新型2,4,6-三取代嘧啶衍生物的合成及抗增殖活性评价

doi:10.6023/cjoc202205048

有机化学 ›› 2022, Vol. 42 ›› Issue (11): 3824-3834.DOI: 10.6023/cjoc202205048 上一篇下一篇

研究论文

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)

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摘要/Abstract

为了寻找新型高效的抗肿瘤药物, 设计合成了一系列2,4,6-三取代嘧啶衍生物, 并采用噻唑蓝(MTT)法测定目标化合物对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. 结果显示大部分化合物表现出中度至强效的抗增殖活性, 其中N-(3-(2-((4-((1,3,4-噻二唑-2-基)硫代)-6-(三氟甲基)嘧啶-2-基)硫代)乙酰胺基)苯基)丙烯酰胺(19q)对PC-3细胞具有最好的抑制活性, IC₅₀值为(0.87±0.15) μmol•L^－1, 抗肿瘤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19q可以诱导PC-3细胞凋亡. 此外, 化合物19q可能是通过下调抗凋亡蛋白Bcl-2的表达, 上调促凋亡蛋白Bax和p53的表达而发挥抗肿瘤作用.

关键词: 嘧啶衍生物, 合成, 抗增殖活性

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

引用此文

高潮, 张玉桐, 池玲玲, 王浩, 马家婕, 毕梦鑫, 戴洪林, 司晓杰, 刘丽敏, 张洋, 郑甲信, 可钰, 刘宏民, 张秋荣. 新型2,4,6-三取代嘧啶衍生物的合成及抗增殖活性评价[J]. 有机化学, 2022, 42(11): 3824-3834.

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.

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图/表 7

图1. 新型2,4,6-三取代嘧啶衍生物的设计

Figure 1. Design of novel 2,4,6-trisubstituted pyrimidine derivatives

图式1. 化合物19a~19u的合成路线

Scheme 1. Synthetic route of compounds 19a~19u Reagents and conditions: (i) absolute ethanol, KOH, 80 ℃, 8 h; (ii) acetone, Et3N, r.t., 4 h; (iii) H2O, KOH, 70 ℃, 5 h; (iv) POCl3, 60 ℃, 4 h; (v) CH3CN, Et3N, different thiol-containing compounds and substituted piperazines, 82 ℃, 4 h; (vi) water-absolute ethanol, Fe, NH4Cl, 80 ℃, 5 h; (vii) DCM, Et3N, acryloyl chloride, r.t., 2 h.

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

表1. 目标化合物19a~19u的体外抗增殖活性评价

Table 1. In vitro antiproliferative activity evaluation results of compounds 19a~19u

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

表2. 化合物19q对人正常细胞的体外抗增殖活性

Table 2. In vitro antiproliferative activity of compound 19q against human normal cells

图2. 化合物19q对PC-3细胞核形态的影响

Figure 2. Effect of compound 19q on nuclear morphology of PC-3 cells The arrows in the figure indicate the cells whose nuclei have shrunk or broken

图3. 化合物19q对PC-3细胞凋亡的影响

Figure 3. Effect of compound 19q on apoptosis of PC-3 cells (A) Annexin V-FITC/PI detected apoptosis of PC-3 cells treated with different concentrations of compound 19q for 48 h; (B) Annexin V-FITC/PI detected apoptosis of PC-3 cells treated with different concentrations of compound 19q for 72 h; (C) Quantitative analysis of apoptosis cells of PC-3 cells for 48 h; (D) Quantitative analysis of apoptosis cells of PC-3 cells for 72 h. Compared with the control group, *P<0.05, ***P<0.001.

图4. 化合物19q对凋亡相关蛋白的影响

Figure 4. Effect of compound 19q on apoptosis-related proteins Changes in protein expression after treatment with different concentrations of compound 19q. GAPDH is the reference protein. (B, C, and D) Quantitative analysis diagrams of each protein. Compared with the control group, *P<0.05, ***P<0.001.

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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

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