Bio-Inspired Dual-Selective BCL-2/ c-MYC G-Quadruplex Binders: Design, Synthesis, and Anticancer Activity of Drug-like Imidazo[2,1- i]purine Derivatives

J Med Chem. 2020 Mar 12;63(5):2035-2050. doi: 10.1021/acs.jmedchem.9b00262. Epub 2019 Jul 10.


In the search for new drug-like selective G-quadruplex binders, a bioinspired design focused on the use of nucleobases as synthons in a multicomponent reaction was herein proved to be viable and successful. Hence, a new class of multifunctionalized imidazo[2,1-i]purine derivatives, easily synthesized with a convergent approach, allowed for the identification of the first dual BCL2/c-MYC gene promoter G-quadruplex ligand. Biophysical studies involving circular dichroism melting experiments, microscale thermophoresis measurements, NMR titrations, and computational docking calculations, as well as biological investigations including cytotoxicity and apoptotic assays, and quantitative polymerase chain reaction and Western blot analyses, were performed to assess the potency and to characterize the binding mode of the newly identified lead compound. The absence of toxicity toward normal cells, together with the small molecular weight (≅500 Da), the water solubility, the ease of functionalization, and the selectivity profile, are promising and desirable features to develop G-quadruplex binders as safe and effective anticancer agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism*
  • Biological Products / chemistry*
  • Biological Products / metabolism
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / metabolism*
  • Drug Design*
  • G-Quadruplexes*
  • HCT116 Cells
  • Humans
  • Imidazoles / chemistry
  • Imidazoles / metabolism
  • Jurkat Cells
  • MCF-7 Cells
  • Molecular Docking Simulation / methods
  • Protein Binding / physiology
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Purines / chemistry
  • Purines / metabolism
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism*


  • Antineoplastic Agents
  • BCL2 protein, human
  • Biological Products
  • DNA-Binding Proteins
  • Imidazoles
  • MYCBP protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • Purines
  • Transcription Factors
  • imidazole
  • purine