Synthesis and biological evaluation of 3-aryl-quinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives as hypoxic selective anti-tumor agents.
Synthesis and biological evaluation of 3-aryl-quinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives as hypoxic selective anti-tumor agents.
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低氧选择性抗肿瘤药物3-芳基喹喔啉-2-甲腈1,4-二氮氧化物衍生物的合成及生物学评价
DOI：
10.3390/molecules17089683
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发表时间：
2012-08-13
期刊：
影响因子：
--
通讯作者：
Sheng R
中科院分区：
文献类型：
--
作者：
Hu Y;Xia Q;Shangguan S;Liu X;Hu Y;Sheng R
设计、合成了一系列3-芳基-2-喹喔啉腈1，4-二氮氧化物衍生物，并对人SMMC-7721、K562、KB、A549和PC-3细胞进行了缺氧和常氧细胞毒活性测定。在基于肿瘤细胞的评价中，与TX-402和TPZ相比，这些新化合物中的许多显示出更强的低氧细胞毒活性，这证实了我们的假设，即用TX-402的取代的芳基环取代3-胺增加了低氧抗肿瘤活性。初步的SAR表明，3-氯是一个有利的取代基的苯环缺氧细胞毒性和7-甲基或7-甲氧基取代的衍生物表现出更好的缺氧选择性对大多数测试的细胞系。选择最有效的化合物7-甲基-3-（3-氯苯基）-喹喔啉-2-甲腈1，4-二氧化物（9 h）用于进一步的抗肿瘤评价和机制研究。对BEL-7402、HepG 2、HL-60、NCI-H460、HCT-116和CHP 126等细胞株在缺氧条件下也表现出明显的细胞毒活性，IC 50值为0.31 ~ 3.16 μM，初步机制研究表明，9 h诱导细胞凋亡是通过半胱天冬酶依赖的途径。
A series of 3-aryl-2-quinoxaline-carbonitrile 1,4-di-N-oxide derivatives were designed, synthesized and evaluated for hypoxic and normoxic cytotoxic activity against human SMMC-7721, K562, KB, A549 and PC-3 cell lines. Many of these new compounds displayed more potent hypoxic cytotoxic activity compared with TX-402 and TPZ in the tumor cells based evaluation, which confirmed our hypothesis that the replacement of the 3-amine with the substituted aryl ring of TX-402 increases the hypoxic anti-tumor activity. The preliminary SAR revealed that 3-chloro was a favorable substituent in the phenyl ring for hypoxic cytotoxicity and 7-methyl or 7-methoxy substituted derivatives exhibited better hypoxic selectivity against most of the tested cell lines. The most potent compound, 7-methyl-3-(3-chlorophenyl)-quinoxaline-2-carbonitrile 1,4-dioxide (9h) was selected for further anti-tumor evaluation and mechanistic study. It also exhibited significant cytotoxic activity against BEL-7402, HepG2, HL-60, NCI-H460, HCT-116 and CHP126 cell lines in hypoxia with IC50 values ranging from 0.31 to 3.16 μM, and preliminary mechanism study revealed that 9h induced apoptosis in a caspase-dependent pathway.
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影响因子：
7.3
作者：
Herschhorn, Alon;Lerman, Lena;Hizi, Amnon
通讯作者：
Hizi, Amnon
DOI：
10.1002/cber.19490820318
发表时间：
1949-01-01
期刊：
CHEMISCHE BERICHTE-RECUEIL
影响因子：
--
作者：
DORNOW, A;KUHLCKE, I;BAXMANN, F
通讯作者：
BAXMANN, F
影响因子：
3.4
作者：
Weng, Qinjie;Zhang, Jun;Yang, Bo
通讯作者：
Yang, Bo
影响因子：
5.1
作者：
Jiang, Faqin;Weng, Qinjie;Hu, Yongzhou
通讯作者：
Hu, Yongzhou
影响因子：
6.7
作者：
Vicente, Esther;Lima, Lidia M.;Monge, Antonio
通讯作者：
Monge, Antonio