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

doi:10.6023/cjoc202205048

Chinese Journal of Organic Chemistry ›› 2022, Vol. 42 ›› Issue (11): 3824-3834.DOI: 10.6023/cjoc202205048 Previous Articles Next Articles

ARTICLES

新型2,4,6-三取代嘧啶衍生物的合成及抗增殖活性评价

高潮^a^,^b, 张玉桐^a^,^b, 池玲玲^a^,^b, 王浩^a^,^b, 马家婕^a^,^b, 毕梦鑫^a^,^b, 戴洪林^a^,^b, 司晓杰^a^,^b, 刘丽敏^a^,^b, 张洋^a^,^b, 郑甲信^a^,^b, 可钰^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和药物质量与评价中心郑州450001
^c郑州大学省部共建食管癌防治国家重点实验室郑州 450052
^d教育部药物制备关键技术重点实验室郑州 450001

收稿日期:2022-05-28 修回日期:2022-06-27 发布日期:2022-07-13
通讯作者: 可钰, 刘宏民, 张秋荣
基金资助:
国家自然科学基金(U21A20416); 省部共建食管癌防治国家重点实验室开放基金(K2020000X)

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

Chao Gao^a^,^b, Yutong Zhang^a^,^b, Lingling Chi^a^,^b, Hao Wang^a^,^b, Jiajie Ma^a^,^b, Mengxin Bi^a^,^b, Honglin Dai^a^,^b, Xiaojie Si^a^,^b, Limin Liu^a^,^b, Yang Zhang^a^,^b, Jiaxin Zheng^a^,^b, Yu Ke^a^,^b^,^c^,^d(), Hongmin Liu^a^,^b^,^c^,^d(), Qiurong Zhang^a^,^b^,^c^,^d()

^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

Received:2022-05-28 Revised:2022-06-27 Published:2022-07-13
Contact: Yu Ke, Hongmin Liu, Qiurong Zhang
Supported by:
National Natural Science Foundation of China(U21A20416); Opening Fund from State Key Laboratory of Esophageal Cancer Prevention & Treatment(K2020000X)

1. .pdf(9075KB)

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.

Export EndNote|Reference Manager|ProCite|BibTeX|RefWorks

share this article

Fig. & Tab. 7

References 23

[1]	Siegel, R. L.; Miller, K. D.; Fuchs, H. E.; Jemal, A. Ca-Cancer J. Clin. 2022, 72, 7. doi: 10.3322/caac.21708
[2]	Hernandez-Lopez, A.; Tellez-Gonzalez, M. A.; Mondragon-Teran, P.; Meneses-Acosta, A. Front Pharmacol. 2021, 12, 720692. doi: 10.3389/fphar.2021.720692
[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. doi: 10.1002/adma.202007778
[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. doi: 10.1021/acs.jmedchem.6b01075
[6]	Tian, B.; Liu, Y.; Liu, J. Eur. Polym. J. 2021, 154, 110533. doi: 10.1016/j.eurpolymj.2021.110533
[7]	Patra, S.; Pradhan, B.; Nayak, R.; Behera, C.; Rout, L.; Jena, M.; Efferth, T.; Bhutia, S. K. Semin. Cancer Biol. 2021, 73, 310. doi: 10.1016/j.semcancer.2020.10.010
[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. doi: 10.1016/j.phrs.2017.01.003
[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. doi: 10.1021/jm500973a
[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) doi: 10.6023/cjoc201903022
	( 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.) doi: 10.6023/cjoc201903022
[11]	Meanwell, N. A. J. Med. Chem. 2018, 61, 5822. doi: 10.1021/acs.jmedchem.7b01788
[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. doi: 10.1182/blood-2018-08-869008
[14]	Chen, L.; Zhang, Y.; Liu, J.; Wang, W.; Li, X.; Zhao, L.; Wang, W.; Li, B. Eur. J. Med. Chem. 2017, 138, 689. doi: S0223-5234(17)30469-5 pmid: 28711703
[15]	Hou, W.; Ren, Y.; Zhang, Z.; Sun, H.; Ma, Y.; Yan, B. Bioorg. Med. Chem. 2018, 26, 1740. doi: 10.1016/j.bmc.2018.02.022
[16]	Patel, H.; Pawara, R.; Ansari, A.; Surana, S. Eur. J. Med. Chem. 2017, 142, 32. doi: 10.1016/j.ejmech.2017.05.027
[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. doi: 10.1021/acs.jmedchem.8b01594
[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. doi: 10.1021/acs.jmedchem.9b00280
[19]	Fu, S.; Chen, X.; Lo, H. W.; Lin, J. Cancer Lett. 2019, 448, 11. doi: 10.1016/j.canlet.2019.01.026
[20]	Abdel-Mohsen, H. T.; Conrad, J.; Harms, K.; Nohr, D.; Beifuss, U. RSC Adv. 2017, 7, 17427. doi: 10.1039/C6RA28102H
[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. doi: 10.1016/j.ejmech.2014.02.018
[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. doi: 10.1021/acs.jmedchem.5b00037 pmid: 25610955
[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. doi: 10.1016/j.bmc.2016.11.054

Compd.	R	IC₅₀^a/(μmol•L^－1)
Compd.	R	PC-3	MGC-803	MCF-7	HGC-27
19a	2,3-Cl₂C₆H₃S	11.20±1.05	4.24±0.63	15.28±1.18	13.70±1.14
19b	2,4-Cl₂C₆H₃S	15.17±1.18	4.60±0.66	14.49±1.16	13.49±1.13
19c	2,5-Cl₂C₆H₃S	11.94±1.08	4.41±0.67	12.85±1.11	10.75±1.03
19d	2,6-Cl₂C₆H₃S	12.57±0.96	10.05±1.02	13.93±1.14	12.45±1.09
19e	3,4-Cl₂C₆H₃S	11.65±1.07	7.53±0.88	16.18±1.21	11.16±1.05
19f	2,4-F₂C₆H₃S	24.18±1.38	4.29±1.03	26.54±1.42	22.83±1.36
19g	3,4-F₂C₆H₃S	22.54±1.35	4.47±1.09	24.16±1.38	22.24±1.35
19h	2-ClC₆H₄S	13.20±1.12	4.57±0.87	16.96±1.23	21.60±1.33
19i	3-ClC₆H₄S	13.22±1.04	3.95±1.22	20.10±1.30	18.20±1.26
19j	4-ClC₆H₄S	16.29±1.15	6.09±0.78	18.71±1.27	16.70±1.22
19k		19.23±1.28	2.51±0.57	22.42±1.35	22.75±1.35
19l		12.09±1.08	7.64±0.88	9.13±0.96	10.18±1.01
19m		5.97±0.85	15.72±1.16	19.27±1.28	16.08±1.21
19n		10.21±1.01	15.42±1.19	13.12±1.12	13.77±1.14
19o		11.26±1.06	25.71±1.41	20.96±1.32	17.23±1.24
19p		2.30±0.21	3.55±0.55	5.46±0.74	3.64±0.56
19q		0.87±0.15	0.97±0.18	1.38±0.14	1.17±0.07
19r		0.96±0.11	1.36±0.16	1.77±0.25	1.93±0.29
19s		1.86±0.27	2.19±0.34	3.57±0.55	1.51±0.18
19t		4.15±0.62	8.61±0.94	2.71±0.43	2.81±0.45
19u		8.30±0.92	9.66±0.98	17.22±1.24	8.01±0.90
5-Fu^b	—	6.39±0.71	10.64±1.09	10.23±0.68	7.25±0.72

Compd.	R	IC₅₀^a/(μmol•L^－1)
Compd.	R	PC-3	MGC-803	MCF-7	HGC-27
19a	2,3-Cl₂C₆H₃S	11.20±1.05	4.24±0.63	15.28±1.18	13.70±1.14
19b	2,4-Cl₂C₆H₃S	15.17±1.18	4.60±0.66	14.49±1.16	13.49±1.13
19c	2,5-Cl₂C₆H₃S	11.94±1.08	4.41±0.67	12.85±1.11	10.75±1.03
19d	2,6-Cl₂C₆H₃S	12.57±0.96	10.05±1.02	13.93±1.14	12.45±1.09
19e	3,4-Cl₂C₆H₃S	11.65±1.07	7.53±0.88	16.18±1.21	11.16±1.05
19f	2,4-F₂C₆H₃S	24.18±1.38	4.29±1.03	26.54±1.42	22.83±1.36
19g	3,4-F₂C₆H₃S	22.54±1.35	4.47±1.09	24.16±1.38	22.24±1.35
19h	2-ClC₆H₄S	13.20±1.12	4.57±0.87	16.96±1.23	21.60±1.33
19i	3-ClC₆H₄S	13.22±1.04	3.95±1.22	20.10±1.30	18.20±1.26
19j	4-ClC₆H₄S	16.29±1.15	6.09±0.78	18.71±1.27	16.70±1.22
19k		19.23±1.28	2.51±0.57	22.42±1.35	22.75±1.35
19l		12.09±1.08	7.64±0.88	9.13±0.96	10.18±1.01
19m		5.97±0.85	15.72±1.16	19.27±1.28	16.08±1.21
19n		10.21±1.01	15.42±1.19	13.12±1.12	13.77±1.14
19o		11.26±1.06	25.71±1.41	20.96±1.32	17.23±1.24
19p		2.30±0.21	3.55±0.55	5.46±0.74	3.64±0.56
19q		0.87±0.15	0.97±0.18	1.38±0.14	1.17±0.07
19r		0.96±0.11	1.36±0.16	1.77±0.25	1.93±0.29
19s		1.86±0.27	2.19±0.34	3.57±0.55	1.51±0.18
19t		4.15±0.62	8.61±0.94	2.71±0.43	2.81±0.45
19u		8.30±0.92	9.66±0.98	17.22±1.24	8.01±0.90
5-Fu^b	—	6.39±0.71	10.64±1.09	10.23±0.68	7.25±0.72

Compd.	IC₅₀/(μmol•L^－1)
Compd.	GES-1
19q	23.12±1.36
5-Fu	13.30±1.12

Compd.	IC₅₀/(μmol•L^－1)
Compd.	GES-1
19q	23.12±1.36
5-Fu	13.30±1.12

新型2,4,6-三取代嘧啶衍生物的合成及抗增殖活性评价

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

RichHTML

PDF

Supporting Info.

Knowledge

Abstract

Cite this article

share this article

Fig. & Tab. 7

References 23

Related Articles 15

Recommended Articles

Metrics

Comments

[1]	Fakai Zou, Nengzhong Wang, Hui Yao, Hui Wang, Mingguo Liu, Nianyu Huang. Regio- and Stereo-selective Synthesis of 1β-/3R-Aryl Thiosugar [J]. Chinese Journal of Organic Chemistry, 2024, 44(2): 593-604.
[2]	Luyao Li, Zhongwen He, Zhenguo Zhang, Zhenhua Jia, Teck-Peng Loh. Application of Triaryl Carbenium in Organic Synthesis [J]. Chinese Journal of Organic Chemistry, 2024, 44(2): 421-437.
[3]	Qinggang Mei, Qinghan Li. Recent Progress of Visible Light-Induced the Synthesis of C(3) (Hetero)arylthio Indole Compounds [J]. Chinese Journal of Organic Chemistry, 2024, 44(2): 398-408.
[4]	Penghui Li, Qingyang Xie, Fuxian Wan, Yuanhong Zhang, Lin Jiang. Synthesis and Fungicidal Activity of Novel Substituted Pyrimidine-5-carboxamides Bearing Cyclopropyl Moiety [J]. Chinese Journal of Organic Chemistry, 2024, 44(2): 650-656.
[5]	Weiqing Yang, Yanbing Ge, Yuanyuan Chen, Ping Liu, Haiyan Fu, Menglin Ma. Design and Synthesis of Fluorescent 1,8-Napthalimide Derivatives and Their Identification of Cysteine [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 180-194.
[6]	Shihang Yu, Jiawei Liu, Biyu An, Qinghua Bian, Min Wang, Jiangchun Zhong. Asymmetric Synthesis of the Contact Sex Pheromone of Neoclytus acuminatus acuminatus (Fabricius) [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 301-308.
[7]	Qianfan Zhao, Yongzheng Chen, Shiming Zhang. Application and Mechanism Study of Carbon-Based Metal-Free Catalysts in Organic Synthesis [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 137-147.
[8]	Shan Chen, Zhilin Chen, Qiong Hu, Yanshuang Meng, Yue Huang, Pingfang Tao, Liru Lu, Guobao Huang. Recognition of Bis-thiourea Tweezers to Neutral Molecules in Non-Polar Solvent [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 277-281.
[9]	Huakun Wang, Xiaolong Ren, Yining Xuan. Study of the Halide Salt Catalyzed [3＋2] Cycloaddition of α,β-Epoxy Carboxylate with Isocyanate [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 251-258.
[10]	Yukun Jin, Baoyi Ren, Fushun Liang. Visible Light-Mediated Selective C—F Bond Cleavage of Trifluoromethyl Groups and Its Application in Synthesizing gem-Difluoro-Containing Compounds [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 85-110.
[11]	Cuiyun Ma, Hailan Luo, Fuhua Zhang, Dan Guo, Shuxing Chen, Fei Wang. Green Biosynthesis, Photophysical Properties and Application of 3-Pyrrolyl BODIPY [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 216-223.
[12]	Bozhen Wang, Jie Zhang, Chunhui Nian, Mingming Jin, Miaomiao Kong, Wulan Li, Wenfei He, Jianzhang Wu. Synthesis and Antitumor Activity of 3,4-Dichlorophenyl Amides [J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 232-241.
[13]	Yang Li, Jinding Yuan, Di Zhao. Deep Eutectic Solvent of 1,3-Dimethylurea/L-(+)-Tartaric Acid for the Green Synthesis of (E)-2-Styrylquinoline-3-carboxylic Acid Derivatives [J]. Chinese Journal of Organic Chemistry, 2023, 43(9): 3268-3276.
[14]	Dandan Sui, Nannan Cen, Ruoqu Gong, Yang Chen, Wenbo Chen. Supporting-Electrolyte-Free Electrochemical Synthesis of Trifluoromethylated Oxindoles in Continuous Flow [J]. Chinese Journal of Organic Chemistry, 2023, 43(9): 3239-3245.
[15]	Ruixia Cao, Yuping Jia. Synthesis and Biological Activity of Novel Pyrrolo[2,3-d]pyrimidine Derivatives Containing Coumarin [J]. Chinese Journal of Organic Chemistry, 2023, 43(9): 3304-3311.