Synthesis and Antitumor Evaluation of 2,4,6-Trisubstituted Pyrimidine Derivatives Containing Benzothiazole Moiety

doi:10.6023/cjoc201907016

Chinese Journal of Organic Chemistry ›› 2020, Vol. 40 ›› Issue (2): 417-422.DOI: 10.6023/cjoc201907016 Previous Articles Next Articles

含苯并噻唑砌块的2,4,6-三取代嘧啶衍生物的合成及抗肿瘤活性评价

李二冬^a,d, 孟娅琪^a,d, 张路野^a,b, 张洋^a,b, 周蕊^a, 刘丽敏^a, 栗娜^b,c, 辛景超^b,c, 郑甲信^a,d, 单丽红^a,b,c,d, 刘宏民^a,b,c,d, 张秋荣^a,b,c,d

a 郑州大学药学院郑州 450001;
b 新药创制与药物安全性评价河南省协同创新中心郑州 450001;
c 河南省药物质量评价重点实验室郑州 450001;
d 教育部药物制备关键技术重点实验室郑州 450001

收稿日期:2019-07-08 修回日期:2019-10-14 发布日期:2019-10-25
通讯作者: 张秋荣, 刘宏民, 单丽红 E-mail:zqr409@yeah.net;liuhm@zzu.edu.cn;343785851@qq.com
基金资助:
国家自然科学基金（No.U1904163）和蛋白关键研究（No.2018YFE0195100）资助项目.

Synthesis and Antitumor Evaluation of 2,4,6-Trisubstituted Pyrimidine Derivatives Containing Benzothiazole Moiety

Li Erdong^a,d, Meng Yaqi^a,d, Zhang Luye^a,b, Zhang Yang^a,b, Zhou Rui^a, Liu Limin^a, Li Nab^b,c, Xin Jingchao^b,c, Zheng Jiaxin^a,d, Shan Lihong^a,b,c,d, Liu Hongmin^a,b,c,d, Zhang Qiurong^a,b,c,d

a School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001;
b Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou 450001;
c Key Laboratory of Henan Province for Drug Quality and Evaluation, Zhengzhou 450001;
d Key Laboratory of Technology of Drug Preparation, Ministry of Education, Zhengzhou 450001

Received:2019-07-08 Revised:2019-10-14 Published:2019-10-25
Supported by:
Project supported by the National Natural Science Foundation of China (No. U1904163) and the National Key Research Program of Proteins (No. 2018YFE0195100).

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Abstract

In order to find high-efficiency antitumor drugs, a series of 2,4,6-trisubstituted pyrimidine derivatives containing benzothiazole moiety were designed, synthesized and evaluated for antitumor activities against four cancer cells (EC-109, human esophageal cancer cells; MGC-803, human gastric cancer cells; PC-3, human prostate cancer cells; HepG-2, human liver cancer cells), GES-1 (human normal gastric mucosal epithelial cells), and HEEC (human normal esophagus) using thiazolyl blue (MTT) method. The results showed that some compounds exhibited moderate to strong antitumor activities against MGC-803 and PC-3 cells. Among them, 2-(((4-(4-(pyridin-2-yl)piperazin-1-yl)-6-(trifluoromethyl)pyrimidin-2-yl)-thio)methyl)benzo[d]thiazole (13h) and 2-(((4-(4-(pyrimidin-2-yl)piperazin-1-yl)-6-(trifluoromethyl)pyrimidin-2-yl)thio)-methyl)benzo[d]thiazole (13i) showed the most potent antitumor activities against PC-3 cells with IC₅₀ values of 3.82 and 2.29 μmol/L, respectively. The toxicities of compounds 13h and 13i to GES-1 cells were significantly lower than the positive control 5-fluorouracil.

Key words: pyrimidine, benzothiazole, synthesis, antitumor activity

Cite this article

Li Erdong, Meng Yaqi, Zhang Luye, Zhang Yang, Zhou Rui, Liu Limin, Li Nab, Xin Jingchao, Zheng Jiaxin, Shan Lihong, Liu Hongmin, Zhang Qiurong. Synthesis and Antitumor Evaluation of 2,4,6-Trisubstituted Pyrimidine Derivatives Containing Benzothiazole Moiety[J]. Chinese Journal of Organic Chemistry, 2020, 40(2): 417-422.

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[1] Samadder, N. J.; Giridhar, K. V.; Baffy, N.; Riegert, J. D.; Couch, F. J. Mayo Clin. Proc. 2019, 94, 1084.
[2] Siegel, R. L.; Miller, K. D.; Jemal, A. CA-Cancer J. Clin. 2015, 65, 5.
[3] Ferlay, J.; Colombet, M.; Soerjomataram, I.; Mathers, C.; Parkin, D. M.; Piñeros, M.; Znaor, A.; Bray, F. Int. J. Cancer. 2019, 144, 1941.
[4] Banerjee, S.; Arnst, K. E.; Wang, Y.; Kumar, G.; Deng, S.; Yang, L.; Miller, D. D. J. Med. Chem. 2018, 61, 1704.
[5] Abdel, M.; Heba, T.; Ragab, F. A.; Ramla, M. M. Eur. J. Med. Chem. 2010, 45, 2336.
[6] Bekhit, A. A.; Fahmy, H. T.; Rostom, S. A.; Baraka, A. M. Eur. J. Med. Chem. 2003, 38, 27.
[7] Rostamizadeh, S.; Nojavan, M.; Aryan, R.; Sadeghian, H.; Davoodnejad, M. Chin. Chem. Lett. 2013, 24, 629.
[8] Tozkoparan, B.; Ertan, M.; Kelicen, P. Farmaco 1999, 54, 588.
[9] Deyanov, A. B.; Niyazov, R. K.; Syropyatov, B. Y.; Kolla, V. E.; Konshin, M. E. J. Pharm. Chem. 1991, 25, 248.
[10] Nalini, C. N.; Amuthalakshmi, S.; Shanthanakrishnan, V. S. Curr. Microwave Chem. 2018, 5, 189.
[11] Noolvi, M. N.; Harun, M. P.; Manpreet, K. Eur. J. Med. Chem. 2012, 54, 447.
[12] Cai, J.; Sun, M.; Wu, X.; Chen, J.; Wang, P.; Zong, X.; Ji, M. Eur. J. Med. Chem. 2013, 63, 702.
[13] Christopher, J.; Bungard, P. D.; Williams, J. S. Med. Chem. Lett. 2017, 8, 1292.
[14] Zhang, Q. W.; Zhang, B. Y.; Zhou, A. N.; Zhang, Y.; Li, J. Q. Chin. J. Med. Chem. 2015, 4, 255.
[15] Meng, Y. Q.; Li, E. D.; Zhang, Y.; Liu, S.; Bao, C. N.; Yang, P.; Zhang, L. Y.; Zhang, D. Q.; Wang, J. K.; Chen, Y. X.; Li, N.; Xin, J. C.; Zhao, P. R.; Ke, Y.; Zhang, Q. R.; Liu, H. M. Chin. J. Org. Chem. 2019, 39, 2541(in Chinese). (孟娅琪, 李二冬, 张洋, 刘栓, 包崇男, 杨鹏, 张路野, 张丹青, 王继宽, 陈雅欣, 栗娜, 辛景超, 赵培, 可钰, 张秋荣, 刘宏民, 有机化学, 2019, 39, 2541.)
[16] Li, N.; Xin, J. C.; Ma, Q. S.; Li, E. D.; Meng, Y. Q.; Bao, C. N.; Yang, P.; Song, P. P.; Cui, F.; Cheng, P. J.; Gu, Y. F.; Zhao, P. R.; Ke, Y.; Liu, H. M.; Zhang, Q. R. Chin. J. Org. Chem. 2018, 38, 665(in Chinese). (栗娜, 辛景超, 马启胜, 李二冬, 孟娅琪, 包崇男, 杨鹏, 宋攀攀, 崔飞, 陈鹏举, 顾一飞, 赵培,可钰, 刘宏民, 张秋荣, 有机化学, 2018, 38, 665.)
[17] Xin, J. C.; Li, N.; Ma, Q. S.; Li, E. D.; Meng, X. C.; Ke, Y.; Liu, H. M.; Zhang, Q. R. Chin. J. Org. Chem. 2018, 38, 451(in Chinese). (辛景超, 栗娜, 马启胜, 李二冬, 孟祥川, 可钰, 刘宏民, 张秋荣, 有机化学, 2018, 38, 451.)
[18] Song, P. P.; Li, N.; Cui, F.; Xin, J. C.; Zhang, X. S; Cao, Q. P; Wang, C. J.; Dai, W. J.; Meng, X. C.; Liu, M.; Chang, T. H.; Liu. Q. Y.; Sun, Y. H.; Ke, Y.; Zhang, Q. R.; Liu, H. M. Chin. J. Org. Chem. 2017, 37, 2725(in Chinese). (宋攀攀, 栗娜, 崔飞, 辛景超, 张孝松, 曹钦坡, 王超杰, 戴文杰, 孟祥川, 刘梦, 常通航, 柳晴怡, 孙月红, 可钰, 张秋荣, 刘宏民, 有机化学, 2017, 37, 2725.)
[19] Miller, W. H.; Dessert, A. M.; Anderson, G. W. J. Am. Chem. Soc. 1948, 70, 500.
[20] Puranik, N. V.; Hemalata, M. P.; Srivastava, P. Med. Chem. Res. 2016, 4, 805.

含苯并噻唑砌块的2,4,6-三取代嘧啶衍生物的合成及抗肿瘤活性评价

Synthesis and Antitumor Evaluation of 2,4,6-Trisubstituted Pyrimidine Derivatives Containing Benzothiazole Moiety

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