Potent inhibitors of CDK5 derived from roscovitine: Synthesis, biological evaluation and molecular modelling

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• 作者：Luc Demange^a ; ^{luc.demange@parisdescartes.fr} ; Fatma Nait Abdellah^a ; Olivier Lozach^b ; Yoan Ferandin^b ; Nohad Gresh^a ; Laurent Meijer^b ; ^c ; ^{meijer@manros-therapeutics.com} ; Herv33 ; Galons^c ; ^d
• 关键词：CDK5 ; Kinase ; Roscovitine ; Buchwald&ndash ; Hartwig amination
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：1 January, 2013
• 年：2013
• 卷：23
• 期：1
• 页码：125-131
• 全文大小：1059 K

文摘

Cyclin dependent kinase 5 (CDK5) is a serine/threonine kinase belonging to the cyclin dependent kinase (CDK) family. CDK5 is involved in numerous neuronal diseases (including Alzheimer¡¯s or Parkinson¡¯s diseases, stroke, traumatic brain injury), pain signaling and cell migration. In the present Letter, we describe syntheses and biological evaluations of new 2,6,9-trisubstituted purines, structurally related to roscovitine, a promising CDK inhibitor currently in clinical trials (CDK1/Cyclin B, IC₅₀ = 350 nM; CDK5/p25, IC₅₀ = 200 nM). These new molecules were synthesized using an original Buchwald-Hartwig catalytic procedure; several compounds (3j, 3k, 3l, 3e, 4k, 6b, 6c) displayed potent kinase inhibitory potencies against CDK5 (IC₅₀ values ranging from 17 to 50 nM) and showed significant cell death inducing activities (IC₅₀ values ranging from 2 to 9 ¦ÌM on SH-SY5Y). The docking of the inhibitors into the ATP binding domain of the CDK5 catalytic site highlighted the discriminatory effect of a hydrogen bond involving the CDK5 Lys-89. In addition, the calculated final energy balances for complexation measured for several inhibitors is consistent with the ranking of the IC₅₀ values. Lastly, we observed that several compounds exhibit submicromolar activities against DYRK1A (dual specificity, tyrosine phosphorylation regulated kinase 1A), a kinase involved in Down syndrome and Alzheimer¡¯s disease (3g, 3h, 4m; IC₅₀ values ranging from 300 to 400 nM).