含三氟甲基的2,4,6-三取代喹唑啉衍生物的合成及抗肿瘤活性研究

doi:10.6023/cjoc202107026

有机化学 ›› 2022, Vol. 42 ›› Issue (1): 249-256.DOI: 10.6023/cjoc202107026 上一篇下一篇

研究论文

含三氟甲基的2,4,6-三取代喹唑啉衍生物的合成及抗肿瘤活性研究

汪正捷^a^,^b, 戴洪林^a^,^b, 司晓杰^a^,^b, 高潮^a^,^b, 刘丽敏^a^,^b, 张路野^a^,^b, 张洋^a^,^b, 宋亚丹^a^,^b, 赵培荣^a^,^b^,^c, 郑甲信^a^,^b, 可钰^a^,^b^,^*(), 刘宏民^a^,^b^,^c^,^d^,^*(), 张秋荣^a^,^b^,^d^,^*()

a 郑州大学药学院郑州 450001
b 郑州大学新药研究与安全评价协同创新中心郑州 450001
c 郑州大学食管癌防治国家重点实验室郑州 450052
d 郑州大学教育部药物制备关键技术重点实验室郑州 450001

收稿日期:2021-07-12 修回日期:2021-08-13 发布日期:2021-08-28
通讯作者: 可钰, 刘宏民, 张秋荣
基金资助:
国家自然科学基金(U1904163); 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)

Synthesis and Antitumor Activity of 2,4,6-Trisubstituted Novel Quinazoline Derivatives Containing Trifluoromethyl

Zhengjie Wang^a^,^b, Honglin Dai^a^,^b, Xiaojie Si^a^,^b, Chao Gao^a^,^b, Limin Liu^a^,^b, Luye Zhang^a^,^b, Yang Zhang^a^,^b, Yadan Song^a^,^b, Peirong Zhao^a^,^b^,^c, Jiaxin Zheng^a^,^b, Yu Ke^a^,^b(), Hongmin Liu^a^,^b^,^c^,^d(), Qiurong Zhang^a^,^b^,^d()

a School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001
b Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, 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 University, Zhengzhou 450001

Received:2021-07-12 Revised:2021-08-13 Published:2021-08-28
Contact: Yu Ke, Hongmin Liu, Qiurong Zhang
Supported by:
National Natural Science Foundation of China(U1904163); National Key Research Program of Proteins(2018YFE0195100); Opening Fund from State Key Laboratory of Esophageal Cancer Prevention & Treatment(K2020000X)

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摘要/Abstract

为了寻找高效低毒的抗肿瘤药物, 设计并合成了一系列新型的含三氟甲基基团的2,4,6-三取代喹唑啉喹唑啉类衍生物, 并采用噻唑蓝(MTT)比色法测定目标化合物对人前列腺癌细胞系(PC-3)、人乳腺癌细胞系(MCF-7)、人食管癌细胞系(Eca-109)、人胃癌细胞系(MGC-803)、人未分化胃癌细胞系(HGC-27)、人非小细胞肺癌细胞系(A549)和人非小细胞肺癌细胞系(H1975)的抗肿瘤活性. 结果显示部分化合物表现出中度至强效的抗肿瘤活性, 其中N-(3-溴苯基)-6-甲氧基-2-((4-(三氟甲基)苄基)硫代)喹唑啉-4-胺(16l)对PC-3细胞具有最好的抗肿瘤活性, IC₅₀值为(2.22±0.15) μmol/L, 抗肿瘤活性明显优于阳性对照品吉非替尼. 此外, 化合物16l对PC-3细胞以浓度依赖与时间依赖的方式诱导其凋亡.

关键词: 三氟甲基, 喹唑啉, 合成, 抗肿瘤活性

In order to find efficient and low toxicity antitumor drugs, a series of novel 2,4,6-trisubstituted quinazoline derivatives containing trifluoromethyl were synthesized and evaluated for their antitumor activities against human cancer cell lines (PC-3, MCF-7, Eca-109, MGC-803, HGC-27, A549, H1975) by using methyl thiazolyl tetrazolium (MTT) assay. Most of compounds exerted moderate to excellent antitumor activity against seven human cancer cells. Among them, N-(3-bromophenyl)-6-methoxy-2-((4-(trifluoromethyl)benzyl)thio)quinazolin-4-amine (16l) showed the best antitumor activity against PC-3 cancer cell line, with the IC₅₀ values of (2.22±0.15) μmol/L, which was better than the positive control of gefitinib. At the same time, and compound 16l could dose-dependently and time-dependently induce PC-3 cells apoptosis.

Key words: trifluoromethyl, quinazoline, synthesis, antitumor activity

引用此文

汪正捷, 戴洪林, 司晓杰, 高潮, 刘丽敏, 张路野, 张洋, 宋亚丹, 赵培荣, 郑甲信, 可钰, 刘宏民, 张秋荣. 含三氟甲基的2,4,6-三取代喹唑啉衍生物的合成及抗肿瘤活性研究[J]. 有机化学, 2022, 42(1): 249-256.

Zhengjie Wang, Honglin Dai, Xiaojie Si, Chao Gao, Limin Liu, Luye Zhang, Yang Zhang, Yadan Song, Peirong Zhao, Jiaxin Zheng, Yu Ke, Hongmin Liu, Qiurong Zhang. Synthesis and Antitumor Activity of 2,4,6-Trisubstituted Novel Quinazoline Derivatives Containing Trifluoromethyl[J]. Chinese Journal of Organic Chemistry, 2022, 42(1): 249-256.

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Compound	R	IC₅₀/(μmol•L^–1)
Compound	R	PC-3	MCF-7	Eca-109	MGC-803	HGC-27	A549	H1975
16a	H	24.66±0.80	21.32±0.52	25.35±1.28	22.12±1.10	28.51±1.26	29.48±0.77	24.92±1.60
16b	2-F	17.13±0.65	27.03±1.25	24.53±1.62	15.89±0.82	16.40±1.21	26.83±1.17	26.80±1.32
16c	2-Cl	22.27±1.12	>50	>50	32.80±1.65	>50	>50	24.41±1.21
16d	2-Br	16.50±0.53	22.03±0.87	>50	17.07±0.86	35.75±1.55	16.49±0.56	>50
16e	2-CF₃	45.19±1.24	44.22±1.23	43.69±1.55	35.94±1.26	25.07±1.39	45.51±1.19	44.17±1.62
16f	2-CH₃	15.90±1.08	26.23±0.95	32.10±1.85	21.09±1.02	19.00±1.27	39.83±1.61	37.14±1.66
16g	2-OCH₃	36.99±1.63	>50	>50	30.67±1.75	20.09±1.41	28.51±0.45	23.24±0.76
16h	2-OC₂H₅	9.67±0.68	43.55±1.87	47.17±1.81	40.33±1.12	21.47±1.33	29.13±0.65	31.20±1.81
16i	3-Cl-4-F	9.08±0.52	18.90±0.48	13.38±0.32	15.13±0.60	8.26±0.91	18.34±0.60	25.94±0.97
16j	3-Cl	9.38±0.55	18.29±0.68	17.16±0.68	20.66±1.31	18.35±1.26	27.17±0.49	25.20±0.77
16k	3,4-diCl	7.77±0.46	16.00±0.76	9.41±0.22	10.36±1.01	23.86±0.83	26.09±0.85	9.41±0.22
16l	3-Br	2.22±0.15	7.62±0.77	6.21±0.66	4.07±0.79	7.55±0.87	5.93±0.25	8.45±0.41
16m	3-CF₃	3.11±0.15	13.29±0.40	16.30±0.19	5.60±0.29	6.06±0.78	14.71±0.86	21.13±0.81
16n	3-CH₃	7.06±0.67	23.34±0.62	26.65±0.85	14.44±0.75	9.59±1.24	17.22±0.21	24.78±1.69
16o	3-OCH₃	8.81±0.59	26.55±1.64	22.64±1.41	10.84±1.03	22.54±1.33	30.05±1.21	22.64±1.41
16p	3-CN	6.24±0.42	>50	29.23±1.83	3.59±0.55	20.36±0.90	28.12±1.02	29.23±1.83
16q	3-NO₂	3.25±0.51	6.62±0.81	10.00±1.00	6.99±0.84	22.69±0.96	26.60±1.07	10.00±1.00
16r	4-F	7.02±0.58	20.01±0.94	10.28±0.35	19.44±1.28	17.39±0.55	25.28±0.95	10.28±0.35
16s	4-Cl	7.22±0.66	15.06±0.66	15.88±0.56	8.23±0.91	25.75±0.80	21.15±1.35	15.88±0.56
16t	4-Br	9.10±0.40	17.50±0.52	10.55±0.47	17.66±1.24	28.38±0.88	28.95±1.20	10.55±0.47
16u	4-CF₃	3.14±0.41	14.39±0.69	10.82±0.96	11.37±1.05	15.05±0.50	14.75±0.85	10.82±0.96
16v	4-CH₃	13.42±0.47	21.50±1.36	19.04±0.83	25.47±1.87	26.91±1.40	29.77±1.81	19.04±0.83
16w	4-OCH₃	6.55±0.75	28.78±1.29	28.87±0.80	9.51±0.97	30.10±1.26	18.31±0.46	28.87±0.80
Gefitinib^b	—	8.92±0.41	8.15±0.28	10.90±0.81	8.19±0.67	7.91±0.22	6.26±0.83	9.20±0.76

Compound	R	IC₅₀/(μmol•L^–1)
Compound	R	PC-3	MCF-7	Eca-109	MGC-803	HGC-27	A549	H1975
16a	H	24.66±0.80	21.32±0.52	25.35±1.28	22.12±1.10	28.51±1.26	29.48±0.77	24.92±1.60
16b	2-F	17.13±0.65	27.03±1.25	24.53±1.62	15.89±0.82	16.40±1.21	26.83±1.17	26.80±1.32
16c	2-Cl	22.27±1.12	>50	>50	32.80±1.65	>50	>50	24.41±1.21
16d	2-Br	16.50±0.53	22.03±0.87	>50	17.07±0.86	35.75±1.55	16.49±0.56	>50
16e	2-CF₃	45.19±1.24	44.22±1.23	43.69±1.55	35.94±1.26	25.07±1.39	45.51±1.19	44.17±1.62
16f	2-CH₃	15.90±1.08	26.23±0.95	32.10±1.85	21.09±1.02	19.00±1.27	39.83±1.61	37.14±1.66
16g	2-OCH₃	36.99±1.63	>50	>50	30.67±1.75	20.09±1.41	28.51±0.45	23.24±0.76
16h	2-OC₂H₅	9.67±0.68	43.55±1.87	47.17±1.81	40.33±1.12	21.47±1.33	29.13±0.65	31.20±1.81
16i	3-Cl-4-F	9.08±0.52	18.90±0.48	13.38±0.32	15.13±0.60	8.26±0.91	18.34±0.60	25.94±0.97
16j	3-Cl	9.38±0.55	18.29±0.68	17.16±0.68	20.66±1.31	18.35±1.26	27.17±0.49	25.20±0.77
16k	3,4-diCl	7.77±0.46	16.00±0.76	9.41±0.22	10.36±1.01	23.86±0.83	26.09±0.85	9.41±0.22
16l	3-Br	2.22±0.15	7.62±0.77	6.21±0.66	4.07±0.79	7.55±0.87	5.93±0.25	8.45±0.41
16m	3-CF₃	3.11±0.15	13.29±0.40	16.30±0.19	5.60±0.29	6.06±0.78	14.71±0.86	21.13±0.81
16n	3-CH₃	7.06±0.67	23.34±0.62	26.65±0.85	14.44±0.75	9.59±1.24	17.22±0.21	24.78±1.69
16o	3-OCH₃	8.81±0.59	26.55±1.64	22.64±1.41	10.84±1.03	22.54±1.33	30.05±1.21	22.64±1.41
16p	3-CN	6.24±0.42	>50	29.23±1.83	3.59±0.55	20.36±0.90	28.12±1.02	29.23±1.83
16q	3-NO₂	3.25±0.51	6.62±0.81	10.00±1.00	6.99±0.84	22.69±0.96	26.60±1.07	10.00±1.00
16r	4-F	7.02±0.58	20.01±0.94	10.28±0.35	19.44±1.28	17.39±0.55	25.28±0.95	10.28±0.35
16s	4-Cl	7.22±0.66	15.06±0.66	15.88±0.56	8.23±0.91	25.75±0.80	21.15±1.35	15.88±0.56
16t	4-Br	9.10±0.40	17.50±0.52	10.55±0.47	17.66±1.24	28.38±0.88	28.95±1.20	10.55±0.47
16u	4-CF₃	3.14±0.41	14.39±0.69	10.82±0.96	11.37±1.05	15.05±0.50	14.75±0.85	10.82±0.96
16v	4-CH₃	13.42±0.47	21.50±1.36	19.04±0.83	25.47±1.87	26.91±1.40	29.77±1.81	19.04±0.83
16w	4-OCH₃	6.55±0.75	28.78±1.29	28.87±0.80	9.51±0.97	30.10±1.26	18.31±0.46	28.87±0.80
Gefitinib^b	—	8.92±0.41	8.15±0.28	10.90±0.81	8.19±0.67	7.91±0.22	6.26±0.83	9.20±0.76

含三氟甲基的2,4,6-三取代喹唑啉衍生物的合成及抗肿瘤活性研究

Synthesis and Antitumor Activity of 2,4,6-Trisubstituted Novel Quinazoline Derivatives Containing Trifluoromethyl

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