State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
Eur J Med Chem. 2013 Oct;68:1-9. doi: 10.1016/j.ejmech.2013.07.003. Epub 2013 Jul 19.
It was discovered that a number of cyclin dependent kinase inhibitors containing the pyrazole core structure exhibited high inhibitory potency against broad-range CDKs and corresponding anti-proliferative activities. This information guided us to design and synthesize a series of 1,3-diphenyl-N-(phenylcarbamothioyl)-1H-pyrazole-4-carboxamide derivatives (5a-10d), and evaluate their biological activities as CDKs inhibitors. Among all the synthesized compounds, compound 10b inhibited CDK2 with an IC50 value of 25 nM, counteracting tumor cell proliferation of three cancer cell lines (H460, MCF-7, A549) in the micromolar range (from 0.75 μM to 4.21 μM), In addition, flow cytometry indicated that compound 10b could induce cycle G0/G1 phase arrest in A549 cells with a dose dependent. Taken together, compound 10b could be selected for further preclinical evaluation.
研究发现，含有吡唑核心结构的多种细胞周期蛋白依赖性激酶抑制剂对广谱 CDKs 具有高抑制活性和相应的抗增殖活性。这一信息指导我们设计并合成了一系列 1,3-二苯基-N-(苯氨基甲硫基)-1H-吡唑-4-甲酰胺衍生物（5a-10d），并评估了它们作为 CDK 抑制剂的生物活性。在所合成的化合物中，化合物 10b 对 CDK2 的抑制作用的 IC50 值为 25 nM，在微摩尔范围内（0.75-4.21 μM）对三种癌细胞系（H460、MCF-7、A549）的肿瘤细胞增殖具有拮抗作用。此外，流式细胞术表明，化合物 10b 可诱导 A549 细胞周期 G0/G1 期阻滞，呈剂量依赖性。综上所述，化合物 10b 可被选择进行进一步的临床前评估。
