Synthesis and Antiproliferative Activity of 2,4,5,6-Tetrasubstituted Pyrimidine Derivatives Containing Anisole

doi:10.6023/cjoc202201048

Chinese Journal of Organic Chemistry ›› 2022, Vol. 42 ›› Issue (6): 1677-1686.DOI: 10.6023/cjoc202201048 Previous Articles Next Articles

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含苯甲醚结构的2,4,5,6-四取代嘧啶衍生物的合成及抗增殖活性研究

高潮^a^,^b, 司晓杰^a^,^b, 池玲玲^a^,^b, 王浩^a^,^b, 戴洪林^a^,^b, 刘丽敏^a^,^b, 汪正捷^a^,^b, 张洋^a^,^b, 王涛^a^,^b, 周耀传^a, 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:2022-01-28 修回日期:2022-03-08 发布日期:2022-03-21
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资助的开放基金(K2020000X)

Synthesis and Antiproliferative Activity of 2,4,5,6-Tetrasubstituted Pyrimidine Derivatives Containing Anisole

Chao Gao^a^,^b, Xiaojie Si^a^,^b, Lingling Chi^a^,^b, Hao Wang^a^,^b, Honglin Dai^a^,^b, Limin Liu^a^,^b, Zhengjie Wang^a^,^b, Yang Zhang^a^,^b, Tao Wang^a^,^b, Yaochuan Zhou^a, Jiaxin Zheng^a^,^b, Yu Ke^a^,^b^,^c^,^d(), Hongmin Liu^a^,^b^,^c^,^d(), Qiurong Zhang^a^,^b^,^c^,^d()

a School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001
b Collaborative Innovation Center of New Drug Research & Quality and Safety Evaluation, Zhengzhou 450001
c State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052
d Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou 450001

Received:2022-01-28 Revised:2022-03-08 Published:2022-03-21
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)

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Abstract

In order to find efficient new anti-tumor drugs, a series of 2,4,5,6-tetrasubstituted pyrimidine derivatives containing anisole structure were designed, synthesized and evaluated for antiproliferative activity against four human cancer cell lines of PC-3, MGC-803, MCF-7 and HGC-27 using methyl thiazolyl tetrazolium (MTT) assay. Most of compounds displayed moderate to excellent antiproliferative activity against the four human tumor cell lines, among which the compound 5-ethyl-6- ((4-methoxyphenyl)thio)-N⁴-(3,4,5-trimethoxyphenyl)pyrimidine-2,4-diamine (14t) showed the best antiproliferative activity on HGC-27 cells, with IC₅₀value of (0.98±0.12) μmol•L^–1, the antiproliferative activity is significantly better than that of the positive control 5-fluorouracil. Further research on anti-tumor mechanism showed that compound 14t could significantly inhibit the colony formation and migration of HGC-27 cells and induce apoptosis. At the same time, compound 14t can down-regulate the expression of anti-apoptotic protein Bcl-2 and up-regulate the expression of pro-apoptotic proteins Bax and P53.

Key words: pyrimidine, anisole, synthesis, antiproliferative activity

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Chao Gao, Xiaojie Si, Lingling Chi, Hao Wang, Honglin Dai, Limin Liu, Zhengjie Wang, Yang Zhang, Tao Wang, Yaochuan Zhou, Jiaxin Zheng, Yu Ke, Hongmin Liu, Qiurong Zhang. Synthesis and Antiproliferative Activity of 2,4,5,6-Tetrasubstituted Pyrimidine Derivatives Containing Anisole[J]. Chinese Journal of Organic Chemistry, 2022, 42(6): 1677-1686.

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Fig. & Tab. 10

Figure 1. Structures of some pyrimidine derivatives and derivatives containing anisole

Figure 2. Design strategy for 2,4,5,6-tetrasubstituted pyrimidine derivatives containing anisole

Scheme 1. Synthetic route of compounds 14a~14t

Compd.	R	IC₅₀^a/(μmol·L^–1)
Compd.	R	PC-3	MGC-803	MCF-7	HGC-27
14a	—	>50	>50	>50	>50
14b	2-F	15.70±1.19	25.36±0.76	27.67±1.44	30.96±1.49
14c	3-F	19.03±0.99	39.79±1.60	45.20±1.66	37.87±1.44
14d	4-F	20.67±1.03	44.66±1.65	>50	35.73±1.55
14e	2-Cl	11.13±1.05	20.68±1.32	23.65±1.64	14.32±1.16
14f	3-Cl	>50	24.89±1.40	41.63±1.62	>50
14g	4-Cl	26.58±1.42	>50	27.72±1.44	49.93±1.60
14h	2-Br	10.08±1.00	14.59±1.16	33.74±1.53	12.22±1.09
14i	3-Br	>50	>50	>50	>50
14j	4-Br	12.39±0.97	17.99±1.25	35.95±1.14	28.75±1.46
14k	2-CH₃	>50	40.01±1.60	>50	>50
14l	3-CH₃	>50	>50	>50	>50
14m	4-CH₃	>50	>50	>50	>50
14n	2-OCH₃	5.22±0.72	10.06±1.00	7.79±0.89	5.15±0.71
14o	3-OCH₃	8.41±0.92	32.69±1.51	17.53±1.24	27.55±1.44
14p	4-OCH₃	10.70±1.03	18.18±1.26	15.36±1.19	11.75±1.07
14q	3,4-Cl₂	10.91±1.04	13.77±1.14	6.64±0.88	11.52±1.06
14r	2,4-Cl₂	>50	>50	42.73±1.63	>50
14s	3-Cl-4-F	27.97±0.90	42.36±1.63	29.99±1.48	>50
14t	3,4,5-(OCH₃)₃	5.59±0.75	2.41±0.38	5.94±0.77	0.98±0.12
5-Fu^b	—	6.39±0.71	10.64±1.09	10.23±0.68	7.25±0.72

Table 1. In vitro antiproliferative activity evaluation results of compounds 14a~14t

Compd.	IC₅₀/(μmol·L^–1)
Compd.	GES-1	HEEC
14t	43.98±1.64	>100
5-Fu	13.30±1.12	>100

Table 2. In vitro antiproliferative activity of compound 14t against human normal cells

Figure 3. Effect of compound 14t on colony formation of HGC-27 cells (A) HGC-27 Cell colonies treated with compound 14t at different concentrations; (B) Quantitative analysis of colony formation inhibition rate

Figure 4. In vitro wound healing assay on HGC-27 cells (A) Phase contrast images were obtained by the treatment of compound 14t at indicated concentrations for 0, 12 and 24 h; (B) Quantitative analysis of cell migration rate. Compared with the control group, *P<0.05, **P<0.01, ***P<0.001

Figure 5. Effect of compound 14t on nuclear morphology of HGC-27 cells The arrows in the figure indicate the cells whose nuclei have shrunk or broken

Figure 6. Effect of compound 14t on apoptosis of HGC-27 cells (A) Annexin V-FITC/PI detected apoptosis of HGC-27 cells treated with different concentrations of compound 14t for 48 h; (B) annexin V-FITC/PI detected apoptosis of HGC-27 cells treated with different concentrations of compound 14t for 72 h; (C) quantitative analysis of apoptosis cells of HGC-27 for 48 h; (D) quantitative analysis of apoptosis cells of HGC-27 for 72 h (Compared with the control group, ***P<0.001)

Figure 7. Effect of compound 14t on apoptosis-related proteins (A) Changes in protein expression after treatment with different concentrations of compound 14t. GAPDH is the reference protein. (B, C, and D) quantitative analysis diagrams of each protein. Compared with the control group, *P<0.05, **P<0.01, ***P<0.001

References 28

[1]	Sung, H.; Ferlay, J.; Siegel, R. L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. CA Cancer J Clin. 2021, 71, 209. doi: 10.3322/caac.21660
[2]	Mao, J. J.; Pillai, G. G.; Andrade, C. J.; Ligibel, J. A.; Basu, P.; Cohen, L.; Khan, I. A.; Mustian, K. M.; Puthiyedath, R.; Dhiman, K. S.; Lao, L.; Ghelman, R.; Caceres Guido, P.; Lopez, G.; Gallego-Perez, D. F.; Salicrup, L. A. CA Cancer J Clin. 2022, 72, 144. doi: 10.3322/caac.21706
[3]	Tilaoui, M.; Ait Mouse, H.; Zyad, A. Front Pharmacol. 2021, 12, 719694. doi: 10.3389/fphar.2021.719694
[4]	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
[5]	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.)
[6]	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
[7]	Guillemont, J.; Pasquier, E.; Palandjian, P.; Vernier, D.; Gaurrand, S.; Lewi, P. J.; Heeres, J.; de Jonge, M. R.; Koymans, L. M.; Daeyaert, F. F.; Vinkers, M. H.; Arnold, E.; Das, K.; Pauwels, R.; Andries, K.; de Bethune, M. P.; Bettens, E.; Hertogs, K.; Wigerinck, P.; Timmerman, P.; Janssen, P. A. J. Med. Chem. 2005, 48, 2072. pmid: 15771449
[8]	Wang, L.; Tang, J.; Huber, A. D.; Casey, M. C.; Kirby, K. A.; Wilson, D. J.; Kankanala, J.; Xie, J.; Parniak, M. A.; Sarafianos, S. G.; Wang, Z. Eur. J. Med. Chem. 2018, 156, 652. doi: S0223-5234(18)30595-6 pmid: 30031976
[9]	Kumar, N.; Chauhan, A.; Drabu, S. Biomed. Pharmacother. 2011, 65, 375. doi: 10.1016/j.biopha.2011.04.023
[10]	Tale, R. H.; Rodge, A. H.; Hatnapure, G. D.; Keche, A. P. Bioorg. Med. Chem. Lett. 2011, 21, 4648. doi: 10.1016/j.bmcl.2011.03.062
[11]	Fouda, A. M.; Abbas, H. S.; Ahmed, E. H.; Shati, A. A.; Alfaifi, M. Y.; Elbehairi, S. E. I. Molecules 2019, 24, 1080. doi: 10.3390/molecules24061080
[12]	Shaaban, O. G.; Issa, D. A. E.; El-Tombary, A. A.; Abd El Wahab, S. M.; Abdel Wahab, A. E.; Abdelwahab, I. A. Bioorg. Chem. 2019, 88, 102934. doi: 10.1016/j.bioorg.2019.102934
[13]	Cassidy, J.; Clarke, S.; Diaz-Rubio, E.; Scheithauer, W.; Figer, A.; Wong, R.; Koski, S.; Rittweger, K.; Gilberg, F.; Saltz, L. Br. J. Cancer 2011, 105, 58. doi: 10.1038/bjc.2011.201
[14]	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
[15]	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
[16]	Cross, D. A.; Ashton, S. E.; Ghiorghiu, S.; Eberlein, C.; Nebhan, C. A.; Spitzler, P. J.; Orme, J. P.; Finlay, M. R.; Ward, R. A.; Mellor, M. J.; Hughes, G.; Rahi, A.; Jacobs, V. N.; Red Brewer, M.; Ichihara, E.; Sun, J.; Jin, H.; Ballard, P.; Al-Kadhimi, K.; Rowlinson, R.; Klinowska, T.; Richmond, G. H.; Cantarini, M.; Kim, D. W.; Ranson, M. R.; Pao, W. Cancer Discovery 2014, 4, 1046. doi: 10.1158/2159-8290.CD-14-0337
[17]	Jabbour, E. Am. J. Hematol. 2016, 91, 59. doi: 10.1002/ajh.24249 pmid: 26769227
[18]	Kategaya, L.; Di Lello, P.; Rougé, L.; Pastor, R.; Clark, K. R.; Drummond, J.; Kleinheinz, T.; Lin, E.; Upton, J.-P.; Prakash, S.; Heideker, J.; McCleland, M.; Ritorto, M. S.; Alessi, D. R.; Trost, M.; Bainbridge, T. W.; Kwok, M. C. M.; Ma, T. P.; Stiffler, Z.; Brasher, B.; Tang, Y.; Jaishankar, P.; Hearn, B. R.; Renslo, A. R.; Arkin, M. R.; Cohen, F.; Yu, K.; Peale, F.; Gnad, F.; Chang, M. T.; Klijn, C.; Blackwood, E.; Martin, S. E.; Forrest, W. F.; Ernst, J. A.; Ndubaku, C.; Wang, X.; Beresini, M. H.; Tsui, V.; Schwerdtfeger, C.; Blake, R. A.; Murray, J.; Maurer, T.; Wertz, I. E. Nature 2017, 550, 534. doi: 10.1038/nature24006
[19]	Di Lello, P.; Pastor, R.; Murray, J. M.; Blake, R. A.; Cohen, F.; Crawford, T. D.; Drobnick, J.; Drummond, J.; Kategaya, L.; Kleinheinz, T.; Maurer, T.; Rouge, L.; Zhao, X.; Wertz, I.; Ndubaku, C.; Tsui, V. J. Med. Chem. 2017, 60, 10056. doi: 10.1021/acs.jmedchem.7b01293
[20]	Modranka, J.; Drogosz-Stachowicz, J.; Pietrzak, A.; Janecka, A.; Janecki, T. Eur. J. Med. Chem. 2021, 219, 113429. doi: 10.1016/j.ejmech.2021.113429
[21]	Barghash, R. F.; Eldehna, W. M.; Kovalova, M.; Vojackova, V.; Krystof, V.; Abdel-Aziz, H. A. Eur. J. Med. Chem. 2022, 227, 113952. doi: 10.1016/j.ejmech.2021.113952
[22]	Li, J.; Hu, X.; Luo, T.; Lu, Y.; Feng, Y.; Zhang, H.; Liu, D.; Fan, X.; Wang, Y.; Jiang, L.; Wang, Y.; Hao, X.; Shi, T.; Wang, Z. Eur. J. Med. Chem. 2021, 226, 113817. doi: 10.1016/j.ejmech.2021.113817
[23]	Ren, Y.; Ruan, Y.; Cheng, B.; Li, L.; Liu, J.; Fang, Y.; Chen, J. Bioorg. Med. Chem. 2021, 46, 116376. doi: 10.1016/j.bmc.2021.116376
[24]	Ma, J.; Liang, W.; Qiang, Y.; Li, L.; Du, J.; Pan, C.; Chen, B.; Zhang, C.; Chen, Y.; Wang, Q. Cell Commun. Signal. 2021, 19, 122. doi: 10.1186/s12964-021-00804-0
[25]	Fu, S.; Chen, X.; Lo, H. W.; Lin, J. Cancer Lett. 2019, 448, 11. doi: 10.1016/j.canlet.2019.01.026
[26]	Legraverend, M.; Bisagni, E. Tetrahedron Lett. 1985, 26, 2001. doi: 10.1016/S0040-4039(00)98364-3
[27]	Legraverend, M.; Ngongo-Tekam, R. M.; Bisagni, E.; Zerial, A. J Med. Chem. 1985, 28, 1477. pmid: 2995667
[28]	Jansa, P.; Holy, A.; Dracinsky, M.; Kolman, V.; Janeba, Z.; Kostecka, P.; Kmonickova, E.; Zidek, Z. Med. Chem. Res. 2014, 23, 4482. doi: 10.1007/s00044-014-1018-9 pmid: 32214763

含苯甲醚结构的2,4,5,6-四取代嘧啶衍生物的合成及抗增殖活性研究

Synthesis and Antiproliferative Activity of 2,4,5,6-Tetrasubstituted Pyrimidine Derivatives Containing Anisole

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