Design, synthesis, and structure-activity relationships of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety as potent antitumor agents
Design, synthesis, and structure-activity relationships of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety as potent antitumor agents
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DOI：
10.1016/j.ejmech.2014.08.058
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发表时间：
2014-10-30
影响因子：
6.7
通讯作者：
Gong, Ping
中科院分区：
文献类型：
--
作者：
Ma, Junjie;Chen, Dong;Gong, Ping
设计并合成了一系列含邻羟基氨基甲酰腙结构的苯并噻唑衍生物，并对5种肿瘤细胞（NCI-H226，SK-N-SH，HT 29，MKN 45，MDA-MB-231）进行了体外细胞毒活性筛选。它们中的大多数对所有测试的细胞系显示出中等至优异的活性。其中，化合物15 g（半胱天冬酶原-3 EC 50 = 1.42 μ M）和16 b（半胱氨酸天冬氨酸蛋白酶原-3 EC 50 = 0.25 μ M）显示出优异的抗肿瘤活性，对所有癌细胞系的IC 50值范围为0.14 μ M至0.98 μ M，其活性是第一种半胱天冬酶原活化化合物（PAC-1）的1.8-8.7倍（半胱天冬酶原-3 EC 50 = 4.08 μ M）。构效关系（SAR）分析表明，在2-羟基苯环的4-位引入亲脂性基团（苄氧基或杂芳氧基）有利于提高抗肿瘤活性，在生理pH下带正电荷的含氮取代基的存在也能提高抗肿瘤活性。还证实了苄氧基的4-位取代基的空间效应对细胞毒活性具有显著影响。(C)2014年Elsevier Masson SAS。All rights reserved.
A series of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety were designed and synthesized and their cytotoxic activities against five cancer cell lines (NCI-H226, SK-N-SH, HT29, MKN45, and MDA-MB-231) were screened in vitro. Most of them showed moderate to excellent activity against all the tested cell lines. Among them, compounds 15g (procaspase-3 EC50 = 1.42 mu M) and 16b (procaspase-3 EC50 = 0.25 mu M) exhibited excellent antitumor activity with IC50 values ranging from 0.14 mu M to 0.98 mu M against all cancer cell lines, which were 1.8-8.7 times more active than the first procaspase activating compound (PAC-1) (procaspase-3 EC50 = 4.08 mu M). The structure activity relationship (SAR) analyses indicated that the introduction of a lipophilic group (a benzyloxy or heteroaryloxy group) at the 4-position of the 2-hydroxy phenyl ring was beneficial to antitumor activity, and the presence of substituents containing nitrogen that are positively charged at physiological pH could also improve antitumor activity. It was also confirmed that the steric effect of the 4-position substituent of the benzyloxy group had a significant influence on cytotoxic activity. (C) 2014 Elsevier Masson SAS. All rights reserved.