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Chinese Journal of Organic Chemistry >

2022 , Vol. 42 >Issue 11: 3824 - 3834

DOI: https://doi.org/10.6023/cjoc202205048

ARTICLES

Synthesis and Antiproliferative Activity Evaluation of Novel 2,4,6-Trisubstituted Pyrimidine Derivatives

  • Chao Gao ,
  • Yutong Zhang ,
  • Lingling Chi ,
  • Hao Wang ,
  • Jiajie Ma ,
  • Mengxin Bi ,
  • Honglin Dai ,
  • Xiaojie Si ,
  • Limin Liu ,
  • Yang Zhang ,
  • Jiaxin Zheng ,
  • Yu Ke ,
  • Hongmin Liu ,
  • Qiurong Zhang
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  • aSchool of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001
    bCollaborative Innovation Center of New Drug Research & Quality and Safety Evaluation, Zhengzhou 450001
    cState Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052
    dKey Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou 450001
*E-mail: ;
;

Received date: 2022-05-28

  Revised date: 2022-06-27

  Online published: 2022-07-14

Supported by

National Natural Science Foundation of China(U21A20416); Opening Fund from State Key Laboratory of Esophageal Cancer Prevention & Treatment(K2020000X)

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Abstract

In order to find new and efficient anti-tumor drugs, a series of 2,4,6-trisubstituted pyrimidine derivatives were designed and synthesized, and the antiproliferative activities were evaluated against four cancer cell lines of PC-3 (human prostate cancer cells), MGC-803 (human gastric cancer cells), MCF-7 (human breast cancer cells) and HGC-27 (human gastric carcinoma cell line) using methyl thiazolyl tetrazolium (MTT) assay. The results showed that most of the compounds exhibited moderate to potent antiproliferative activities against the four human tumor cell lines, among which N-(3-(2-((4-((1,3,4-thiadiazol-2-yl)thio)-6-(trifluoromethyl)pyrimidin-2-yl)thio)acetamido)phenyl)acrylamide (19q) had the best inhibitory activity against PC-3 cells with IC50 value of (0.87±0.15) μmol•L－1, the antitumor activity was significantly better than the positive control 5-fluorouracil. Further anti-tumor mechanism studies showed that compound 19q could induce apoptosis in PC-3 cells. In addition, compound 19q might play an anti-tumor effect by down-regulating the expression of anti-apoptotic protein Bcl-2 and up-regulating the expression of pro-apoptotic proteins Bax and p53.

Key words： pyrimidine derivatives; synthesis; antiproliferative activity

Cite this article

Chao Gao , Yutong Zhang , Lingling Chi , Hao Wang , Jiajie Ma , Mengxin Bi , Honglin Dai , Xiaojie Si , Limin Liu , Yang Zhang , Jiaxin Zheng , Yu Ke , Hongmin Liu , Qiurong Zhang . Synthesis and Antiproliferative Activity Evaluation of Novel 2,4,6-Trisubstituted Pyrimidine Derivatives[J]. Chinese Journal of Organic Chemistry, 2022 , 42(11) : 3824 -3834 . DOI: 10.6023/cjoc202205048

References

[1]
Siegel, R. L.; Miller, K. D.; Fuchs, H. E.; Jemal, A. Ca-Cancer J. Clin. 2022, 72, 7.
[2]
Hernandez-Lopez, A.; Tellez-Gonzalez, M. A.; Mondragon-Teran, P.; Meneses-Acosta, A. Front Pharmacol. 2021, 12, 720692.
[3]
Giri, V. N.; Morgan, T. M.; Morris, D. S.; Berchuck, J. E.; Hyatt, C.; Taplin, M. E. Ca-Cancer J. Clin. 2022, 73, 1.
[4]
Guo, X.; Yang, N.; Ji, W.; Zhang, H.; Dong, X.; Zhou, Z.; Li, L.; Shen, H. M.; Yao, S. Q.; Huang, W. Adv. Mater. 2021, 33, 2007778.
[5]
Gu, X.; Huang, Z.; Ren, Z.; Tang, X.; Xue, R.; Luo, X.; Peng, S.; Peng, H.; Lu, B.; Tian, J.; Zhang, Y. J. Med. Chem. 2017, 60, 928.
[6]
Tian, B.; Liu, Y.; Liu, J. Eur. Polym. J. 2021, 154, 110533.
[7]
Patra, S.; Pradhan, B.; Nayak, R.; Behera, C.; Rout, L.; Jena, M.; Efferth, T.; Bhutia, S. K. Semin. Cancer Biol. 2021, 73, 310.
[8]
Passaro, A.; Guerini-Rocco, E.; Pochesci, A.; Vacirca, D.; Spitaleri, G.; Catania, C. M.; Rappa, A.; Barberis, M.; de Marinis, F. Pharmacol. Res. 2017, 117, 406.
[9]
Finlay, M. R.; Anderton, M.; Ashton, S.; Ballard, P.; Bethel, P. A.; Box, M. R.; Bradbury, R. H.; Brown, S. J.; Butterworth, S.; Campbell, A.; Chorley, C.; Colclough, N.; Cross, D. A.; Currie, G. S.; Grist, M.; Hassall, L.; Hill, G. B.; James, D.; James, M.; Kemmitt, P.; Klinowska, T.; Lamont, G.; Lamont, S. G.; Martin, N.; McFarland, H. L.; Mellor, M. J.; Orme, J. P.; Perkins, D.; Perkins, P.; Richmond, G.; Smith, P.; Ward, R. A.; Waring, M. J.; Whittaker, D.; Wells, S.; Wrigley, G. L. J. Med. Chem. 2014, 57, 8249.
[10]
Meng, Y.; Li, E.; Zhang, Y.; Liu, S.; Bao, C.; Yang, P.; Zhang, L.; Zhang, D.; Wang, J.; Chen, Y.; Li, N.; Xin, J.; Zhao, P.; Ke, Y.; Zhang, Q.; Liu, H. Chin. J. Org. Chem. 2019, 39, 2541. (in Chinese)
[10]
( 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, 赵培荣, 可钰, 张秋荣, 刘宏民, 有机化学 2019, 39, 2541.)
[11]
Meanwell, N. A. J. Med. Chem. 2018, 61, 5822.
[12]
Clegg, N. J.; Wongvipat, J.; Joseph, J. D.; Tran, C.; Ouk, S.; Dilhas, A.; Chen, Y.; Grillot, K.; Bischoff, E. D.; Cai, L.; Aparicio, A.; Dorow, S.; Arora, V.; Shao, G.; Qian, J.; Zhao, H.; Yang, G.; Cao, C.; Sensintaffar, J.; Wasielewska, T.; Herbert, M. R.; Bonnefous, C.; Darimont, B.; Scher, H. I.; Smith-Jones, P.; Klang, M.; Smith, N. D.; De Stanchina, E.; Wu, N.; Ouerfelli, O.; Rix, P. J.; Heyman, R. A.; Jung, M. E.; Sawyers, C. L.; Hager, J. H. Cancer Res. 2012, 72, 1494.
[13]
Stein, E. M.; DiNardo, C. D.; Fathi, A. T.; Pollyea, D. A.; Stone, R. M.; Altman, J. K.; Roboz, G. J.; Patel, M. R.; Collins, R.; Flinn, I. W.; Sekeres, M. A.; Stein, A. S.; Kantarjian, H. M.; Levine, R. L.; Vyas, P.; MacBeth, K. J.; Tosolini, A.; VanOostendorp, J.; Xu, Q.; Gupta, I.; Lila, T.; Risueno, A.; Yen, K. E.; Wu, B.; Attar, E. C.; Tallman, M. S.; de Botton, S. Blood 2019, 133, 676.
[14]
Chen, L.; Zhang, Y.; Liu, J.; Wang, W.; Li, X.; Zhao, L.; Wang, W.; Li, B. Eur. J. Med. Chem. 2017, 138, 689.
[15]
Hou, W.; Ren, Y.; Zhang, Z.; Sun, H.; Ma, Y.; Yan, B. Bioorg. Med. Chem. 2018, 26, 1740.
[16]
Patel, H.; Pawara, R.; Ansari, A.; Surana, S. Eur. J. Med. Chem. 2017, 142, 32.
[17]
Liang, X.; Wang, B.; Chen, C.; Wang, A.; Hu, C.; Zou, F.; Yu, K.; Liu, Q.; Li, F.; Hu, Z.; Lu, T.; Wang, J.; Wang, L.; Weisberg, E. L.; Li, L.; Xia, R.; Wang, W.; Ren, T.; Ge, J.; Liu, J.; Liu, Q. J. Med. Chem. 2019, 62, 875.
[18]
Wu, Y.; Wang, B.; Wang, J.; Qi, S.; Zou, F.; Qi, Z.; Liu, F.; Liu, Q.; Chen, C.; Hu, C.; Hu, Z.; Wang, A.; Wang, L.; Wang, W.; Ren, T.; Cai, Y.; Bai, M.; Liu, Q.; Liu, J. J. Med. Chem. 2019, 62, 6083.
[19]
Fu, S.; Chen, X.; Lo, H. W.; Lin, J. Cancer Lett. 2019, 448, 11.
[20]
Abdel-Mohsen, H. T.; Conrad, J.; Harms, K.; Nohr, D.; Beifuss, U. RSC Adv. 2017, 7, 17427.
[21]
Tala, S. D.; Ou, T.-H.; Lin, Y.-W.; Tala, K. S.; Chao, S.-H.; Wu, M.-H.; Tsai, T.-H.; Kakadiya, R.; Suman, S.; Chen, C.-H.; Lee, T.-C.; Su, T.-L. Eur. J. Med. Chem. 2014, 76, 155.
[22]
Ma, L. Y.; Zheng, Y. C.; Wang, S. Q.; Wang, B.; Wang, Z. R.; Pang, L. P.; Zhang, M.; Wang, J. W.; Ding, L.; Li, J.; Wang, C.; Hu, B.; Liu, Y.; Zhang, X. D.; Wang, J. J.; Wang, Z. J.; Zhao, W.; Liu, H. M. J. Med. Chem. 2015, 58, 1705.
[23]
Ge, Y.; Yang, H.; Wang, C.; Meng, Q.; Li, L.; Sun, H.; Zhen, Y.; Liu, K.; Li, Y.; Ma, X. Bioorg. Med. Chem. 2017, 25, 765.
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