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

doi:10.6023/cjoc202201048

有机化学 ›› 2022, Vol. 42 ›› Issue (6): 1677-1686.DOI: 10.6023/cjoc202201048 上一篇下一篇

研究论文

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)

文章分享

1. 221677S.pdf(9574KB)

摘要/Abstract

为了寻找高效的新型抗肿瘤药物, 设计并合成了一系列含苯甲醚结构的2,4,5,6-四取代嘧啶衍生物, 并采用噻唑蓝(MTT)法测定了目标化合物对PC-3(人前列腺癌细胞)、MGC-803(人胃癌细胞)、MCF-7(人乳腺癌细胞)、HGC-27(人未分化胃癌细胞)四种人肿瘤细胞的抗增殖活性. 结果显示部分化合物表现出中度至强效的抗增殖活性, 其中5-乙基- 6-((4-甲氧基苯基)硫代)-N⁴-(3,4,5-三甲氧基苯基)嘧啶-2,4-二胺(14t)对HGC-27细胞具有最好的抗增殖活性, IC₅₀值为(0.98±0.12) μmol•L^–1, 抗增殖活性明显优于阳性对照5-氟尿嘧啶. 进一步抗肿瘤机制研究表明, 化合物14t可以显著抑制HGC-27细胞的克隆形成和迁移, 诱导细胞凋亡. 同时化合物14t可以下调抗凋亡蛋白Bcl-2的表达, 上调促凋亡蛋白Bax和P53的表达.

关键词: 嘧啶, 苯甲醚, 合成, 抗增殖活性

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

引用此文

高潮, 司晓杰, 池玲玲, 王浩, 戴洪林, 刘丽敏, 汪正捷, 张洋, 王涛, 周耀传, 郑甲信, 可钰, 刘宏民, 张秋荣. 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[J]. 有机化学, 2022, 42(6): 1677-1686.

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.

导出引用 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

分享此文

图/表 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

参考文献 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

RichHTML

PDF

补充材料

可视化

摘要/Abstract

引用此文

分享此文

图/表 10

参考文献 28

相关文章 15

编辑推荐

相关统计

本文评价

[1]	冯康博, 陈炯, 古双喜, 王海峰, 陈芬儿. 全连续流反应技术在药物合成中的新进展(2019~2022)[J]. 有机化学, 2024, 44(2): 378-397.
[2]	李鹏辉, 谢青洋, 万福贤, 张元红, 姜林. 含环丙基的新型取代嘧啶-5-甲酰胺的合成及杀菌活性研究[J]. 有机化学, 2024, 44(2): 650-656.
[3]	邹发凯, 王能中, 姚辉, 王慧, 刘明国, 黄年玉. 1β-/3R-芳基硫代糖的区域与立体选择性合成[J]. 有机化学, 2024, 44(2): 593-604.
[4]	李路瑶, 贺忠文, 张振国, 贾振华, 罗德平. 三芳基碳正离子在有机合成中的应用[J]. 有机化学, 2024, 44(2): 421-437.
[5]	梅青刚, 李清寒. 可见光促进C(3)(杂)芳硫基吲哚化合物的合成研究进展[J]. 有机化学, 2024, 44(2): 398-408.
[6]	杨维清, 葛宴兵, 陈元元, 刘萍, 付海燕, 马梦林. 1,8-萘酰亚胺衍生物的设计、合成及其对半胱氨酸的识别研究[J]. 有机化学, 2024, 44(1): 180-194.
[7]	赵茜帆, 陈永正, 张世明. 碳基非金属催化剂在有机合成领域的应用及机理研究[J]. 有机化学, 2024, 44(1): 137-147.
[8]	陈珊, 陈志林, 胡琼, 蒙艳双, 黄悦, 陶萍芳, 卢丽如, 黄国保. 含双硫脲基团分子钳在非极性溶剂中识别中性分子[J]. 有机化学, 2024, 44(1): 277-281.
[9]	王化坤, 任晓龙, 宣宜宁. 卤盐催化的α,β-环氧羧酸酯与异氰酸酯[3＋2]环加成反应研究[J]. 有机化学, 2024, 44(1): 251-258.
[10]	金玉坤, 任保轶, 梁福顺. 可见光介导的三氟甲基的选择性C－F键断裂及其在偕二氟类化合物合成中的应用[J]. 有机化学, 2024, 44(1): 85-110.
[11]	马翠云, 罗海澜, 张福华, 郭丹, 陈树兴, 王飞. 3-Pyrrolyl BODIPY的绿色生物合成、光物理性质及应用研究[J]. 有机化学, 2024, 44(1): 216-223.
[12]	王博珍, 张婕, 粘春惠, 金茗茗, 孔苗苗, 李物兰, 何文斐, 吴建章. 含有3,4-二氯苯基的酰胺类化合物的合成及抗肿瘤活性研究[J]. 有机化学, 2024, 44(1): 232-241.
[13]	于士航, 刘嘉威, 安碧玉, 边庆花, 王敏, 钟江春. 黑腹尼虎天牛接触性信息素的不对称合成[J]. 有机化学, 2024, 44(1): 301-308.
[14]	李阳, 袁锦鼎, 赵頔. 低共熔溶剂1,3-二甲基脲/L-(+)-酒石酸中(E)-2-苯乙烯基喹啉-3-羧酸类衍生物的绿色合成[J]. 有机化学, 2023, 43(9): 3268-3276.
[15]	岁丹丹, 岑南楠, 龚若蕖, 陈阳, 陈文博. 无支持电解质条件下连续流电化学合成三氟甲基化氧化吲哚[J]. 有机化学, 2023, 43(9): 3239-3245.