左氧氟沙星3-芳苄叉基-喹啉-4-酮衍生物的合成及抗肿瘤活性

doi:10.11944/j.issn.1000-0518.2020.12.200177

摘要/Abstract

摘要： 为进一步发现提高氟喹诺酮抗肿瘤活性的有效结构修饰策略,基于片段药物设计原理,通过喹啉-4(1H)-酮与芳香醛缩合反应合成了(S)-6-氟-7-(4-甲基-哌嗪-基)-8,1-(1,3-氧丙基)-3-芳苄叉基-2,3-二氢-喹啉-4(1H)-酮(3a-3l)目标化合物。体外抗肿瘤活性结果表明,所合成的12个新化合物的活性均强于母体左氧氟沙星,其中F、Cl、Br取代的卤苯基化合物对人肝癌细胞株(SMMC-7721)和人胰腺癌细胞株(Capan-1)的半数抑制浓度(IC₅₀)低于其它取代基化合物,尤其是氯苯基化合物(3k)与对照抗肿瘤药阿霉素活性相当。为此,芳苄叉基替代C-3羧基构建的3-芳苄叉基-喹啉-4-酮化合物有助于提高氟喹诺酮的抗肿瘤活性,提示α,β-不饱和酮片段作为一个有发展前景的氟喹诺酮的候选修饰基团值得进一步发展。

关键词: 拓扑异构酶, 氟喹诺酮, 喹啉, α,β-不饱和酮, 抗肿瘤活性

Abstract: To further explore an efficient structural modification strategy, a fragment-based drug design, for improving the antitumor activity of fluoroquinolones, twelve novel 3-arylidene-quinolin-4(1H)-ones as levofloxacin derivatives (3a-3l) were synthesized by a condensation reaction of dihydroquinolin-4(1H)-one with aromatic aldehydes. The measured half inhibition concentration(IC₅₀) values using human hepatocellular carcinoma cell lines (SMMC-7721), human pancreatic cancer cell lines (Capan-1) and human leukemia cell line (HL60) cell lines reveal that the antitumor activities of the synthesized compounds are more potent than that of levofloxacin. Meanwhile, the halophenyl compounds such as fluorophenyl (3i, 3j), chlorophenyl (3k) or bromophenyl compounds (3l) display better activities than the control compounds, especially the IC₅₀value of chlorophenyl (3k) against SMMC-7721 and Capan-1 cell is comparable to that of doxorubicin. Thus, 3-arylidene-quinolin-4(1H)-one skeleton instead of quinolin-4(1H)-one-3-carboxylic acid is beneficial to improve the antitumor activities of fluoroquinolones. Furthermore, an α,β-unsaturated ketone fragment as a promising candidate pharmacophore for an alternative modified group of fluoroquinolone needs to be developed.

Key words: topoisomerase, fluoroquinolone, quinoline, α,β-unsaturated ketone, antitumor activity

中图分类号:

O626.2

张会丽, 崔红艳, 黄文龙, 胡国强. 左氧氟沙星3-芳苄叉基-喹啉-4-酮衍生物的合成及抗肿瘤活性[J]. 应用化学, 2020, 37(12): 1426-1431.

ZHANG Huili, CUI Hongyan, HUANG Wenlong, HU Guoqiang. Synthesis and Antitumor Activity of 3-Arylidene-Quinolin-4-Ones Derivatives of Levofloxacin[J]. Chinese Journal of Applied Chemistry, 2020, 37(12): 1426-1431.

参考文献

[1] Liang X,Wu Q,Luan S,et al. A Comprehensive Review of Topoisomerase Inhibitors as Anticancer Agents in the Past Decade[J]. Eur J Med Chem,2019,171:129-168.
[2] Mohammed H H H,Abuo-Rahma G E A A,Abbas S H,et al. Current Trends and Future Directions of Fluoroquinolones[J]. Curr Med Chem,2019,26(17):3132-3149.
[3] Musiol R. An Overview of Quinoline as a Privileged Scaffold in Cancer Drug Discovery[J]. Expert Opin Drug Discov,2017,12(6):583-597.
[4] Suaifan G A R Y,Mohammed A A M. Fluoroquinolones Structural and Medicinal Developments (2013-2018): Where are We Now?[J]. Bioorg Med Chem,2019,27(14):3005-3060.
[5] You Q D,Li Z Y,Huang C H,et al. Discovery of a Novel Series of Quinolone and Naphthyridine Derivatives as Potential Topoisomerase I Inhibitors by Scaffold Modification[J]. J Med Chem,2009,52(18):5649-5661.
[6] Ge R L,Zhao Q,Xie Z L,et al. Synthesis and Biological Evaluation of 6-Fluoro-3-phenyl-7-piperazinyl Quinolone Derivatives as Potential Topoisomerase I Inhibitors[J]. Eur J Med Chem,2016,122:465-474.
[7] XIE Yusuo,GAO Liuzhou,YAN Qiang,et al. Synthesis and Antitumor Activity of Fluoroquinolon-3-yl-s-Triazole Sulfide-ketone Thiosemicarbazone Derivatives of Ofloxacin[J]. Chinese J Appl Chem,2016,33(1):25-31(in Chinese).
谢玉锁,高柳州,闫强,等. 氟喹诺酮C-3均三唑硫醚酮缩氨基硫脲衍生物的合成及抗肿瘤活性[J]. 应用化学,2016,33(1):25-31.
[8] LI Yuanyuan,ZHANG Chengxian,HUANG Wenlong,et al. Synthesis and Antitumor Activities of C-3 Thiazolotriazole Unsaturated Ketone Derivatives of Levofloxacoin[J]. Chinese J Appl Chem,2019,36(6):671-676(in Chinese).
李元元,张呈霞,黄文龙,等. 左氧氟沙星的噻唑并均三唑衍生物的合成及抗肿瘤活性[J]. 应用化学,2019,36(6):671-676.
[9] ZHANG Huili,LI Ke,HUANG Wenlong,et al. Synthesis and Antitumor Activity of N-Arylidene-Rhodanine Levofloxacin Amides[J]. Chinese J Appl Chem,2019,36(8):897-903(in Chinese).
张会丽,李珂,黄文龙,等. N-(5-芳苄叉基饶丹宁)左氧氟沙星酰胺的合成及抗肿瘤活性[J]. 应用化学,2019,36(8):897-903.
[10] Zhuang C L,Zhang W,Sheng C Q,et al. Chalcone:A Privileged Structure in Medicinal Chemistry[J]. Chem Rev,2017,117(12):7762-7810.

[1]	张成路, 暴金迪, 于丰铭, 董文静, 张洋, 宫荣庆, 张彦朋, 张璐. 以喹唑啉酮为核心高选择高灵敏识别次氯酸根离子的荧光探针的合成及应用[J]. 应用化学, 2021, 38(8): 986-994.
[2]	张会丽, 崔红艳, 黄文龙, 胡国强. 饶丹宁甲叉基取代左氧氟沙星衍生物的合成与抗肿瘤活性[J]. 应用化学, 2021, 38(2): 188-194.
[3]	吴学姣, 苟光淋, 杨小兰, 杨家强. 二肽类膦酸酯衍生物的合成与抗肿瘤活性[J]. 应用化学, 2021, 38(1): 36-43.
[4]	张思佳, 徐彩娜, 陈杰, 田华雨, 陈学思. 通过调控肿瘤代谢增强T细胞抗肿瘤活性[J]. 应用化学, 2020, 37(9): 977-984.
[5]	张成路, 孙越冬, 丁言伟, 王静, 刘兴兵, 王楠, 宋府璐. 以喹啉酮为核心高选择快速检测谷胱甘肽的荧光探针[J]. 应用化学, 2020, 37(7): 847-854.
[6]	王硕文, 刘缘, 徐振华, 曾蓉, 陈义, 唐石. 可见光诱导的烯炔和多氟烷基卤环化合成含氟异喹啉酮[J]. 应用化学, 2020, 37(4): 424-432.
[7]	宫益林, 史建涛, 王洋, 陈烨, 丁实, 刘洋, 刘举. 新型吲唑-查尔酮杂合物的合成及抗肿瘤活性[J]. 应用化学, 2019, 36(9): 1015-1022.
[8]	张会丽, 李珂, 黄文龙, 王蕊, 胡国强. N-(5-芳苄叉基饶丹宁)左氧氟沙星酰胺的合成及抗肿瘤活性[J]. 应用化学, 2019, 36(8): 897-903.
[9]	李元元,张呈霞,黄文龙,陈超然,胡国强. 左氧氟沙星的噻唑并均三唑衍生物的合成及抗肿瘤活性[J]. 应用化学, 2019, 36(6): 671-676.
[10]	毛晓明, 唐鑫, 李敏, 李慧, 梁亚琴, 李燕. BiOCl/蒙脱土复合光催化剂的制备及其光催化活性[J]. 应用化学, 2019, 36(4): 474-481.
[11]	张斌,孙雪娇,吕成伟,于世钧. 含8-羟基喹啉侧基聚酯及其锌和铝配合物的合成与荧光性质[J]. 应用化学, 2019, 36(3): 306-313.
[12]	郭照南, 张斌, 孙雪娇, 吕成伟, 于世钧. 新型双8-羟基喹啉配体及其锌、铝配位聚合物的合成和性能[J]. 应用化学, 2018, 35(5): 544-551.
[13]	桂舒雅,熊昊,林智,夏霖亚,钟启升,李东风,侯瑞斌,夏艳. 新型含有金刚烷苯乙烯结构单元化合物的合成和初步抗肿瘤增殖[J]. 应用化学, 2018, 35(4): 420-425.
[14]	王宏雁, 委旭宁. 3-芳硫基-4-羟基香豆素及其类似物的制备[J]. 应用化学, 2018, 35(10): 1184-1189.
[15]	王昭昀, 张萍, 张敏, 焦莉娟. 喹啉取代的氟硼二吡咯染料类三价铁离子荧光探针的合成与性能[J]. 应用化学, 2018, 35(1): 46-52.