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

SYSNO ASEP	0459008
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	Synthesis, biological evaluation and molecular modeling of a novel series of 7-azaindole based tri-heterocyclic compounds as potent CDK2/Cyclin E inhibitors
Author(s)	Baltus, C.B. (FR) Jorda, Radek (UEB-Q)_{ORCID, RID} Marot, Ch. (FR) Berka, K. (CZ) Bazgier, Václav (UEB-Q)_{ORCID, RID} Kryštof, Vladimír (UEB-Q)_{RID, ORCID} Prie, G. (FR) Viaud-Massuard, M.C. (FR)
Source Title	European Journal of Medicinal Chemistry. - : Elsevier - ISSN 0223-5234 Roč. 108, JAN 27 (2016), s. 701-719
Number of pages	19 s.
Language	eng - English
Country	FR - France
Keywords	Cyclin-dependent kinase 2 ; Kinase inhibitors ; Anti-tumor agent
Subject RIV	EB - Genetics ; Molecular Biology
R&D Projects	LO1204 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
Institutional support	UEB-Q - RVO:61389030
UT WOS	000369191800061
DOI	10.1016/j.ejmech.2015.12.023
Annotation	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.
Workplace	Institute of Experimental Botany
Contact	David Klier, knihovna@ueb.cas.cz, Tel.: 220 390 469
Year of Publishing	2017

Number of the records: 1