Wang Shu-Fu, Zhu Yin-Ling, Zhu Ping-Ting, Makawana Jigar A, Zhang Ya-Liang, Zhao Meng-Yue, Lv Peng-Cheng, Zhu Hai-Liang
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
Bioorg Med Chem. 2014 Nov 1;22(21):6201-8. doi: 10.1016/j.bmc.2014.08.029. Epub 2014 Sep 6.
A series of novel 5-phenyl-1H-pyrazole derivatives (5 a-5 u) containing niacinamide moiety were synthesized and evaluated for biological activity as potential BRAF(V600E) inhibitors. Among them, compound 5h exhibited the most potent inhibitory activity with an IC50 value of 0.33 μM for BRAF(V600E). Antiproliferative assay results indicated that compound 5h has better antiproliferative activity against WM266.4 and A375 in vitro with IC50 value of 2.63 and 3.16 μM, respectively, being comparable with the positive control vemurafenib. Molecular docking of 5h into the BRAF(V600E) active site was performed to determine the probable binding mode. Furthermore, molecular docking and 3D QSAR study by means of DS 3.5 (Discovery Studio 3.5, Accelrys, Co. Ltd) explored the binding modes and the structure and activity relationship (SAR) of these derivatives.
合成了一系列含有烟酰胺部分的新型5-苯基-1H-吡唑衍生物（5a - 5u），并对其作为潜在BRAF（V600E）抑制剂的生物活性进行了评估。其中，化合物5h表现出最有效的抑制活性，对BRAF（V600E）的IC50值为0.33μM。抗增殖试验结果表明，化合物5h在体外对WM266.4和A375具有较好的抗增殖活性，IC50值分别为2.63和3.16μM，与阳性对照维莫非尼相当。对5h进行了BRAF（V600E）活性位点的分子对接，以确定可能的结合模式。此外，借助DS 3.5（Discovery Studio 3.5，Accelrys有限公司）进行了分子对接和3D QSAR研究，探索了这些衍生物的结合模式以及结构与活性关系（SAR）。
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