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

作　　者：刘威琴 邵利辉 李成朋 邹雅玉 龙海洮 李焱[1] 戈强胜 王贞超[1,2] 欧阳贵平[1,2,3] Liu Weiqina;Shao Lihui;Li Chengpeng;Zou Yayu;Long Haitao;Li Yan;Ge Qiangsheng;Wang Zhenchao;Ouyang Guiping(College of Pharmacy,Guizhou University,Guiyang 550025;State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering,Guizhou University,Guiyang 550025;Drug Synthetic Engineering Laboratory of Guizhou Province,Guizhou University,Guiyang 550025)

机构地区：[1]贵州大学药学院,贵阳550025 [2]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 [3]贵州省合成药物工程实验室,贵阳550025

出　　处：《有机化学》2023年第1期214-222,共9页Chinese Journal of Organic Chemistry

基　　金：国家级大学生创新创业训练计划(No.2020033);国家自然科学基金(No.21867004);贵州省教育厅重点(No.QjhKYZi[2021]041)资助项目。

摘　　要：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、Hep G2、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Hep G2细胞的IC_(50)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IC_(50)值为(10.70±0.78)μmol/L,抑制活性均优于阳性对照药吉非替尼[IC_(50)=(23.33±4.14)μmol/L,IC_(50)=(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.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 IC_(50)value of(E)-N-((2-chloro-1-methyl-1H-indol-3-yl)methylene)-2-(7-fluoro-4-oxoquinazolin-3(4H)-yl)acetohydrazide(H1)on Hep G2was(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)methylene)acetohydrazide(H2)on PC-3 was(10.70±0.78)μmol/L.The inhibitory activities were better than those of positive control drug gefitinib[IC_(50)=(23.33±4.14)μmol/L,IC_(50)=(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 and4’,6-diamidino-2-phenylindole(DAPI)staining experiments showed that the compound H2 could induce apoptosis in PC-3cells,and the cell cycle experiment further demonstrated that the compound H2 arrested PC-3 cells in G0/G1 phase.

关 键 词：3-腙喹唑啉酮 抗肿瘤活性 细胞凋亡 细胞周期 合成 

分 类 号：TQ460.1[化学工程—制药化工]