Synthesis, structure-activity relationships and preliminary mechanism of action of novel water-soluble 4-quinolone-3-carboxamides as antiproliferative agents
Synthesis, structure-activity relationships and preliminary mechanism of action of novel water-soluble 4-quinolone-3-carboxamides as antiproliferative agents
复制标题
新型水溶性4-喹诺酮-3-甲酰胺抗增殖剂的合成、构效关系及初步作用机制
DOI：
10.1016/j.ejmech.2017.09.017
复制
发表时间：
2017-11-10
影响因子：
6.7
通讯作者：
Du, Runlei
中科院分区：
文献类型：
--
作者：
Zhang, Zeyan;Xiao, Xingpeng;Du, Runlei
合成了一系列新型水溶性4-喹诺酮-3-甲酰胺类化合物，并对其抗增殖活性进行了评价。初步结果表明，本研究中测试的大多数化合物显示出对人肿瘤细胞系的有效抗增殖效力，并且发现化合物8 k是最有效的抗增殖剂，其对9种人肿瘤细胞系的IC 50值低于10 μ M。这些结果表明：（1）烷基氨基侧链取代基是该类化合物抗增殖活性增强的最佳药效基团;（2）烷基氨基侧链的长度也影响其抗增殖活性，三个亚甲基取代基的抗增殖活性更好;（3）在喹诺酮的N1位引入芳基烷基取代基有利于该类化合物的抗增殖活性。对这类化合物的作用机制的进一步研究表明，代表性化合物8 k可以通过诱导ROS积累来触发p53/p53非依赖性结肠直肠癌细胞凋亡。(C)2017 Elsevier Masson SAS。All rights reserved.
A series of novel water-soluble 4-quinolone-3-carboxamides was prepared and evaluated as anti proliferative agents. Preliminary results indicated that most compounds tested in this study showed potent antiproliferative potencies against human tumor cell lines, and compound 8k was found to be the most potent antiproliferative agents with IC50 value of lower than 10 mu M against nine human tumor cell lines. These results suggested that (1) the alkylamino side chain substituent was the advisable pharmacophoric group for the enhanced antiproliferative activities; (2) the length of the alkylamino side chain moiety also affected their antiproliferative potencies, and three methylene units were more favorable; (3) introducing arylated alkyl substituent into N1-position of quinolone facilitated anti proliferative activities of this class of compounds. Further investigations on mechanism of action of this class of compound demonstrated that the representative compound 8k could trigger p53/Bax-independent colorectal cancer cell apoptosis via inducing ROS accumulation. (C) 2017 Elsevier Masson SAS. All rights reserved.