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,*()   

  1. 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 Liua, Lihui Shaoa,b, Chengpeng Lia, Yayu Zoua, Haitao Longa, Yan Lia, Qiangsheng Gea, Zhenchao Wanga,b(), Guiping Ouyanga,b,c()   

  1. 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)

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