3-芳苄叉基-氟喹啉-4-酮衍生物的设计、合成与抗肿瘤活性  

Design,synthesis and antitumor activity of 3-arylidene-4-fluoroquinolin-4-ones as ciprofloxacin derivatives

作　　者：张会丽 姜亚玲 赵辉[2] 黄文龙[3] 胡国强[2] ZHANG Hui-li;JIANG Ya-ling;ZHAO Hui;HUANG Wen-long;HU Guo-qiang(Water Environment and Health of Henan Engineering Technology Research Center,Zhengzhou University of Industrial Technology,Zhengzhou 451150,China;Institute of Drugs,Henan University,Kaifeng 475001,China;Center of Drug Discovery,China Pharmaceutical University,Nanjing 210009,China)

机构地区：[1]郑州工业应用技术学院河南省水环境与健康工程技术研究中心,河南郑州451150 [2]河南大学药物研究所,河南开封475001 [3]中国药科大学新药研究中心,江苏南京210009

出　　处：《药学学报》2020年第9期2170-2175,共6页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助(20872028,21072045);河南省科技发展计划项目资助(162102310392);河南省教育厅科学技术研究重点项目资助(15A350004)。

摘　　要：为发现氟喹诺酮有效结构修饰方法以提高其抗肿瘤活性,基于片段药物分子设计策略,芳苄叉基作为C-3羧基的生物电子排体,并与4-羰基共同构建α,β-不饱和酮骨架,进而设计合成了1-环丙基-6-氟-7-(4-甲基哌嗪-1-基)-3-芳苄叉基-喹啉-4(1H)-酮(4a^4p)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,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,卤代苯基或芳香杂环基化合物的活性强于其他取代的活性,尤其是氯苯基化合物(4j、4k)对Capan-1的IC50与对照药多柔比星相当。为此,芳叉苄基替代C-3羧基所构建的氟喹诺酮不饱和酮有利于提高其抗肿瘤活性,提示α,β-不饱和酮结构或其片段作为C-3羧基的潜在等排体有待进一步发展。To identify an effective structural modification strategy for improving the antitumor activity of fluoroquinolones,sixteen new 1-cyclopropyl-6-fluoro-7-(4-methyl-piperazin-1-yl)-3-arylidene-2,3-dihydroquinolin-4(1H)-ones compounds(4a-4p),were designed and synthesized by a condensation reaction of dihydroquinolin-4-one(3)and aromatic aldehydes,based on the structure of ciprofloxacin(1).Their structures were characterized by elemental analysis and spectral data,and anti-cell proliferative activities against Hep-3B,Capan-1 and HL60 cell lines were measured by an MTT assay.Preliminary pharmacological results indicated that the synthesized target compounds had greater potency than ciprofloxacin(1).SAR revealed that the halophenyl compounds such as fluorophenyl(4h,4i),chlorophenyl(4j,4k)or bromophenyl compounds(4l,4m)and aromatic heterocyclic compounds such as furanly(4n)or pyridyl compounds(4o,4p)demonstrated better activity than the control compounds,and the IC50values of the chlorophenyl compounds 4j and 4k against Capan-1 cell growth were comparable to that of doxorubicin.Thus,a 3-arylidene as an isostere of the C-3 carboxylic acid group appears to be beneficial in improving the antitumor activity of fluoroquinolone.Furthermore,anα,β-unsaturated ketone fragment used as a potential bioisostere of C-3 carboxylic acid group may warrant further study.

关 键 词：氟喹诺酮 二氢喹啉酮 不饱和酮 生物电子等排体 抗肿瘤活性 

分 类 号：R916[医药卫生—药学]