Synthesis and in vitro anti-bladder cancer activity evaluation of quinazolinyl-arylurea derivatives
Synthesis and in vitro anti-bladder cancer activity evaluation of quinazolinyl-arylurea derivatives
复制标题
喹唑啉基芳基脲衍生物的合成及体外抗膀胱癌活性评价
DOI：
10.1016/j.ejmech.2020.112661
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发表时间：
2020-11-01
影响因子：
6.7
通讯作者：
Zhang, Guang-Ji
中科院分区：
文献类型：
--
作者：
Chen, Jia-Nian;Li, Ting;Zhang, Guang-Ji
基于分子靶向剂索拉非尼的结构修饰，合成了一系列喹唑并芳基脲类化合物，并评价了它们对6种人癌细胞株的抗增殖活性。与所测试的其他细胞株相比，T24对大多数化合物更敏感。化合物7J具有较低的IC50值和良好的选择性。在本研究中，我们重点研究了7J诱导的T24细胞的死亡形式，并试图阐明其强大的增殖抑制活性的原因。复方7J处理可引起细胞凋亡、铁下垂和自噬三种不同的死亡形式，其发生方式取决于7J的浓度和孵育时间：(1)7J处理后8h内的低浓度可导致细胞的凋亡依赖性死亡。(2)通过有效调控SXC(-)/Gpx4/ROS和PI3K/Akt/mTOR/ULK1信号通路，在较高浓度和延长孵育时间的条件下，细胞发生铁性下垂和自噬。(3)上述死亡形式与7J诱导的细胞内ROS生成和线粒体膜电位降低密切相关。在分子对接和构效关系分析中，7J能很好地与相应受体谷胱甘肽过氧化物酶4(Gpx4)的活性部位结合。化合物7J有望成为分子靶向抗膀胱癌药物发现的先导化合物。(C)2020年爱思唯尔·马森公司。版权所有。
Based on the structural modification of molecular-targeted agent sorafenib, a series of quinazolinylarylurea derivatives were synthesized and evaluated for their anti-proliferative activities against six human cancer cell lines. Compared with other cell lines tested, T24 was more sensitive to most compounds. Compound 7j exhibited the best profile with lower IC50 value and favorable selectivity. In this study, we focused on 7j-induced death forms of T24 cells and tried to elucidate the reason for its potent proliferative inhibitory activity. Compound 7j treatment could trigger three different cell death forms including apoptosis, ferroptosis, and autophagy; which form would occur depended on the concentrations and incubation time of 7j: (1) Lower concentrations within the initial 8 h of 7j treatment led to apoptosis-dependent death. (2) Ferroptosis and autophagy occurred in the case of higher concentrations combining with extended incubation time through effectively regulating the Sxc(-)/GPx4/ROS and PI3K/ Akt/mTOR/ULK1 pathways, respectively. (3) The above death forms were closely associated with intracellular ROS generation and decreased mitochondrial membrane potential induced by 7j. In molecular docking and structure-activity relationship analyses, 7j could bind well to the active site of the corresponding receptor glutathione peroxidase 4 (GPx4). Compound 7j could be a promising lead for molecular-targeted anti-bladder cancer agents' discovery. (C) 2020 Elsevier Masson SAS. All rights reserved.