The effect of side chain variations on quinazoline-pyrimidine G-quadruplex DNA ligands

Eur J Med Chem. 2023 Feb 15:248:115103. doi: 10.1016/j.ejmech.2023.115103. Epub 2023 Jan 8.

Abstract

G-quadruplex (G4) DNA structures are involved in central biological processes such as DNA replication and transcription. These DNA structures are enriched in promotor regions of oncogenes and are thus promising as novel gene silencing therapeutic targets that can be used to regulate expression of oncoproteins and in particular those that has proven hard to drug with conventional strategies. G4 DNA structures in general have a well-defined and hydrophobic binding area that also is very flat and featureless and there are ample examples of G4 ligands but their further progression towards drug development is limited. In this study, we use synthetic organic chemistry to equip a drug-like and low molecular weight central fragment with different side chains and evaluate how this affect the compound's selectivity and ability to bind and stabilize G4 DNA. Furthermore, we study the binding interactions of the compounds and connect the experimental observations with the compound's structural conformations and electrostatic potentials to understand the basis for the observed improvements. Finally, we evaluate the top candidates' ability to selectively reduce cancer cell growth in a 3D co-culture model of pancreatic cancer which show that this is a powerful approach to generate highly active and selective low molecular weight G4 ligands with a promising therapeutic window.

MeSH terms

  • DNA / metabolism
  • G-Quadruplexes*
  • Ligands
  • Oncogenes
  • Pyrimidines

Substances

  • Ligands
  • DNA
  • Pyrimidines