Synthesis, Biological Evaluation and Molecular Modeling of a Novel Series of 7-azaindole Based Tri-Heterocyclic Compounds as Potent CDK2/Cyclin E Inhibitors

Eur J Med Chem. 2016 Jan 27;108:701-719. doi: 10.1016/j.ejmech.2015.12.023. Epub 2015 Dec 19.


From four molecules, inspired by the structural features of fascaplysin, with an interesting potential to inhibit cyclin-dependent kinases (CDKs), we designed a new series of tri-heterocyclic derivatives based on 1H-pyrrolo[2,3-b]pyridine (7-azaindole) and triazole heterocycles. Using a Huisgen type [3 + 2] cycloaddition as the convergent key step, 24 derivatives were synthesized and their biological activities were evaluated. Comparative molecular field analysis (CoMFA), based on three-dimensional quantitative structure-activity relationship (3D-QSAR) studies, was conducted on a series of 30 compounds from the literature with high to low known inhibitory activity towards CDK2/cyclin E and was validated by a test set of 5 compounds giving satisfactory predictive r(2) value of 0.92. Remarkably, it also gave a good prediction of pIC50 for our tri-heterocyclic series which reinforce the validation of this model for the pIC50 prediction of external set compounds. The most promising compound, 43, showed a micro-molar range inhibitory activity against CDK2/cyclin E and also an antiproliferative and proapoptotic activity against a panel of cancer cell lines.

Keywords: 1,4-Triazole; 1,5-Triazole; 1H-pyrrolo[2,3-b]pyridine; 3D-QSAR CoMFA; Anti-tumor agent; Cyclin-dependent kinase 2; Kinase inhibitors; [3+2] cycloaddition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin E / antagonists & inhibitors*
  • Cyclin E / metabolism
  • Cyclin-Dependent Kinase 2 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 2 / metabolism
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology*
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Models, Molecular*
  • Molecular Structure
  • Quantitative Structure-Activity Relationship


  • 7-azaindole dimer
  • Antineoplastic Agents
  • Cyclin E
  • Enzyme Inhibitors
  • Heterocyclic Compounds
  • Indoles
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2