Isaindigotone Derivatives: A New Class of Highly Selective Ligands for Telomeric G-Quadruplex DNA

Abstract

Four isaindigotone derivatives (5a,b and 6a,b) designed as telomeric G-quadruplex ligands have been synthesized and characterized. The unfused aromatic rings in these compounds allow a flexible and adaptive conformation in G-quadruplex recognition. The interaction of human telomeric G-quadruplex DNA with these designed ligands was explored by means of FRET melting, fluorescence titration, CD spectroscopy, continuous variation, and molecular modeling studies. Our results showed that the adaptive scaffold might not only allow the ligands to well occupy the G-quartet but also perfectly bind to the grooves of the G-quadruplex. The synergetic effect of the multiple binding modes might be responsible for the improved binding ability and high selectivity of these ligands toward G-quadruplex over duplex DNA. Long-term exposure of HL60 and CA46 cancer cells to compound 5a showed a remarkable decrease in population growth, cellular senescence phenotype, and shortening of the telomere length, which is consistent with the behavior of an effective telomeric G-quadruplex ligand and telomerase inhibitor.

The interactions of phenanthroline compounds with DNAs: Preferential binding to telomeric quadruplex over duplex

“…Fluorescence emission or absorption difference spectra were used to obtain accurate values of binding stoichiometry between the compounds and either G-quadruplex DNA or i-motif DNA [29,30]. Stock solutions of 10 M compounds and 10 M quadruplex DNA were prepared in their corresponding buffer solutions.…”

Recent Developments in G-Quadruplex Probes

“…In 2012, Huang and co-workers reported a colorimetric probe for a variety of G-quadruplex structures by fusion of the TO and isaindigotone skeleton (Yan et al, 2012). Isaindigotone derivatives have shown potent binding affinity and selectivity for G-quadruplex DNA (Hou et al, 2011;Tan et al, 2009). These authors envisioned that the TO and isaindigotone scaffolds could be combined to generate fusion molecules with an expanded p-conjugate aromatic system as G-quadruplex probes.…”

Targeting G-quadruplex nucleic acids with heterocyclic alkaloids and their derivatives

“…The unfused aromatic rings and tethered side chains of these derivatives seemed to allow flexible and adaptive conformations, which will help for recognition of telomeric G-quadruplex cores and grooves in a 4:1 binding mode. Moreover, the most active compound 5a (28) significantly induced cell senescence and telomere shortening of HL-60 cells and CA46 cells at micromolar concentrations [97]. To better investigate how the planarity of an unfused aromatic ligand impacts its quadruplex binding properties, the aliphatic ring size in the middle core of these ligands was modified.…”