Design, synthesis and biological evaluation of novel 3-substituted 4-anilino-coumarin derivatives as antitumor agents
Design, synthesis and biological evaluation of novel 3-substituted 4-anilino-coumarin derivatives as antitumor agents
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新型3-取代4-苯胺基香豆素衍生物抗肿瘤药物的设计、合成及生物学评价
DOI：
10.1016/j.bmcl.2017.01.013
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发表时间：
2017-02-15
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;Muyaba, Moses;Xiang, Hua
设计、合成了3-取代-4-苯胺基香豆素衍生物，并研究了它们的抗肿瘤活性。通过MIT试验对MCF-7、HepG 2、HCT 116和Panc-1癌细胞系进行体外细胞毒性筛选。大多数合成的化合物对这四种测试的癌细胞系表现出与阳性对照5-氟尿嘧啶相当的抗增殖活性。在香豆素骨架C-3位的不同取代基中，3-三氟乙酰基显示出最有希望的结果。特别是化合物33 d（IC 50 = 16.57、5.45、4.42和5.16 μ M）和33 e（IC 50 = 20.14、6.71、4.62和5.62 μ M）分别对MCF-7、HepG 2、Hcf 116和Panc-1细胞系显示出优异的抗增殖活性。细胞周期分析和凋亡激活实验表明，33 d可诱导MCF-7细胞发生G2/M期阻滞和凋亡，并呈剂量依赖性。观察到化合物33 d和33 e对人脐静脉内皮细胞（HUVEC）的低毒性，表明它们在正常细胞中可接受的安全性。此外，计算机模拟ADME研究的结果表明，33 d和33 e均表现出良好的药代动力学特性。(C)2017爱思唯尔有限公司版权所有
Various 3-substituted 4-anilino-coumarin derivatives have been designed, synthesized and their anti-proliferative properties have been studied. The in vitro cytotoxicity screening was performed against MCF-7, HepG2, HCT116 and Panc-1 cancer cell lines by MIT assay. Most of the synthesized compounds exhibited comparable anti-proliferative activity to the positive control 5-Fluorouracil against these four tested cancer cell lines. Among the different substituents at C-3 position of coumarin scaffold, 3-trifluoroacetyl group showed the most promising results. Especially, compounds 33d (IC50 = 16.57, 5.45, 4.42 and 5.16 mu M) and 33e (IC50 = 20.14, 6.71, 4.62 and 5.62 mu M) showed excellent anti-proliferative activities on MCF-7, HepG2, HCf116 and Panc-1 cell lines respectively. In addition, cell cycle analysis and apoptosis activation revealed that 33d induced G2/M phase arrest and apoptosis in MCF-7 cells in a dose-dependent manner. Low toxicity of compounds 33d and 33e was observed against human umbilical vein endothelial cells (HUVECs), suggesting their acceptable safety profiles in normal cells. Furthermore, the results of in silico ADME studies indicated that both 33d and 33e exhibited good pharmacokinetic properties. (C) 2017 Elsevier Ltd. All rights reserved.