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

doi:10.6023/cjoc202007067

Chinese Journal of Organic Chemistry ›› 2021, Vol. 41 ›› Issue (1): 310-317.DOI: 10.6023/cjoc202007067 Previous Articles Next Articles

Article

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)

1. cjoc202007067辅助材料.pdf(1839KB)

Abstract

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

Cite this article

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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Fig. & Tab. 6

References 25

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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

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

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

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

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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