熊果酸拼接抗肿瘤活性分子衍生物的合成及抗肺癌活性研究  

Synthesis and antiproliferation activities of new ursolic acid spliced antitumor active molecule derivatives on lung cancer

作　　者：杨俊 梁玉清 黄蕊 梁光平 姚震 刘雄伟 刘雄利[3] YANG Jun;LIANG Yu-qing;HUANG Rui;LIANG Guang-ping;YAO Zhen;LIU Xiong-wei;LIU Xiong-li(Pharmacy Department,Zunyi Medical And Pharmaceutical College,Zunyi 563006,China;College of Pharmacy,Guizhou University of Traditional Chinese Medicine,Guiyang 550025,China;National&Local Joint Engineering Research Center for the Exploition of Homology Resources of Medicine and Food,Guizhou University,Guiyang 550025,China)

机构地区：[1]遵义医药高等专科学校药学系,贵州遵义563006 [2]贵州中医药大学药学院,贵州贵阳550025 [3]贵州大学西南药食两用资源开发利用技术国家地方联合工程研究中心,贵州贵阳550025

出　　处：《化学研究与应用》2024年第10期57-67,共11页Chemical Research and Application

基　　金：遵义市科技合作计划项目(遵市科合HZ字(2023)459号,(2022)146号,(2023)454号)资助;贵州省第六批高层次创新型人才遴选培养计划-千层次人才项目(黔委人领办发[2022]3号)资助

摘　　要：研究熊果酸拼接抗肿瘤活性分子衍生物的抗肺癌活性及其机制。以熊果酸为原料,琥珀酰基作为linker,分别与鬼臼毒素、吲哚、奎宁、喜树碱、双氢青蒿素进行拼接,得到5个目标化合物。采用CCK-8法评价其对人非小细胞肺癌细胞株(A549)、人肺腺癌耐顺铂细胞株(A549/DDP)的抗增殖活性;不同浓度的化合物3d作用于A549/DDP后,AO/EB双荧光染色法检测,Annexin V-FITC/PI双染法检测细胞凋亡,细胞划痕实验检测细胞的迁移能力,PI染色法检测细胞周期。化合物3d对A549/DDP的体外抗增殖活性优于阳性对照药物(顺铂、依托泊苷),且表现较好的选择性,初步机制研究表明:化合物3d作用于A549/DDP之后,呈正常形态的活细胞不断减少,呈核染色质固缩状等形态的细胞不断增加,显著地阻滞A549/DDP细胞G_(2)/M期,干扰细胞分裂过程诱导其发生凋亡,同时抑制其细胞迁徙能力,且与化合物3d的浓度呈正相关。The inhibitory effects of ursolic acid spliced antitumor active molecule derivatives on lung cancer cells and its mecha-nisms was studied in this paper.Using ursolic acid as raw material and succinyl group as linker,five final compounds were obtained by reacting with podophyllotoxin,indole,quinine,camptothecin,and dihydroartemisinine,respectively.Its antiproliferative activity in vitro against human non-small cell lung cancer cells(A549 cells)and cisplatin-resistant human lung adenocarcinoma cells(A549/DDP cells)was evaluated using the cell counting kit-8(CCK-8).After A549/DDP cells were treated with compound 3d at different concentrations,the nuclear state,apoptosis,migration ability of cells and cell cycle were individually detected by AO/EB double flu-orescence staining,Annexin V-FITC/PI double staining,wound healing assay and Propidium Iodide staining.Compound 3d exhibi-ted better in the vitro antiproliferative activity against A549/DDP than the positive control drug(cisplatin,etoposide),and showed good selectivity.Preliminary mechanistic studies indicated that after the treatment of compound 3d on A549/DDP,the number of cells in normal form decreased,while the number of cells in the form of nuclear chromatin condensation continued to increase.A549/DDP cells were significantly delayed in the G_(2)/M phase,were interfered in the cell division process,to induce apoptosis,in-hibiting the migration ability of cells,which was positively correlated with the concentration of compound 3d.

关 键 词：熊果酸 奎宁 喜树碱 吲哚 青蒿素 人肺癌耐顺铂株A549/DDP 

分 类 号：O626[理学—有机化学]