity is a result of the dimensions of the triazole-acridine compounds, and in particular the separation of the two alkyl-amino terminal groups. Both lead compounds also have selective inhibitory effects on the proliferation of cancer cell lines compared to a normal cell line, and one has been shown to inhibit the activity of the telomerase enzyme, which is selectively expressed in tumor cells, where it plays a role in maintaining telomere integrity and cellular immortalization.

Molecular dynamics simulations of G-DNA and perspectives on the simulation of nucleic acid structures

“…Computer-aided and/or structure-based drug design methodologies are often applied to find and optimize ligands interacting with specific quadruplex targets. This includes straightforward modeling and structural analysis [168,169], and more detailed molecular docking [170–173], molecular dynamics and free energy simulation approaches [36,51,61–65,67,68,70,73,174–179]. Recent reviews provide more in-depth discussion of the use of modeling methods to target not only G-DNA [180] but also G-RNA [181].…”

Platinum(II) Phenanthroimidazoles for Targeting Telomeric G‐Quadruplexes

“…These preliminary data indicate that complex 6 causes preferential cell cytotoxicity in cancer cell lines while being less toxic toward normal cells, a selectivity that compares well with previously reported strong G4 binders. [17] These complexes warrant further investigation for use as therapies for stabilizing G4 structures at telomeres and/or G-rich oncogene promoter regions.…”

“…To date, many compounds with varying degrees of efficacy in their ability to target this higher-order DNA structure have been reported. [14,15] Based on this wealth of empirical data obtained not only from binding studies, but also from molecular modeling and crystal structure determination of G4-ligand complexes, [16,17] several clues about the rational design of G4 binders have been uncovered, including the need for an electron-poor aromatic p-surface, positive charges in the scaffold, and the presence of positively charged side arms.…”

Topology Specific Stabilization of Promoter over Telomeric G-Quadruplex DNAs by Bisbenzimidazole Carboxamide Derivatives

“…For example, acridine based ligands bind specifically to telomeric DNA over promoter quadruplexes (c-KIT1, c-KIT2). 38 Receptor-based virtual screening strategies also identified specific telomeric binding ligands. 39 In addition, ligands which discriminate between various telomeric quadruplexes are also reported.…”