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

0459008 - ÚEB 2017 RIV FR eng J - Journal Article
Baltus, C.B. - Jorda, Radek - Marot, Ch. - Berka, K. - Bazgier, Václav - Kryštof, Vladimír - Prie, G. - Viaud-Massuard, M.C.
Synthesis, biological evaluation and molecular modeling of a novel series of 7-azaindole based tri-heterocyclic compounds as potent CDK2/Cyclin E inhibitors.
European Journal of Medicinal Chemistry. Roč. 108, JAN 27 (2016), s. 701-719. ISSN 0223-5234. E-ISSN 1768-3254
R&D Projects: GA MŠMT(CZ) LO1204
Institutional support: RVO:61389030
Keywords : Cyclin-dependent kinase 2 * Kinase inhibitors * Anti-tumor agent
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 4.519, year: 2016

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 pIC(50) for our tri-heterocyclic series which reinforce the validation of this model for the pIC(50) 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.
Permanent Link: http://hdl.handle.net/11104/0259205