C-3芳苄叉基取代氧氟沙星不饱和酮衍生物的合成及抗肿瘤活性  

Synthesis and Antitumor Activity of C-3 Arylidene-Substituted Ofloxacin Unsaturated Ketone Derivatives

作　　者：张会丽 崔红艳 李珂 黄文龙[3] 胡国强 ZHANG Hui-li;CUI Hong-yan;LI Ke;HUANG Wen-long;HU Guo-qiang(Henan Engineering Technology Research Center of Water Environment and Health,Zhengzhou University 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工程技术研究中心,郑州451150 [2]河南大学临床医学院,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》2021年第6期436-439,共4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：目的进一步优化氟喹诺酮C-3羧基等排体以期提高其抗肿瘤活性。方法基于片段和药效团骨架迁越药物分子设计策略,用C-3羧基的等排体-芳苄叉基与氟喹诺酮骨架的4-羰基构建新的α,β-不饱和酮药效团,设计合成了C-3芳苄叉基取代氧氟沙星不饱和酮目标化合物(3a~3l)。用元素分析和光谱数据确证化合物的结构,MTT法评价体外对SMMC-7721、Capan-1和HL603种癌细胞株的抗增值活性。结果合成的12个新结构不饱和酮目标化合物体外抗肿瘤活性显著强于母体氧氟沙星(1),尤其是氯苯基化合物对Capan-1的活性与对照抗肿瘤药多柔比星相当。结论芳苄叉基替代氟喹诺酮C-3羧基构建的氟喹诺酮不饱和酮化合物有利于提高其抗肿瘤活性,提示α,β-不饱和酮片段可能是有潜力的药效团结构。OBJECTIVE To further optimize the bioisostere of the C-3 carboxylic group for improving antitumor activity of fluoroquinolones.METHODS A fragment or pharmacophore skeleton hopping-based drug molecular design,the title fluoroquinolone unsaturated ketones(3a-3l)were designed and synthesized with an arylidene group both as an isostere of the C-3 carboxylic group and as a fragment ofα,β-unsaturated ketone from ofloxacin(1).The structures of title compounds were characterized by spectral data and elemental analysis,and the in vitro antitumor activity against the three tested tumor cell lines was evaluated by a MTT assay.RESULTS Twelve new title compounds were synthesized,and exhibited more potent than parent 1,especially the chlorophenyl compound showed a comparable activity to comparison doxorubicin against Capan-1 cell lines.CONCLUSION A arylidene group as an isostere of the C-3 carboxylic acid group is beneficial to improve antitumor activity,and it further suggests that anα,β-unsaturated ketone skeleton appears to be a promising pharmacophore for further design of lead antitumor fluoroquinolone.

关 键 词：氟喹诺酮 氧氟沙星 不饱和酮 等排体取代 抗肿瘤活性 

分 类 号：R284[医药卫生—中药学]