State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China.
Bioorg Med Chem. 2012 Jul 15;20(14):4430-6. doi: 10.1016/j.bmc.2012.05.031. Epub 2012 May 26.
In present study, a series of 3-(1,3-diphenyl-1H-pyrazol-4-yl)-N-phenylacrylamide derivatives (5a-8d) were designed, synthesized, and evaluated for HDAC inhibition and tumor cell antiproliferation. All of these compounds are reported for the first time, the chemical structures of these compounds were confirmed by means of (1)H NMR, ESI-MS and elemental analyzes. Among the compounds, compound 8c showed the most potent biological activity against HCT116 cancer cell line (IC(50) of 0.42 ± 0.02 μM for HDAC-1 and IC(50)=0.62 ± 0.02 for HCT116). Docking simulation was performed to position compound 8c into the HDAC active site to determine the probable binding model. The results of antiproliferative assay and western-blot demonstrated that compound 8c with potent inhibitory activity in tumor growth inhibition may be a potential anticancer agent against HCT116 cancer cell.
在本研究中，设计、合成了一系列 3-(1,3-二苯基-1H-吡唑-4-基)-N-苯基丙烯酰胺衍生物（5a-8d），并对其组蛋白去乙酰化酶（HDAC）抑制活性和肿瘤细胞增殖抑制活性进行了评价。这些化合物均为首次报道，其结构通过 1H NMR、ESI-MS 和元素分析得到了确证。在所合成的化合物中，化合物 8c 对 HCT116 肿瘤细胞系表现出最强的生物活性（对 HDAC-1 的半数抑制浓度（IC50）为 0.42±0.02 μM，对 HCT116 的 IC50 为 0.62±0.02 μM）。通过对接模拟将化合物 8c 定位到 HDAC 的活性部位，以确定可能的结合模型。增殖抑制实验和 Western blot 结果表明，化合物 8c 具有较强的抑制肿瘤生长的活性，可能是一种有潜力的针对 HCT116 肿瘤细胞的抗癌药物。
