N-芳基-2-氨基噻唑的合成与生物活性：细胞周期蛋白依赖性激酶的强效泛抑制剂
Synthesis and biological activity of N-aryl-2-aminothiazoles: potent pan inhibitors of cyclin-dependent kinases.
作者信息
Misra Raj N, Xiao Hai-yun, Williams David K, Kim Kyoung S, Lu Songfeng, Keller Kristen A, Mulheron Janet G, Batorsky Roberta, Tokarski John S, Sack John S, Kimball S David, Lee Francis Y, Webster Kevin R
机构信息
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
出版信息
Bioorg Med Chem Lett. 2004 Jun 7;14(11):2973-7. doi: 10.1016/j.bmcl.2004.02.105.
N-Aryl aminothiazoles 6-9 were prepared from 2-bromothiazole 5 and found to be CDK inhibitors. In cells they act as potent cytotoxic agents. Selectivity for CDK1, CDK2, and CDK4 was dependent of the nature of the N-aryl group and distinct from the CDK2 selective N-acyl analogues. The N-2-pyridyl analogues 7 and 19 showed pan CDK inhibitory activity. Elaborated analogues 19 and 23 exhibited anticancer activity in mice against P388 murine leukemia. The solid-state structure of 7 bound to CDK2 shows a similar binding mode to the N-acyl analogues.
N-芳基氨基噻唑6-9由2-溴噻唑5制备而成，被发现是细胞周期蛋白依赖性激酶（CDK）抑制剂。在细胞中，它们作为强效细胞毒性剂发挥作用。对CDK1、CDK2和CDK4的选择性取决于N-芳基基团的性质，且与CDK2选择性N-酰基类似物不同。N-2-吡啶基类似物7和19表现出泛CDK抑制活性。经过优化的类似物19和23在小鼠体内对P388鼠白血病显示出抗癌活性。与CDK2结合的7的固态结构显示出与N-酰基类似物相似的结合模式。
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