新型2,4,6,-取代嘧啶衍生物的设计、合成和抗肿瘤活性研究

doi:10.6023/cjoc202007067

有机化学 ›› 2021, Vol. 41 ›› Issue (1): 310-317.DOI: 10.6023/cjoc202007067 上一篇下一篇

研究论文

新型2,4,6,-取代嘧啶衍生物的设计、合成和抗肿瘤活性研究

张洋^a^,^b, 张路野^a^,^b, 王继宽^a^,^b, 刘丽敏^a^,^b, 王涛^a^,^b, 栗娜^a^,^b, 汪正捷^a^,^b, 刘秀娟^a^,^b, 陈雅欣^a^,^b, 赵丹琳^a^,^b, 郑甲信^a^,^c, 单丽红^a^,^b^,^c^,^*(), 刘宏民^a^,^b^,^c^,^d^,^*(), 张秋荣^a^,^b^,^c^,^*()

a 郑州大学药学院郑州 450001
b 新药创制与药物安全性评价协同创新中心郑州 450001
c 教育部药物关键制备技术重点实验室郑州 450001
d 食管癌防治国家重点实验室郑州 450052

收稿日期:2020-07-29 修回日期:2020-08-26 发布日期:2020-08-31
通讯作者: 单丽红, 刘宏民, 张秋荣
作者简介:
* Corresponding authors. E-mail: shlh@zzu.edu.cn; liuhm@zzu.edu.cn; zqr409@yeah.net
基金资助:
国家自然科学基金(81773562); 国家蛋白质研究项目(2018YFE0195100); 省部共建食管癌防治国家重点实验室资助的开放基金(K2020000X)

Design, Synthesis and Antitumor Activity Evaluation Research of Novel 2,4,6-Substituted Pyrimidine Derivatives

Yang Zhang^a^,^b, Luye Zhang^a^,^b, Jikuan Wang^a^,^b, Limin Liu^a^,^b, Tao Wang^a^,^b, Na Li^a^,^b, Zhengjie Wang^a^,^b, Xiujuan Liu^a^,^b, Yaxin Chen^a^,^b, Danlin Zhao^a^,^b, Jiaxin Zheng^a^,^c, Lihong Shan^a^,^b^,^c^,^*(), Hongmin Liu^a^,^b^,^c^,^d^,^*(), Qiurong Zhang^a^,^b^,^c^,^*()

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

Received:2020-07-29 Revised:2020-08-26 Published:2020-08-31
Contact: Lihong Shan, Hongmin Liu, Qiurong Zhang
Supported by:
the National Natural Science Foundation of China(81773562); the National Key Research Program of Proteins(2018YFE0195100); the Openning Fund from State Key Laboratory of Esophageal Cancer Prevention & Treatment(K2020000X)

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摘要/Abstract

为了寻找高效的新型抗肿瘤药物, 设计合成了一系列2,4,6-取代嘧啶衍生物, 并使用噻唑蓝(MTT)法对4种人的肿瘤细胞人结肠癌细胞(SW-620)、人前列腺癌细胞(PC-3)、人非小细胞肺癌细胞(A549)和人胃癌细胞(MGC-803)进行了体外抗肿瘤活性研究. 其中化合物 N-((4-乙基苯基)氨基甲酰基)-2-((4-(对甲苯基氨基)-6-(三氟甲基)嘧啶-2-基)硫代)乙酰胺(5i), 2-((4-((4-乙氧基苯基)氨基)-6-(三氟甲基)嘧啶-2-基)硫基)- N-((4-乙基苯基)氨基甲酰基)乙酰胺(5o)和 N-((4-乙基苯基)氨基甲酰基)-2-((4-((4-甲氧基苯基)氨基)-6-(三氟甲基)嘧啶-2-基)硫代)乙酰胺(5r)对4种测试的癌细胞系显示出高的抗肿瘤增殖活性, 特别是化合物5r具有最高的抑制活性, 对SW-620的IC₅₀值最低, 为1.46 μmol/L. 进一步机制研究表明, 化合物5r诱导SW-620凋亡, 使细胞周期阻滞在S期. 分子对接揭示了化合物5r可以很好地结合表皮生长因子受体(EGFR)的活性位点, 被认为是一种有前途的化合物, 可用于进一步研究开发新的抗癌药物.

关键词: 嘧啶衍生物, 合成, 抗肿瘤活性, 细胞周期, 凋亡

With the expectation to find out novel and effective anti-tumor agents, a series of novel 2,4,6-substituted pyrimidine derivatives were synthesized and evaluated for their anti-tumor activity against four human cancer cells [SW-620 (human colon cancer cells), PC-3 (human prostate cancer cells), A549 (Human non-small cell lung cancer cells), MGC-803 (human gastric cancer cells)] using methyl thiazolyl tetrazolium (MTT) assay. Among tested compounds, N-((4-ethylphenyl)- carbamoyl)-2-((4-( p-tolylamino)-6-(trifluoromethyl)pyrimidin-2-yl)thio)acetamide (5i), 2-((4-((4-ethoxyphenyl)amino)-6-(tri- fluoromethyl)pyrimidin-2-yl)thio)- N-((4-ethylphenyl)carbamoyl)acetamide (5o) and N-((4-ethylphenyl)carbamoyl)-2-((4-((4- methoxyphenyl)amino)-6-(trifluoromethyl)pyrimidin-2-yl)thio)acetamide (5r) displayed strong antiproliferative activity on 4 tested cancer cell lines. In particular, compound5r has the highest inhibitive activity, and possessed the lowest IC₅₀ value of 1.46 μmol/L towards SW-620 cells. Further mechanism research shows that compound5rinduces SW-620 apoptosis, arrests cell cycle at S phase. Molecular docking reveals that5r can bind well to the active site of epidermal growth factor receptor (EG-FR), and may be considered as a promising compound amenable for further investigation for the development of new anticancer agents.

Key words: pyrimidine derivative, synthesis, antitumor activity, cell cycle, apoptosis

引用此文

张洋, 张路野, 王继宽, 刘丽敏, 王涛, 栗娜, 汪正捷, 刘秀娟, 陈雅欣, 赵丹琳, 郑甲信, 单丽红, 刘宏民, 张秋荣. 新型2,4,6,-取代嘧啶衍生物的设计、合成和抗肿瘤活性研究[J]. 有机化学, 2021, 41(1): 310-317.

Yang Zhang, Luye Zhang, Jikuan Wang, Limin Liu, Tao Wang, Na Li, Zhengjie Wang, Xiujuan Liu, Yaxin Chen, Danlin Zhao, Jiaxin Zheng, Lihong Shan, Hongmin Liu, Qiurong Zhang. Design, Synthesis and Antitumor Activity Evaluation Research of Novel 2,4,6-Substituted Pyrimidine Derivatives[J]. Chinese Journal of Organic Chemistry, 2021, 41(1): 310-317.

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图/表 6

Figure 1. Design of pyrimidine derivatives

. Reagents and conditions: (a) 1,2-dichloroethane, 90 ℃, 4 h; (b) CH 3CH 2OH, KOH, 80 ℃, 3 h; (c) 1,4-dioxane, KOH, POCl 3, 90 ℃, 2 h; (d) DMF, K 2CO 3, 80 ℃, 6 h

Scheme 1. Synthesis of 2,4,6-substituted pyrimidine derivatives

Compd.	R	MGC-803	PC-3	SW-620	A549
5a	2-Cl	13.81±1.14	25.66±1.41	6.73±1.22	23.13±1.37
5b	3-Cl	4.77±0.67	17.67±1.67	24.05±1.38	19.82±1.29
5c	4-Cl	5.05±0.70	18.39±1.70	7.30±0.86	20.19±1.31
5d	2-F	9.37±0.97	19.99±1.89	19.31±1.28	10.13±0.91
5e	3-F	28.52±1.45	32.57±1.55	>50	>50
5f	4-F	6.83±0.83	15.30±1.11	22.77±1.35	24.40±1.38
5g	2-CH ₃	16.88±1.83	26.01±1.41	9.25±0.86	>50
5h	3-CH ₃	13.69±1.13	20.20±1.12	7.78±0.89	29.12±1.46
5i	4-CH ₃	4.96±0.69	7.33±1.00	3.97±0.59	10.38±1.03
5j	3,4,5-(OCH ₃) ₃	4.45±0.64	3.02±0.83	16.42±1.33	22.52±1.35
5k	3-Cl-4-F	9.49±0.97	12.33±1.13	12.71±1.24	10.18±0.89
5l	3,4-Cl ₂	7.37±0.88	8.73±0.13	7.57±0.87	13.48±1.13
5m	2-OCH ₂CH ₃	16.91±1.22	21.03±1.31	>50	>50
5n	3-CH ₂CH ₃	9.51±0.97	17.23±1.28	13.18±1.12	29.30±1.46
5o	4-OCH ₂CH ₃	4.04±0.60	7.23±0.63	9.87±1.47	5.84±0.76
5p	2-OCH ₃	>50	24.38±1.23	>50	>50
5q	3-OCH ₃	9.54±0.98	17.34±1.33	10.97±1.32	23.01±1.36
5r	4-OCH ₃	1.53±0.13	5.62±0.11	1.46±0.11	3.68±0.56
5-Fu	—	12.24±1.23	9.65±0.57	10.32±0.79	13.38±1.25

Table 1. Antiproliferative activities [IC50/(μmol•L–1)] of target compounds against four cancer cell lines

Compd.	Ges-1	HEEC
5r	50.38±1.02	>100
5-Fu	22.61±0.56	>100

Table 2. In vitro antiproliferative activity of compound 5r against human normal cell [IC50/(μmol•L–1)]

Figure 2. Cell cycle arrestment and apoptosis induction of compound5r after 72 h treatment with different concentrations (A) Cells were treated with different concentrations (0, 0.5, 1.0, 2 μmol/L) for 72 h. Then analyze DNA content by flow cytometry. (B) SW-620 cells apoptosis was detected by Annexin V/PI on flow cytometry. Cells treated with 0, 0.5, 1, 2 μmol/L for 72 h were processed for analysis. (C) Quantitative analysis of the cell cycle distribution of SW-620 cells for 72 h. (D) Quantitative analysis of apoptosis cells of SW-620 cells for 72 h

Figure 3. 3D and 2D representation of EGFR crystal structure in complex with5r (PDB code: 5GNK)

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新型2,4,6,-取代嘧啶衍生物的设计、合成和抗肿瘤活性研究

Design, Synthesis and Antitumor Activity Evaluation Research of Novel 2,4,6-Substituted Pyrimidine Derivatives

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