Synthesis and Antitumor Activity of 3-Hydrazone Quinazolinone Derivatives

doi:10.6023/cjoc202206004

Chinese Journal of Organic Chemistry ›› 2023, Vol. 43 ›› Issue (1): 214-222.DOI: 10.6023/cjoc202206004 Previous Articles Next Articles

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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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Abstract

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

Cite this article

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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Fig. & Tab. 7

References 31

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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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