title: 5-Substituted 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidines with anti-proliferative activity as potent and selective inhibitors of cyclin-dependent kinases.
abstract: A series of 5-substituted 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidine derivatives was synthesized and evaluated for their cyclin-dependent kinase (CDK) inhibition activity. The most potent compounds contained various hydroxyalkylamines at the 5 position and possessed low nanomolar IC50 values for CDK2 and CDK5. Preliminary profiling of one of the most active compounds on a panel of 50 protein kinases revealed its high selectivity for CDKs. The compounds arrested cells in S and G2/M phases, and induced apoptosis in various cancer cell lines. Significant dephosphorylation of the C-terminus of RNA polymerase II and focal adhesion kinase (FAK), well-established substrates of CDKs, has been found in treated cells. Cleavage of PARP-1, down-regulation of Mcl-1 and activation of caspases correlated well with CDK inhibition and confirmed apoptosis as the primary type of cell death induced in cancer cells treated with the compounds in vitro. A comparison of known purine-based CDK inhibitor CR8 with its pyrazolo[4,3-d]pyrimidine bioisosteres confirmed that the novel compounds are more potent in cellular assays than purines. Therefore, pyrazolo[4,3-d]pyrimidine may emerge as a novel scaffold in medicinal chemistry and as a source of potent CDK inhibitors.
authors: Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 78371 Olomouc, Czech Republic.
authors: Ladislava
authors: L
authors: Vymětalová
authors: Isotope Laboratory, Institute of Experimental Botany ASCR, Vídeňská 1083, 14220 Prague, Czech Republic.
authors: Libor
authors: L
authors: Havlíček
authors: Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 78371 Olomouc, Czech Republic.
authors: Antonín
authors: A
authors: Šturc
authors: Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 78371 Olomouc, Czech Republic.
authors: Zuzana
authors: Z
authors: Skrášková
authors: Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 78371 Olomouc, Czech Republic.
authors: Radek
authors: R
authors: Jorda
authors: Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 78371 Olomouc, Czech Republic.
authors: Tomáš
authors: T
authors: Pospíšil
authors: Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 78371 Olomouc, Czech Republic.
authors: Miroslav
authors: M
authors: Strnad
authors: Laboratory of Growth Regulators, Centre of the Region Haná for Biotechnological and Agricultural Research, Palacký University and Institute of Experimental Botany AS CR, Šlechtitelů 27, 78371 Olomouc, Czech Republic. Electronic address: vladimir.krystof@upol.cz.
authors: Vladimír
authors: V
authors: Kryštof
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D018844:Cyclin-Dependent Kinases
keywords: Bioisostere; Cyclin-dependent kinase; Inhibitor; Selectivity