2. Academic Validation
  3. Synthesis, biological evaluation and molecular modeling of a novel series of 7-azaindole based tri-heterocyclic compounds as potent CDK2/Cyclin E inhibitors

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.
Christine B Baltus 1,  Radek Jorda 2,  Christophe Marot 1,  Karel Berka 3,  Václav Bazgier 4,  Vladimír Kryštof 5,  Gildas Prié 1,  Marie-Claude Viaud-Massuard 6
Affiliations

Affiliations

  • 1 UMR 7292 GICC Equipe 4 Innovation Moléculaire et Thérapeutique, Labex SYNORG, University of Tours, Faculty of Pharmacy, 31 Avenue Monge, 37200 Tours, France.
  • 2 Laboratory of Growth Regulators & Department of Chemical Biology and Genetics, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, CZ-78371 Olomouc, Czech Republic. Electronic address: radek.jorda@upol.cz.
  • 3 Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacky University Olomouc, 17. Listopadu 12, 77146 Olomouc, Czech Republic; Department of Physical Chemistry, Faculty of Science, Palacký University, 17. Listopadu 1192/12, 771 46 Olomouc, Czech Republic.
  • 4 Laboratory of Growth Regulators & Department of Chemical Biology and Genetics, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, CZ-78371 Olomouc, Czech Republic; Department of Physical Chemistry, Faculty of Science, Palacký University, 17. Listopadu 1192/12, 771 46 Olomouc, Czech Republic.
  • 5 Laboratory of Growth Regulators & Department of Chemical Biology and Genetics, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, CZ-78371 Olomouc, Czech Republic.
  • 6 UMR 7292 GICC Equipe 4 Innovation Moléculaire et Thérapeutique, Labex SYNORG, University of Tours, Faculty of Pharmacy, 31 Avenue Monge, 37200 Tours, France. Electronic address: marie-claude.viaud-massuard@univ-tours.fr.
PMID: 26741853 DOI: 10.1016/j.ejmech.2015.12.023
Abstract

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.

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