title: Synthesis, biological evaluation and molecular modeling of a novel series of 7-azaindole based tri-heterocyclic compounds as potent CDK2/Cyclin E inhibitors.
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.
authors.affiliation: UMR 7292 GICC Equipe 4 Innovation Moléculaire et Thérapeutique, Labex SYNORG, University of Tours, Faculty of Pharmacy, 31 Avenue Monge, 37200 Tours, France.
authors.forename: Christine B
authors.initials: CB
authors.lastname: Baltus
authors.affiliation: 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.
authors.forename: Radek
authors.initials: R
authors.lastname: Jorda
authors.affiliation: UMR 7292 GICC Equipe 4 Innovation Moléculaire et Thérapeutique, Labex SYNORG, University of Tours, Faculty of Pharmacy, 31 Avenue Monge, 37200 Tours, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Marot
authors.affiliation: 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.
authors.forename: Karel
authors.initials: K
authors.lastname: Berka
authors.affiliation: 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.
authors.forename: Václav
authors.initials: V
authors.lastname: Bazgier
authors.affiliation: 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.
authors.forename: Vladimír
authors.initials: V
authors.lastname: Kryštof
authors.affiliation: UMR 7292 GICC Equipe 4 Innovation Moléculaire et Thérapeutique, Labex SYNORG, University of Tours, Faculty of Pharmacy, 31 Avenue Monge, 37200 Tours, France.
authors.forename: Gildas
authors.initials: G
authors.lastname: Prié
authors.affiliation: 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.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Viaud-Massuard
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019927:Cyclin E / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship
chemical_list: C023422:7-azaindole dimer; D000970:Antineoplastic Agents; D019927:Cyclin E; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D007211:Indoles; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2
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