3-腙喹唑啉酮衍生物的合成及抗肿瘤活性研究

doi:10.6023/cjoc202206004

有机化学 ›› 2023, Vol. 43 ›› Issue (1): 214-222.DOI: 10.6023/cjoc202206004 上一篇下一篇

研究论文

3-腙喹唑啉酮衍生物的合成及抗肿瘤活性研究

刘威琴^a, 邵利辉^a^,^b, 李成朋^a, 邹雅玉^a, 龙海洮^a, 李焱^a, 戈强胜^a, 王贞超^a^,^b^,^*(), 欧阳贵平^a^,^b^,^c^,^*()

a 贵州大学药学院贵阳 550025
b 贵州大学绿色农药与农业生物工程国家重点实验室培育基地贵阳 550025
c 贵州省合成药物工程实验室贵阳 550025

收稿日期:2022-06-02 修回日期:2022-07-14 发布日期:2022-09-08
通讯作者: 王贞超, 欧阳贵平
基金资助:
国家级大学生创新创业训练计划(2020033); 国家自然科学基金(21867004); 及贵州省教育厅重点(Qjh KY Zi[2021]041)

Synthesis and Antitumor Activity of 3-Hydrazone Quinazolinone Derivatives

Weiqin Liu^a, Lihui Shao^a^,^b, Chengpeng Li^a, Yayu Zou^a, Haitao Long^a, Yan Li^a, Qiangsheng Ge^a, Zhenchao Wang^a^,^b(), Guiping Ouyang^a^,^b^,^c()

a College of Pharmacy, Guizhou University, Guiyang 550025
b State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Guizhou University, Guiyang 550025
c Drug Synthetic Engineering Laboratory of Guizhou Province, Guizhou University, Guiyang 550025

Received:2022-06-02 Revised:2022-07-14 Published:2022-09-08
Contact: Zhenchao Wang, Guiping Ouyang
Supported by:
National Undergraduate Training Program for Innovation and Entrepreneurship(2020033); National Nature Science Foundation of China(21867004); Guizhou Provincial Education Department(Qjh KY Zi[2021]041)

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摘要/Abstract

通过活性拼接原理在喹唑啉酮3-位引入腙结构, 使用简单的合成路线合成了一系列3-腙喹唑啉酮衍生物. 目标化合物结构经核磁共振波谱(¹H NMR, ¹³C NMR)和高分辨质谱(HRMS)进行了表征确证. 抗肿瘤活性测试结果表明, 该类化合物对A549、PC-3、HepG2、K562等肿瘤细胞系均表现出有效的抑制活性; 其中(E)-N-((2-氯-1-甲基-1H-吲哚-3-基)亚甲基)-2-(7-氟-4-氧喹唑啉-3(4H)-基)乙酰肼(H1)对HepG2细胞的IC₅₀值为(9.90±1.13) μmol/L, (E)-2-(7-氟-4-氧喹唑啉-3(4H)-基)-N-((2-吗啉代-1-丙基-1H-吲哚-3-基)亚甲基)乙酰肼(H2)对PC-3细胞的IC₅₀值为(10.70±0.78) μmol/L, 抑制活性均优于阳性对照药吉非替尼[IC₅₀=(23.33±4.14) μmol/L, IC₅₀=(12.02±5.39) μmol/L]. 细胞凋亡、4',6-联脒-2-苯基吲哚(DAPI)染色实验以及细胞周期实验表明, 化合物H2能够诱导PC-3细胞发生凋亡, 且将细胞阻滞于G0/G1期.

关键词: 3-腙喹唑啉酮, 抗肿瘤活性, 细胞凋亡, 细胞周期, 合成

A series of 3-hydrazone quinazolinone derivatives were synthesized via introducing hydrazone structure into quinazolinone 3-position by active splicing principle. Their structures were confirmed by nuclear magnetic resonance spectroscopy (¹H NMR, ¹³C NMR) and high resolution mass spectrometry (HRMS). The results of antitumor activity test showed that these compounds have effective inhibitory activity on A549, PC-3, HepG2 and K562 tumor cell lines. The IC₅₀ value of (E)-N-((2-chloro-1-methyl-1H-indol-3-yl)methylene)-2-(7-fluoro-4-oxoquinazolin-3(4H)-yl)acetohydrazide (H1) on HepG2 was (9.90±1.13) μmol/L and (E)-2-(7-fluoro-4-oxoquinazolin-3(4H)-yl)-N-((2-morpholino-1-propyl-1H-indol-3-yl)methyl- ene)acetohydrazide (H2) on PC-3 was (10.70±0.78) μmol/L. The inhibitory activities were better than those of positive control drug gefitinib [IC₅₀=(23.33±4.14) μmol/L, IC₅₀=(12.02±5.39) μmol/L]. In order to explore the anti-tumor mechanism of these compounds, a series of cell biological experiments were set out on PC-3 cells with compound H2. The apoptosis and 4',6-diamidino-2-phenylindole (DAPI) staining experiments showed that the compound H2 could induce apoptosis in PC-3 cells, and the cell cycle experiment further demonstrated that the compound H2 arrested PC-3 cells in G0/G1 phase.

Key words: 3-hydrazone quinazolinone, antitumor activity, cell apoptosis, cell cycle, synthesis

引用此文

刘威琴, 邵利辉, 李成朋, 邹雅玉, 龙海洮, 李焱, 戈强胜, 王贞超, 欧阳贵平. 3-腙喹唑啉酮衍生物的合成及抗肿瘤活性研究[J]. 有机化学, 2023, 43(1): 214-222.

Weiqin Liu, Lihui Shao, Chengpeng Li, Yayu Zou, Haitao Long, Yan Li, Qiangsheng Ge, Zhenchao Wang, Guiping Ouyang. Synthesis and Antitumor Activity of 3-Hydrazone Quinazolinone Derivatives[J]. Chinese Journal of Organic Chemistry, 2023, 43(1): 214-222.

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Compound	(Inhibition rate±SD)^a/%
Compound	A549	PC-3	HepG2	K562
H1	32.99±0.94	17.14±6.33	43.76±7.30	10.72±2.47
H2	4.55±1.00	39.43±2.86	12.24±2.32	29.32±0.44
H3	22.16±5.85	19.70±9.64	42.01±2.20	4.23±0.64
H4	4.11±4.02	10.53±2.17	7.45±2.27	4.87±3.07
H5	8.40±4.85	18.83±5.54	7.42±1.56	4.62±1.17
H6	18.74±2.48	18.74±4.96	32.90±5.94	12.98±2.32
H7	5.71±0.37	18.87±9.09	16.19±5.18	8.00±3.10
H8	31.75±4.93	15.57±4.55	47.31±6.11	6.98±4.08
H9	9.11±6.49	18.14±5.55	16.85±6.13	8.08±3.36
H10	12.27±1.71	13.43±5.18	23.76±0.49	9.66±1.41
H11	27.48±9.42	33.93±0.55	48.63±4.75	8.13±3.45
H12	5.93±2.35	25.73±2.02	8.35±5.07	5.31±1.60
H13	13.50±8.67	22.66±4.67	12.80±4.91	6.93±4.91
H14	27.74±6.13	18.85±3.42	34.72±5.99	5.93±1.69
H15	17.05±3.14	24.12±1.09	8.86±5.02	13.05±5.11
Gefitinib^b	23.79±2.15	30.12±2.95	23.38±1.67	27.08±2.41
5-Fluorouracil^b	41.43±6.54	34.01±6.54	38.08±9.74	47.79±6.82

Compound	(Inhibition rate±SD)^a/%
Compound	A549	PC-3	HepG2	K562
H1	32.99±0.94	17.14±6.33	43.76±7.30	10.72±2.47
H2	4.55±1.00	39.43±2.86	12.24±2.32	29.32±0.44
H3	22.16±5.85	19.70±9.64	42.01±2.20	4.23±0.64
H4	4.11±4.02	10.53±2.17	7.45±2.27	4.87±3.07
H5	8.40±4.85	18.83±5.54	7.42±1.56	4.62±1.17
H6	18.74±2.48	18.74±4.96	32.90±5.94	12.98±2.32
H7	5.71±0.37	18.87±9.09	16.19±5.18	8.00±3.10
H8	31.75±4.93	15.57±4.55	47.31±6.11	6.98±4.08
H9	9.11±6.49	18.14±5.55	16.85±6.13	8.08±3.36
H10	12.27±1.71	13.43±5.18	23.76±0.49	9.66±1.41
H11	27.48±9.42	33.93±0.55	48.63±4.75	8.13±3.45
H12	5.93±2.35	25.73±2.02	8.35±5.07	5.31±1.60
H13	13.50±8.67	22.66±4.67	12.80±4.91	6.93±4.91
H14	27.74±6.13	18.85±3.42	34.72±5.99	5.93±1.69
H15	17.05±3.14	24.12±1.09	8.86±5.02	13.05±5.11
Gefitinib^b	23.79±2.15	30.12±2.95	23.38±1.67	27.08±2.41
5-Fluorouracil^b	41.43±6.54	34.01±6.54	38.08±9.74	47.79±6.82

Compound	(IC₅₀±SD)^a/(µmol•L^–1)
Compound	A549	PC-3	HepG2	K562
H1	19.81±6.14	36.77±7.02	9.90±1.13	—
H2	—	10.70±0.78	—	25.78±4.04
H3	19.89±4.47	22.88±9.30	17.37±0.50	—
H6	25.19±3.97	30.10±12.31	—	—
H8	21.23±1.27	—	12.84±0.61	—
H11	24.07±7.59	28.48±3.03	12.55±1.84	—
H14	30.87±9.27	—	—	—
Gefitinib^b	27.07±4.53	12.02±5.39	23.33±4.14	17.54±4.25
5-Fluorouracil^b	7.71±0.19	8.95±0.87	12.04±5.23	4.78±0.40

Compound	(IC₅₀±SD)^a/(µmol•L^–1)
Compound	A549	PC-3	HepG2	K562
H1	19.81±6.14	36.77±7.02	9.90±1.13	—
H2	—	10.70±0.78	—	25.78±4.04
H3	19.89±4.47	22.88±9.30	17.37±0.50	—
H6	25.19±3.97	30.10±12.31	—	—
H8	21.23±1.27	—	12.84±0.61	—
H11	24.07±7.59	28.48±3.03	12.55±1.84	—
H14	30.87±9.27	—	—	—
Gefitinib^b	27.07±4.53	12.02±5.39	23.33±4.14	17.54±4.25
5-Fluorouracil^b	7.71±0.19	8.95±0.87	12.04±5.23	4.78±0.40

3-腙喹唑啉酮衍生物的合成及抗肿瘤活性研究

Synthesis and Antitumor Activity of 3-Hydrazone Quinazolinone Derivatives

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