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, IC(50)=350 nM; CDK5/p25, IC(50)=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 (IC(50) values ranging from 17 to 50 nM) and showed significant cell death inducing activities (IC(50) values ranging from 2 to 9 μM 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 IC(50) 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; IC(50) values ranging from 300 to 400 nM).

译文

:细胞周期蛋白依赖性激酶5(CDK5)是属于细胞周期蛋白依赖性激酶(CDK)家族的丝氨酸/苏氨酸激酶。 CDK5与多种神经元疾病(包括阿尔茨海默氏症或帕金森氏症,中风,脑外伤),疼痛信号和细胞迁移有关。在本信中,我们描述了新的2,6,9-三取代嘌呤的合成和生物学评估,这些嘌呤在结构上与roscovitine有关,roscovitine是目前在临床试验中有希望的CDK抑制剂(CDK1 / Cyclin B,IC(50)= 350 nM; CDK5 / p25,IC(50)= 200 nM)。这些新分子是使用原始的Buchwald-Hartwig催化程序合成的;几种化合物(3j,3k,3l,3e,4k,6b,6c)对CDK5表现出有效的激酶抑制作用(IC(50)值为17至50 nM),并显示出显着的细胞死亡诱导活性(IC(50)值) SH-SY5Y的范围为2至9μM)。抑制剂对接至CDK5催化位点的ATP结合域中,突显了涉及CDK5 Lys-89的氢键的歧视性作用。此外,针对几种抑制剂测得的络合最终能量平衡计算结果与IC(50)值的排名一致。最后,我们观察到几种化合物对DYRK1A表现出亚微摩尔活性(双重特异性,酪氨酸磷酸化调节激酶1A),该激酶与唐氏综合症和阿尔茨海默氏病有关(3g,3h,4m; IC(50)值介于300至400 nM之间)。

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