Screening of Scaffolds for the Design of G-Quadruplex Ligands

In the last decade, progress has been made in G-quadruplex (G4) ligands development, but for most compounds, the ligand binding mode is speculative or based on low resolution methods, with its discovery based on structure-based approaches. Herein, we report the synthesis of small (MW < 400 Da) heterocycle compounds, containing different aromatic scaffolds, such as phenyl, quinoline, naphthalene, phenanthroline and acridine moieties, in order to explore their stabilization effect towards different DNA G4s, such as those found in c-MYC, KRAS21 and VEGF promoters, 21G human telomeric motif and pre-MIR150. The fluorescence resonance energy transfer (FRET) melting assay indicates that the acridine moiety is the most active scaffold, followed by phenanthroline. The different scaffolds are promising in terms of drug-like properties and, in general, the IC50 values of the respective heterocycle compounds are lower in a cancer cell line, when compared with a normal cell line. The acridine derivative C5NH2 has the most favorable cytotoxic profile in terms of cell selectivity.

Automated summary

In this study, small heterocyclic compounds were synthesized to explore their stabilization effect towards different DNA G4s. The acridine moiety was found to be the most active scaffold with favorable cytotoxic profile in terms of cell selectivity.