Synthesis and in vitro biological evaluation of 2,6,9-trisubstituted purines targeting multiple cyclin-dependent kinases

0395483 - ÚEB 2014 RIV FR eng J - Journal Article
Zatloukal, M. - Jorda, Radek - Gucký, T. - Řezníčková, Eva - Voller, Jiří - Pospíšil, T. - Malínková, V. - Adamcová, H. - Kryštof, Vladimír - Strnad, Miroslav
Synthesis and in vitro biological evaluation of 2,6,9-trisubstituted purines targeting multiple cyclin-dependent kinases.
European Journal of Medicinal Chemistry. Roč. 61, SI (2013), s. 61-72. ISSN 0223-5234. E-ISSN 1768-3254
R&D Projects: GA ČR GAP305/12/0783; GA ČR GA301/08/1649
Grant - others:GA MŠk(CZ) ED0007/01/01
Program: ED
Institutional research plan: CEZ:AV0Z50380511
Keywords : Cyclin-dependent kinase * Inhibitor * Roscovitine
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 3.432, year: 2013

Several inhibitors of cyclin-dependent kinases (CDKs), including the 2,6,9-trisubstituted purine derivative roscovitine, are currently being evaluated in clinical trials as potential anticancer drugs. Here, we describe a new series of roscovitine derivatives that show increased potency in vitro. The series was tested for cytotoxicity against six cancer cell lines and for inhibition of CDKs. For series bearing 2-(hydroxyalkylamino) moiety, cytotoxic potency strongly correlated with anti-CDK2 activity. Importantly, structural changes that increase biochemical and anticancer activities of these compounds also increase elimination half-life. The most potent compounds were investigated further to assess their ability to influence cell cycle progression, p53-regulated transcription and apoptosis. All the observed biological effects were consistent with inhibition of CDKs involved in the regulation of cell cycle and transcription.
Permanent Link: http://hdl.handle.net/11104/0223515