3-芳苄叉基噻唑酮-氟喹啉-4-酮氧氟沙星衍生物的合成及抗肿瘤活性  

Synthesis and Antitumor Activity of 3-Arylidenethiazolone-Fluoroquinolin-4-Ones as Ofloxacoin Derivatives

作　　者：李珂 张会丽 崔红艳 黄文龙[3] 胡国强 LI Ke;ZHANG Hui-li;CUI Hong-yan;HUANG Wen-Long;HU Guo-qiang(Henan Enginering Technology Research Center of Water Enwironment and Health,Zhengzhou Universily of Industrial Technology,Zhengzhou 451150,China;School of Clinical Medicine,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河南省工程技术研究中心,郑州451150 [2]河南大学临床医学院,河南开封475001 [3]中国药科大学新药研究中心,南京210009

出　　处：《中国药学杂志》2022年第17期1425-1429,共5页Chinese Pharmaceutical Journal

基　　金：国家自然科学基金项目资助(20872028,21072045);河南省科技发展计划项目资助(162102310392)。

摘　　要：目的 进一步发现氟喹诺酮的有效结构修饰策略以提高其抗肿瘤活性。方法 基于药效团拼合药物设计原理,用噻唑酮作为氧氟沙星C-3羧基的等排体、芳苄叉基为其修饰基,构建了新的3-芳苄叉噻唑酮-氟喹啉-4-酮的氧氟沙星衍生物(6a~6l),其结构经用元素分析和光谱数据确证。MTT方法评价了体外对SMMC-7721、Capan-1和HL60这3种癌细胞株的抗增值活性。结果 12个新结构的氟喹诺酮-3-噻唑不饱和酮目标化合物被合成,其活性显著强于母体氧氟沙星1,其中卤苯基化合物强于其他取代基的活性,尤其是氯苯基化合物(6k)对Capan-1细胞的活性与对照抗肿瘤药多柔比星相当。结论 芳苄叉基噻唑酮替代氟喹诺酮C-3羧基有利于提高其抗肿瘤活性。OBJECTIVE To further discover an efficiently structural modification strategy for improving antitumor activity of fluoroquinolones. METHODS Based on pharmacophore combination drug design principle, novel 3-arylidenethiazolone-fluoroquinolin-4-ones as ofloxacin derivatives(6 a-6 l) were designed and synthesized with a thiazolone ring as an is isostere of the C-3 carboxylic group and an arylidene fragment as a functionalized modifier, respectively. The structures of the synthesized compounds were characterized by spectral data and elemental analysis, and the in vitro antitumor activity against three tumor cell lines was measured by MTT assay. RESULTS Twelve new title compounds were synthesized, and they exhibited more potent in vitro antitumor activity than parent 1. The SAR analysis exhibited that halophenyl compounds displayed better activity than the control compounds, especially the chlorophenyl compound(6 k), of which the ICagainst Capan-1 cell growth was comparable to doxorubicin. CONCLUSION A arylidenethiazolone scaffold appears to be a desirable isostere of the C-3 carboxylic acid group of fluoroquinolones for the improvement of antitumor activity.

关 键 词：氟喹诺酮 氧氟沙星 噻唑 不饱和酮 等排体取代 抗肿瘤活性 

分 类 号：R965[医药卫生—药理学]