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.

Department of Physical Chemistry Faculty of Science Palacký University 17 Listopadu 1192 12 771 46 Olomouc Czech Republic

Laboratory of Growth Regulators and 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

Regional Centre of Advanced Technologies and Materials Department of Physical Chemistry Faculty of Science Palacky University Olomouc 17 Listopadu 12 77146 Olomouc Czech Republic

UMR 7292 GICC Equipe 4 Innovation Moléculaire et Thérapeutique Labex SYNORG University of Tours Faculty of Pharmacy 31 Avenue Monge 37200 Tours France

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