Design, Synthesis and Antitumor Activity Evaluation of 4-Aminoquinazoline Derivatives Containing Urea Moiety

doi:10.6023/cjoc201903062

Chinese Journal of Organic Chemistry ›› 2019, Vol. 39 ›› Issue (10): 2875-2881.DOI: 10.6023/cjoc201903062 Previous Articles Next Articles

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含脲砌块的4-氨基喹唑啉衍生物的设计、合成及抗肿瘤活性研究

李二冬^a^d, 孟娅琪^a^d, 张路野^a^b, 张洋^a^b, 王继宽^a^b, 张丹青^a^b, 宋攀攀^b^c, 辛景超^b^c, 栗娜^b^c, 郑甲信^a^d, 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中心郑州 450001
c 河南省药物质量评价重点实验室郑州 450001
d 教育部药物制备关键技术重点实验室郑州 450001

收稿日期:2019-03-27 修回日期:2019-05-20 发布日期:2019-06-03
通讯作者: 可钰,刘宏民,张秋荣 E-mail:ky@zzu.edu.cn;liuhm@zzu.edu.cn;zqr409@yeah.net
基金资助:
国家自然科学基金(81430085);河南省自然科学基金(182300410321);河南省科技厅(No. 182102310249)

Design, Synthesis and Antitumor Activity Evaluation of 4-Aminoquinazoline Derivatives Containing Urea Moiety

Li, Erdong^a^d, Meng, Yaqi^a^d, Zhang, Luye^a^b, Zhang, Yang^a^b, Wang, Jikuan^a^b, Zhang, Danqing^a^b, Song, Panpan^b^c, Xin, Jingchao^b^c, Li, Na^b^c, Zheng, Jiaxin^a^d, Ke, Yu^a^b^c^d^*(), Liu, Hongmin^a^b^c^d^*(), Zhang, Qiurong^a^b^c^d^*()

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 Henan Province for Drug Quality and Evaluation, Zhengzhou 450001
d Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education, Zhengzhou 450001

Received:2019-03-27 Revised:2019-05-20 Published:2019-06-03
Contact: Ke, Yu,Liu, Hongmin,Zhang, Qiurong E-mail:ky@zzu.edu.cn;liuhm@zzu.edu.cn;zqr409@yeah.net
Supported by:
Project supported by the National Natural Science Foundation of China(81430085);the Natural Science Foundation of Henan Province(182300410321);the Technology Department Project of Henan Province(No. 182102310249)

In order to find new anti-tumor drugs with targeted therapeutic effect, a series of novel 4-aminoquinazoline derivatives bearing urea moiety were designed, synthesized and evaluated for antitumor activity against four human cancer cell lines of MCF-7, MGC-803, SW620 and A549 using methyl thiazolyl tetrazolium (MTT) assay. Most of the target compounds exhibited excellent anti-tumor activity against the four human tumor cell lines. Among them, 2-((4-((3,4,5-trimethoxyphenyl)- amino)quinazolin-2-yl)-thio)-N-((3,4,5-trimethoxyphenyl)carbamoyl)acetamide (10p) showed the best antitumor activity against MGC-803, SW620 and A549 cancer cell lines with IC₅₀ values of (7.02±0.46), (6.00±0.78) and (7.04±1.11) μmol? L ^–1, respectively. Its activity was comparable to the positive control of gefitinib. Molecular docking showed that compound 10p could bind well with EGFR, suggesting that it could be a potential antitumor agent.

Key words: urea moiety, 4-aminoquinazoline, synthesis, antitumor activity

Cite this article

Li, Erdong, Meng, Yaqi, Zhang, Luye, Zhang, Yang, Wang, Jikuan, Zhang, Danqing, Song, Panpan, Xin, Jingchao, Li, Na, Zheng, Jiaxin, Ke, Yu, Liu, Hongmin, Zhang, Qiurong. Design, Synthesis and Antitumor Activity Evaluation of 4-Aminoquinazoline Derivatives Containing Urea Moiety[J]. Chinese Journal of Organic Chemistry, 2019, 39(10): 2875-2881.

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References 21

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Compd.	R	IC₅₀^a/(μmol?L^–1)
Compd.	R	MCF-7	MGC-803	SW620	A549
8	—	17.23±0.85	18.02±0.98	23.25±1.91	25.67±1.78
9	—	18.83±1.07	26.40±1.42	22.02±1.54	25.19±1.20
10a	4-Cl	20.21±1.02	21.31±1.71	11.44±1.06	13.15±1.52
10b	3-Cl	18.04±1.04	17.34±1.48	8.22±0.95	10.76±1.31
10c	2-Cl	10.28±1.25	7.61±0.93	7.66±0.91	8.07±1.02
10d	4-F	25.21±1.35	27.09±1.32	29.89±1.16	21.54±1.93
10e	3-F	20.21±1.42	15.09±1.30	13.68±1.59	14.08±1.08
10f	2-F	15.02±1.21	16.27±1.03	19.92±1.12	18.76±1.94
10g	4-Br	>50	31.05±1.82	35.67±1.24	>50
10h	3-Br	>50	29.48±1.67	39.73±1.43	>50
10i	2-Br	16.24±1.46	17.24±1.51	22.23±0.97	23.20±1.96
10j	4-CH₃	>50	>50	>50	>50
10k	3-CH₃	21.06±1.45	23.82±1.80	>50	24.89±1.07
10l	2-CH₃	10.84±1.03	8.09±1.37	8.38±1.12	16.73±1.81
10m	4-OCH₃	>50	>50	>50	>50
10n	3-OCH₃	17.02±1.36	9.71±0.98	12.16±1.00	20.11±1.95
10o	2-OCH₃	7.88±0.84	5.90±0.69	7.45±0.82	7.92±1.44
10p	3,4,5-(OCH₃)₃	7.62±0.63	7.02±0.46	6.00±0.78	7.04±1.11
10q	H	27.05±1.62	25.07±1.96	15.51±1.13	>50
10r	3-Cl-4-F	25.51±1.35	20.08±1.31	34.53±1.21	14.64±1.27
Gefitinib^b	—	7.34±0.86	8.82±0.63	10.79±0.69	9.28±1.00

Compd.	R	IC₅₀^a/(μmol?L^–1)
Compd.	R	MCF-7	MGC-803	SW620	A549
8	—	17.23±0.85	18.02±0.98	23.25±1.91	25.67±1.78
9	—	18.83±1.07	26.40±1.42	22.02±1.54	25.19±1.20
10a	4-Cl	20.21±1.02	21.31±1.71	11.44±1.06	13.15±1.52
10b	3-Cl	18.04±1.04	17.34±1.48	8.22±0.95	10.76±1.31
10c	2-Cl	10.28±1.25	7.61±0.93	7.66±0.91	8.07±1.02
10d	4-F	25.21±1.35	27.09±1.32	29.89±1.16	21.54±1.93
10e	3-F	20.21±1.42	15.09±1.30	13.68±1.59	14.08±1.08
10f	2-F	15.02±1.21	16.27±1.03	19.92±1.12	18.76±1.94
10g	4-Br	>50	31.05±1.82	35.67±1.24	>50
10h	3-Br	>50	29.48±1.67	39.73±1.43	>50
10i	2-Br	16.24±1.46	17.24±1.51	22.23±0.97	23.20±1.96
10j	4-CH₃	>50	>50	>50	>50
10k	3-CH₃	21.06±1.45	23.82±1.80	>50	24.89±1.07
10l	2-CH₃	10.84±1.03	8.09±1.37	8.38±1.12	16.73±1.81
10m	4-OCH₃	>50	>50	>50	>50
10n	3-OCH₃	17.02±1.36	9.71±0.98	12.16±1.00	20.11±1.95
10o	2-OCH₃	7.88±0.84	5.90±0.69	7.45±0.82	7.92±1.44
10p	3,4,5-(OCH₃)₃	7.62±0.63	7.02±0.46	6.00±0.78	7.04±1.11
10q	H	27.05±1.62	25.07±1.96	15.51±1.13	>50
10r	3-Cl-4-F	25.51±1.35	20.08±1.31	34.53±1.21	14.64±1.27
Gefitinib^b	—	7.34±0.86	8.82±0.63	10.79±0.69	9.28±1.00

含脲砌块的4-氨基喹唑啉衍生物的设计、合成及抗肿瘤活性研究

Design, Synthesis and Antitumor Activity Evaluation of 4-Aminoquinazoline Derivatives Containing Urea Moiety

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