title: A novel series of highly potent 2,6,9-trisubstituted purine cyclin-dependent kinase inhibitors.
abstract: The inhibition of overactive CDKs during cancer remains an important strategy in cancer drug development. We synthesized and screened a novel series of 2-substituted-6-biarylmethylamino-9-cyclopentylpurine derivatives for improved CDK inhibitory activity and antiproliferative effects. One of the most potent compounds, 6b, exhibited strong cytotoxicity in the human melanoma cell line G361 that correlated with robust CDK1 and CDK2 inhibition and caspase activation. In silico modeling of 6b in the active site of CDK2 revealed a high interaction energy, which we believe is due to the 6-heterobiarylmethylamino substitution of the purine moiety.
authors.affiliation: Centre of the Region Haná for Biotechnological and Agricultural Research, Department of Growth Regulators, Faculty of Science, Palacký University, Šlechtitelů 11, 78371 Olomouc, Czech Republic. akrylhydrazid@seznam.cz
authors.forename: Tomáš
authors.initials: T
authors.lastname: Gucký
authors.forename: Radek
authors.initials: R
authors.lastname: Jorda
authors.forename: Marek
authors.initials: M
authors.lastname: Zatloukal
authors.forename: Václav
authors.initials: V
authors.lastname: Bazgier
authors.forename: Karel
authors.initials: K
authors.lastname: Berka
authors.forename: Eva
authors.initials: E
authors.lastname: Řezníčková
authors.forename: Tibor
authors.initials: T
authors.lastname: Béres
authors.forename: Miroslav
authors.initials: M
authors.lastname: Strnad
authors.forename: Vladimír
authors.initials: V
authors.lastname: Kryštof
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D003198:Computer Simulation; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008744:Methylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010766:Phosphorylation; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D003517:Cyclopentanes; D008744:Methylamines; C584253:N2-(4-aminocyclohexyl)-9-cyclopentyl-N6-(6-(2-hydroxyphenyl)pyridin-3-ylmethyl)-9H-purine-2,6-diamine; D011687:Purines; D016160:Retinoblastoma Protein; D016203:CDC2 Protein Kinase; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D000225:Adenine