Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 23, Issue 1, Pages 125-131Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2012.10.141
Keywords
CDK5; Kinase; Roscovitine; Buchwald-Hartwig amination
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Funding
- 'Canceropole Grand-Ouest' Grant
- 'Institut National du Cancer' (INCa Cancer Detection d'innovations)
- 'Association France-Alzheimer Finistere'
- 'Ligue Nationale contre le Cancer (Grand-Ouest)'
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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 mu M 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). (C) 2012 Elsevier Ltd. All rights reserved.
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