State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
Bioorg Med Chem. 2012 Oct 15;20(20):6089-96. doi: 10.1016/j.bmc.2012.08.020. Epub 2012 Aug 25.
A series of novel 4,5-dihydropyrazole derivatives (3a-3t) containing hydroxyphenyl moiety as potential V600E mutant BRAF kinase (BRAF(V600E)) inhibitors were designed and synthesized. Docking simulation was performed to insert compounds 3d (1-(5-(5-chloro-2-hydroxyphenyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) and 3m (1-(3-(4-chlorophenyl)-5-(3,5-dibromo-2-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) into the crystal structure of BRAF(V600E) to determine the probable binding model, respectively. Based on the preliminary results, compound 3d and 3m with potent inhibitory activity in tumor growth may be a potential anticancer agent. Results of the bioassays against BRAF(V600E), MCF-7 human breast cancer cell line and WM266.4 human melanoma cell line all showed several compounds had potent activities IC(50) value in low micromolar range, among them, compound 3d and compound 3m showed strong potent anticancer activity, which were proved by that 3d: IC(50) = 1.31 μM for MCF-7 and IC(50) = 0.45 μM for WM266.5, IC(50) = 0.22 μM for BRAF(V600E), 3m: IC(50) = 0.97 μM for MCF-7 and IC(50) = 0.72 μM for WM266.5, IC(50) = 0.46 μM for BRAF(V600E), which were comparable with the positive control Erlotinib.
设计并合成了一系列新型 4,5-二氢吡唑衍生物（3a-3t），这些化合物含有羟苯基部分，可作为潜在的 V600E 突变 BRAF 激酶（BRAF(V600E))抑制剂。通过对接模拟，将化合物 3d（1-(5-(5-氯-2-羟基苯基)-3-(对甲苯基)-4,5-二氢-1H-吡唑-1-基)乙酮）和 3m（1-(3-(4-氯苯基)-5-(3,5-二溴-2-羟基苯基)-4,5-二氢-1H-吡唑-1-基)乙酮）插入 BRAF(V600E)的晶体结构中，分别确定了可能的结合模型。基于初步结果，具有较强肿瘤生长抑制活性的化合物 3d 和 3m 可能是一种潜在的抗癌药物。对 BRAF(V600E)、MCF-7 人乳腺癌细胞系和 WM266.4 人黑色素瘤细胞系的生物测定结果均表明，几种化合物具有较强的活性，IC50 值在低微摩尔范围内，其中化合物 3d 和化合物 3m 表现出较强的抗癌活性，这是由 3d 证明的：对 MCF-7 的 IC50 值为 1.31 μM，对 WM266.5 的 IC50 值为 0.45 μM，对 BRAF(V600E)的 IC50 值为 0.22 μM，3m 对 MCF-7 的 IC50 值为 0.97 μM，对 WM266.5 的 IC50 值为 0.72 μM，对 BRAF(V600E)的 IC50 值为 0.46 μM，与阳性对照药厄洛替尼相当。
