药学学报, 2019, 54(4): 687-691
引用本文:
王娜, 张会丽, 陈超然, 黄文龙, 胡国强. 氟喹诺酮C-3芳苄叉基噻唑酮衍生物的合成与抗肿瘤活性[J]. 药学学报, 2019, 54(4): 687-691.
WANG Na, ZHANG Hui-li, CHEN Chao-ran, HUANG Wen-long, HU Guo-qiang. Synthesis and antitumor activity of fluoroquinolone C-3 arylidene thiazolone derivatives from ciprofloxacin[J]. Acta Pharmaceutica Sinica, 2019, 54(4): 687-691.

氟喹诺酮C-3芳苄叉基噻唑酮衍生物的合成与抗肿瘤活性
王娜1, 张会丽2, 陈超然3, 黄文龙4, 胡国强1
1. 河南大学药物研究所, 河南 开封 475001;
2. 郑州工业应用技术学院药学院, 河南 郑州 451150;
3. 河南大学护理与健康研究所, 河南 开封 475004;
4. 中国药科大学新药研究中心, 江苏 南京 210009
摘要:
为扩展氟喹诺酮由抗菌活性向抗肿瘤活性转化的结构修饰策略,以噻唑酮为C-3羧基的生物电子排体,芳苄叉基为其功能修饰基,设计合成了1-环丙基-6-氟-7-(4-甲基哌嗪-1-基)-3-[5-芳苄叉基-噻唑-4(5H)-酮-2-基]-喹啉-4(1H)-酮(7a~7p)目标化合物,其结构经元素分析和光谱数据确证。体外抗肿瘤实验结果表明,16个目标化合物对Hep-3B、Capan-1和HL60三种实验癌细胞株的活性显著高于母体环丙沙星,其中,卤代苯苄叉基或芳香杂环苄叉基化合物的活性强于其他取代的活性,尤其是吡啶取代化合物(6o6p)对Capan-1的IC50与对照药多柔比星相当。为此,芳叉苄基修饰的噻唑酮替代C-3羧基有利于提高氟喹诺酮的抗肿瘤活性。
关键词:    氟喹诺酮      噻唑      不饱和酮      生物电子等排体      抗肿瘤活性     
Synthesis and antitumor activity of fluoroquinolone C-3 arylidene thiazolone derivatives from ciprofloxacin
WANG Na1, ZHANG Hui-li2, CHEN Chao-ran3, HUANG Wen-long4, HU Guo-qiang1
1. Institute of Drugs, Henan University, Kaifeng 475001, China;
2. School of Pharmacy, Zhengzhou University of Industrial Technology, Zhengzhou 451150, China;
3. Institute of Nursing and Health, Henan University, Kaifeng 475004, China;
4. Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
Abstract:
To expand an efficient strategy for the conversion of antibacterial activity of fluoroquinolones into an antitumor activity, sixteen new compounds, 1-cyclopropyl-6-fluoro-7-(4-methyl-piperazin-1-yl)-3-(5-arylidene-thiazol-4(5H)-one-2-yl)-quinolon-4(1H)-ones (7a-7p), were designed and synthesized with a thiazolone ring and an arylidene moiety as an isostere and modified group, respectively, from ciprofloxacin. Their structures were characterized by elemental analysis and spectral data. The in vitro antitumor activity of the synthesized compounds were measured using Hep-3B, Capan-1 and HL60 cell lines and were found to be more potent than ciprofloxacin. Meanwhile, the SAR revealed that the halogenated phenyl compounds such as fluorophenyl (7h, 7i), chlorophenyl (7j, 7k) or bromophenyl compounds (7l, 7m), and aromatic heterocyclic substitution such as furyl (6n) or pyridyl compounds (6o, 6p) displayed better activity than the control compounds, especially the IC50 values of pyridyl compounds 6o and 6p against Capan-1 cell growth was comparable to doxorubicin. Thus, an arylidene-modified thiazolone scaffold as the replacement of the C-3 carboxylic acid group appears to be an alternative route for an improved antitumor activity of fluoroquinolones.
Key words:    fluoroquinolone    thiazole    unsaturated ketone    bioisostere    antitumor activity   
收稿日期: 2019-01-11
DOI: 10.16438/j.0513-4870.2019-0036
基金项目: 国家自然科学基金资助项目(20872028,21072045);河南省科技发展计划项目(162102310392);河南省教育厅科学技术研究重点项目(15A350004).
通讯作者: 陈超然, 胡国强
Email: kfccr@126.com;lantsing@163.com,hgqxy@sina.com.cn
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