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

doi:10.6023/cjoc202205028

Chinese Journal of Organic Chemistry ›› 2022, Vol. 42 ›› Issue (11): 3853-3862.DOI: 10.6023/cjoc202205028 Previous Articles Next Articles

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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Abstract

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

Cite this article

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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Fig. & Tab. 7

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

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

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

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)

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)

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)

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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