布洛芬-香豆素杂合衍生物的合成及抗肿瘤活性研究  

Synthesis and Anti-tumor Activity of Ibuprofen-Coumarin Derivatives

作　　者：罗懿文 汤晓雨 陈伟[3] 罗超 马俊凯 胡扬根[2,5] 王天帅 LUO Yi-wen;TANG Xiao-yu;CHEN Wei;LUO Chao;MA Jun-kai;HU Yang-gen;WANG Tian-shuai(The First Hospital of Clinical Medicine,Hubei University of Medicine,Shiyan,Hubei 442000,China;School of Pharmaceutical Sciences,Hubei University of Medicine,Shiyan,Hubei 442000,China;School of General Practice,Hubei University of Medicine,Shiyan,Hubei 442000,China;School of Basic Medicine,Hubei University of Medicine,Shiyan,Hubei 442000,China;Hubei Key Laboratory of Wudang Local Chinese Medicine,Hubei University of Medicine,Shiyan,Hubei 442000,China)

机构地区：[1]湖北医药学院第一临床学院,湖北十堰442000 [2]湖北医药学院药学院,湖北十堰442000 [3]湖北医药学院全科医学院,湖北十堰442000 [4]湖北医药学院基础医学院,湖北十堰442000 [5]湖北医药学院武当特色中药研究湖北省重点实验室,湖北十堰442000

出　　处：《湖北医药学院学报》2024年第6期587-595,共9页Journal of Hubei University of Medicine

基　　金：湖北省科技厅中央引导地方科技发展专项(2022BGE260);湖北省高等学校优势学科群(生物与医学)项目(2024BMXKQY7);湖北省教育厅科学技术研究项目(B202116);湖北医药学院大学生创新创业训练计划项目(X20231092008)。

摘　　要：目的:设计、合成一系列新型的布洛芬-香豆素杂合衍生物,以期获得高效低毒的新型抗肿瘤药物先导化合物。方法:根据药物拼合原理,以双酰肼(-CONHNHOC-)、噁二唑、酰腙键(-CONHN=C-)作为链接基团,以香豆素和布洛芬为药效基团合成布洛芬-香豆素衍生物。通过^(1)H NMR、^(13)C NMR、HRMS等方法对目标化合物的结构进行表征。运用CCK-8法检测目标化合物对人肝癌细胞(HepG2)以及宫颈癌细胞(Hela)的抗增殖活性。结果:共合成11个目标化合物,所有目标化合物的^(1)H NMR、^(13)C NMR、HRMS都与预期目标化合物结构相一致,超高效液相色谱(UPLC)的测定结果显示化合物纯度均大于95%。体外细胞活性结果表明化合物10c的活性最为优异,对HepG2细胞和Hela细胞的IC_(50)分别为5.044μmol/L和3.593μmol/L,优于合成基团之一布洛芬,优于常用抗肿瘤药物吉非替尼。结论:布洛芬与天然亚活性香豆素拼合具有潜在协同抗肿瘤活性,酰腙基团的引入可能对该类化合物抗肿瘤活性具有重要影响,也为进一步的结构修饰提供思路。Objective To design and synthesize new ibuprofen-coumarin derivatives to obtain new lead compounds for antitumor drugs with high efficiency and low toxicity.Methods According to the drug hybridization,ibuprofen-coumarin derivatives were synthesized using the dihydrazide(-CONHNHOC-),oxadiazole,and hydrazone bond(-CONHN=C-)as linking groups,and coumarin and ibuprofen as pharmacophores.The structure of the target compounds was characterized by^(1)H NMR,^(13)C NMR,and HRMS,and their anti-proliferative activity against human hepatoma cells(HepG2)and cervical cancer cells(HeLa)was detected using the CCK-8 assay.Results Eleven target compounds were synthesized,and their^(1)H NMR,^(13)C NMR,and HRMS were consistent with the predicted stuctures.The ultra-high performance liquid chromatogra⁃phy(UPLC)showed that the purity of the compounds was all greater than 95%.The in vitro cell activity analysis found that compound 10c had the optimal activity,with the IC_(50)of 5.044μmol/L and 3.593μmol/L against HepG2 cells and HeLa cells,respectively,which was better than ibuprofen and the commonly used anti-tumor drug gefitinib.Conclusion Ibuprofen combined with natural subactive coumarin has potential synergistic anti-tumor activity,and hydrazone groups have an important effect on the anti-tumor activity.The present study provides ideas for further structural modifications.

关 键 词：布洛芬 香豆素 拼合 抗肿瘤 

分 类 号：TQ460.1[化学工程—制药化工] R914.5[医药卫生—药物化学]