Design, synthesis, biological evaluation and molecular docking studies of novel 3-aryl-4-anilino-2H-chromen-2-one derivatives targeting ERα as anti-breast cancer agents
Design, synthesis, biological evaluation and molecular docking studies of novel 3-aryl-4-anilino-2H-chromen-2-one derivatives targeting ERα as anti-breast cancer agents
复制标题
靶向ER α的新型3-芳基-4-苯胺基-2H-苯胺-2-酮衍生物的设计、合成、生物学评价和分子对接研究作为抗乳腺癌药物
DOI：
10.1016/j.bmcl.2017.04.029
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发表时间：
2017-06-15
影响因子：
2.7
通讯作者：
Xiang, Hua
中科院分区：
文献类型：
--
作者：
Luo, Guoshun;Chen, Mingqi;Xiang, Hua
雌激素受体（ER）在乳腺癌的发生和发展中起着重要作用，是抗癌药物发现的中心靶点。为了开发新型选择性ER α调节剂（SERM），我们在前人报道的先导化合物的基础上，设计合成了18个新型3-芳基-4-苯胺基-2H-色烯-2-酮衍生物。生物学结果表明，大多数化合物表现出有效的ER α结合亲和力，并且对MCF-7和石川细胞系具有比阳性对照他莫昔芬更好的抗增殖活性。哌啶基取代的化合物如16 d和18 d分别表现出强的ER α结合亲和力和优异的抗增殖活性。化合物18 d显示出最强的ER α结合亲和力，RBA值为2.83%，而16 d显示出对MCF-7细胞最好的抗增殖活性，IC 50值为4.52 +/- 2.47 μ M。还进行了进一步的分子对接研究以研究新合成的化合物与ER α的结合模式。所有这些结果以及构效关系（SAR）表明，这些具有碱性侧链的3-芳基-4-苯胺基-2H-色烯-2-酮衍生物可以作为进一步优化的新型SERM的有希望的线索。(C)2017爱思唯尔有限公司版权所有
The estrogen receptor (ER) has played an important role in breast cancer development and progression and is a central target for anticancer drug discovery. In order to develop novel selective ER alpha modulators (SERMs), we designed and synthesized 18 novel 3-aryl-4-anilino-2H-chromen-2-one derivatives based on previously reported lead compounds. The biological results indicated that most of the compounds presented potent ER alpha binding affinity and possessed better anti-proliferative activities against MCF-7 and Ishikawa cell lines than the positive control tamoxifen. The piperidyl substituted compounds such as 16d and 18d demonstrated strong ER alpha binding affinities and excellent anti-proliferative activities respectively. Compound 18d displayed the most potent ER alpha binding affinity with RBA value of 2.83%, while 16d exhibited the best anti-proliferative activity against MCF-7 cells with IC50 value of 4.52 +/- 2.47 mu M. Further molecular docking studies were also carried out to investigate binding pattern of the newly synthesized compounds with ER alpha. All these results together with the structure-activity relationships (SARs) indicated that these 3-aryl-4-anilino-2H-chromen-2-one derivatives with basic side chain could serve as promising leads for further optimization as novel SERMs. (C) 2017 Elsevier Ltd. All rights reserved.