含噻唑结构的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/cjoc202205028

有机化学 ›› 2022, Vol. 42 ›› Issue (11): 3853-3862.DOI: 10.6023/cjoc202205028 上一篇下一篇

研究论文

含噻唑结构的2,4,6-三取代喹唑啉衍生物的合成及抗肿瘤活性研究

戴洪林^a^,^b, 司晓杰^a^,^b, 池玲玲^a^,^b, 王浩^a^,^b, 高潮^a^,^b, 汪正捷^a^,^b, 刘丽敏^a^,^b, 马家婕^a^,^b, 于富强^a^,^b, 刘宏民^a^,^b^,^c^,^d^,^*(), 可钰^a^,^b^,^c^,^d^,^*(), 张秋荣^a^,^b^,^c^,^d^,^*()

^a郑州大学药学院郑州 45001
^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:2022-05-18 修回日期:2022-06-28 发布日期:2022-07-05
通讯作者: 刘宏民, 可钰, 张秋荣
基金资助:
国家自然科学基金(U1904163)

Synthesis and Antitumor Activity Evaluation of 2,4,6-Trisubstituted Quinazoline Derivatives Containing Thiazole Structure

Honglin Dai^a^,^b, Xiaojie Si^a^,^b, Lingling Chi^a^,^b, Hao Wang^a^,^b, Chao Gao^a^,^b, Zhengjie Wang^a^,^b, Limin Liu^a^,^b, Jiajie Ma^a^,^b, Fuqiang Yu^a^,^b, Hongmin Liu^a^,^b^,^c^,^d(), Yu Ke^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 and Safety Evaluation, Zhengzhou 450001
^cKey Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou 450001
^dState Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou 450052

Received:2022-05-18 Revised:2022-06-28 Published:2022-07-05
Contact: Hongmin Liu, Yu Ke, Qiurong Zhang
Supported by:
National Natural Science Foundation of China(U1904163)

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摘要/Abstract

设计合成了一系列含有噻唑结构的2,4,6-三取代喹唑啉衍生物, 并测定了他们对PC-3(人前列腺癌细胞系)、H1975(人肺腺癌细胞系)、MGC-803(人胃癌细胞系)和A549(人非小细胞肺癌细胞系)四种人肿瘤细胞的抗增殖活性. 其中, 3-((2-(((2-氯噻唑-5-基)甲基)硫代)-6-甲氧基喹唑啉-4-基)氨基)苯甲氰(14i)是抗MGC-803细胞增殖活性最好的化合物, IC₅₀为(4.54±0.32) μmol/L, 优于阳性对照5-氟尿嘧啶(5-FU) [(8.14±0.68) μmol/L], 其作用机理实验显示化合物14i具有抑制MGC-803细胞克隆增殖和迁移, 以及可诱导细胞凋亡的作用, 并且可以将MGC-803细胞周期阻滞在DNA合成后期/有丝分裂期(G2/M). 这些结果表明, 化合物14i可作为一种潜在的抗肿瘤药物.

关键词: 噻唑, 喹唑啉, 抗肿瘤活性, 合成

A series of 2,4,6-trisubstituted quinazoline derivatives containing thiazole group were designed and synthesized, and their antiproliferative activities against human tumor cell lines (PC-3, H1975, MGC-803 and A549) were determined. 3-((2-(((2-chlorothiazol-5-yl)methyl)thio)-6-methoxyquinazolin-4-yl)amino)benzonitrile (14i) was identified as the most potent compound in antiproliferation against MGC-803 cells, with the value was (4.54±0.32) μmol/L, which was better than the positive control 5-fluorouracil (5-FU) [(8.14±0.68) μmol/L]. Further mechanistic studies showed that compound 14i could inhibit the clonal proliferation and migration of MGC-803 cells. In addition, compound 14i could induce apoptosis of MGC-803 cells and arrest the cell cycle at late period of DNA synthesis/mitotic phase (G2/M) phase. These results indicated that compound 14i could as a potential antitumor drug.

Key words: thiazole, quinazoline, antitumor activity, synthesis

引用此文

戴洪林, 司晓杰, 池玲玲, 王浩, 高潮, 汪正捷, 刘丽敏, 马家婕, 于富强, 刘宏民, 可钰, 张秋荣. 含噻唑结构的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(11): 3853-3862.

Honglin Dai, Xiaojie Si, Lingling Chi, Hao Wang, Chao Gao, Zhengjie Wang, Limin Liu, Jiajie Ma, Fuqiang Yu, Hongmin Liu, Yu Ke, Qiurong Zhang. Synthesis and Antitumor Activity Evaluation of 2,4,6-Trisubstituted Quinazoline Derivatives Containing Thiazole Structure[J]. Chinese Journal of Organic Chemistry, 2022, 42(11): 3853-3862.

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图/表 7

图1. 2,4,6-取代喹唑啉衍生物的设计

Figure 1. Design rationale of 2,4,6-substituted quinazoline derivatives

图式1. 2,4,6-三取代喹唑啉衍生物的合成

Scheme 1. Synthesis of 2,4,6-substituted pyrimidine derivatives Reaction conditions and reagents: (a) SOCl2, 90 ℃, 2 h. (b) Ammonium hydroxide, 0 ℃, 10 min. (c) Iron, NH4Cl, CH3OH, H2O, 80 ℃, 4 h. (d) KOH, CS2, 85 ℃, 48 h. (e) 2-Chloro-5-chloromethylthiazole, KOH, 90 ℃, 1 h. (f) Phosphorus oxychloride, 65 ℃, 2 h. (g) Differently substituted anilines, K2CO3, DMF, 90 ℃, 0.5 ~ 4 h.

Compd.	R	IC₅₀^a/(μmol•L^－1)
Compd.	R	PC-3	H1975	MGC-803	A549
14a	H	43.33±1.64	35.57±1.55	>50	25.23±1.04
14b	2-F	18.37±1.26	>50	12.16±1.09	23.72±1.38
14c	3-F	12.24±1.09	46.54±1.67	14.06±1.15	29.27±1.47
14d	4-F	34.95±1.54	31.20±1.49	13.60±1.13	23.02±1.36
14e	2-Cl	47.87±1.68	>50	>50	>50
14f	3-Cl	32.87±1.52	35.39 ± 1.55	10.77±1.03	15.58±1.19
14g	4-Cl	22.78±1.36	34.60±1.54	16.24±1.21	20.90±1.32
14h	2-CN	13.42±1.08	20.42±0.95	13.93±1.38	19.07±1.19
14i	3-CN	7.95±0.63	14.82±0.82	4.54±0.32	9.22±0.57
14j	4-CN	10.94±1.13	17.06±0.89	8.38±1.22	10.29±1.42
14k	3-CF₃	25.03±1.40	24.44±1.39	25.89±1.41	19.28±1.29
14l	4-CF₃	17.42±1.24	16.47±1.22	11.87±1.08	15.88±1.20
14m	2-CH₃	43.64±1.64	16.05±1.21	>50	26.78±1.43
14n	3-CH₃	15.99±1.20	35.83±1.55	41.38±1.62	41.41±1.62
14o	4-CH₃	>50	41.93±1.62	>50	>50
14p	2-OCH₃	>50	>50	>50	>50
14q	3-OCH₃	>50	37.45±1.57	>50	>50
14r	4-OCH₃	>50	>50	>50	>50
14s	2-C₂H₅	24.84±1.40	16.66±1.22	>50	41.00±1.61
14t	4-C₂H₅	>50	34.77±1.54	>50	>50
14u	2-OC₂H₅	>50	>50	>50	>50
14v	4-OC₂H₅	>50	>50	>50	>50
14w	3-NHCOCHCH₂	29.86±1.48	48.26±1.68	17.14±1.23	27.82±1.44
5-FU^b	—	6.89±0.65	9.22±0.76	8.14±0.68	10.53±1.03

表1. 目标化合物14a~14w体外抗增殖活性数据

Table 1. In vitro antiproliferative activity data of compounds 14a~14w

图2. (A)化合物14i对MGC-803细胞集落形成的影响; (B)统计直方图表示集落形成抑制率(与对照组相比, **P<0.05, ***P<0.001); (C)化合物14i对MGC-803细胞迁移和侵袭的影响; (D)统计直方图表示细胞数(与对照组相比, **P<0.05, ***P<0.001)

Figure 2. (A) Effects of compounds 14i on the colony formation for MGC-803 cells; (B) statistic histogram indicated the colony formation inhibition rate (compared with the control group, **P<0.05, *** P<0.001); (C) effects of compounds 14i on the migration and invasion for MGC-803 cells; (D) statistic histogram display the number of cells (compared with the control group, **P<0.05, ***P<0.001)

图3. 化合物14i对MGC-803细胞核形态的影响(图中的箭头表示细胞核皱缩或破裂的细胞)

Figure 3. Effect of compound 14i on nuclear morphology for MGC-803 cells (the arrows in the figure display the cells whose nuclei have shrunk or broken)

图4. (A)化合物14i与MGC-803细胞共同孵育48 h对凋亡的影响; (B)统计直方图表示凋亡细胞的百分比(与对照组相比, **P<0.05, ***P<0.001).

Figure 4. (A) The effect on cellular apoptosis after MGC-803 cells were incubated with compound 14i for 48 h; (B) statistic histogram indicated the percentages of apoptotic cells (Compared with the control group, **P<0.05, ***P<0.001)

图5. (A)化合物14i对MGC-803细胞周期的影响; (B)统计直方图表示细胞周期分布

Figure 5. (A) Effect of compound 14i on cell cycle for MGC-803 cells; (B) statistic histogram display cell cycle distribution

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含噻唑结构的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 Evaluation of 2,4,6-Trisubstituted Quinazoline Derivatives Containing Thiazole Structure

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