title: Synthesis and biological evaluation of selective and potent cyclin-dependent kinase inhibitors.
abstract: A new series of 2,6,9-trisubstituted purines, structurally related to the cyclin-dependent kinase (CDK) inhibitor Roscovitine, has been synthesized. These compounds mainly differ by the substituent on the C-2 position which encompasses a diol group. These compounds were screened for kinase inhibitory activities and antiproliferative effects. They were shown to be potent inhibitors of cyclin-dependent kinases but also, for some of them of casein kinase 1 (CK1) and dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). The inhibition of kinases was accompanied by an antiproliferative effect against several tumor cell-lines. The most potent derivatives inhibited SH-SY5Y (neuroblastoma) tumor cell line with an IC(50) < 0.5 μM which means approximately a 30 fold increase compared to Roscovitine. A valine ester was also prepared from the most potent inhibitor to serve as a prodrug.
authors.affiliation: ManRos Therapeutics, Centre de Perharidy, Hôtel de recherche, 29680 Roscoff, France.
authors.forename: Joannah
authors.initials: J
authors.lastname: N'gompaza-Diarra
authors.forename: Karima
authors.initials: K
authors.lastname: Bettayeb
authors.forename: Nohad
authors.initials: N
authors.lastname: Gresh
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Nassima
authors.initials: N
authors.lastname: Oumata
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D011687:Purines; D003577:Cytochrome P-450 Enzyme System; D018844:Cyclin-Dependent Kinases