摘要
查尔酮属于类黄酮类化合物,它们的天然化合物或合成类似物具有广泛的抗癌活性。本文基于反式-查尔酮的结构,采用药效团拼合原理设计了一系列新型吗啉-查尔酮类衍生物,作为抗宫颈癌的潜在药物,其中包括8个新型查尔酮类衍生物(2a~2h),通过克莱森-施密特反应合成化合物2a~2h,通过^(1)H NMR、^(13)C NMR、HR-MS(ESI)进行结构表征。选用人宫颈癌细胞(HeLa、SiHa、C33-A)和人宫颈正常细胞(H8)为体外模型,采用CCK-8法测定了目标化合物的抗增殖活性,选出候选化合物,并通过分子对接技术研究候选化合物对鼠双微体2(MDM2)蛋白的结合能力。结果表明:大部分化合物对宫颈癌细胞有不同程度的抗增殖活性,其中化合物2a的活性较为突出,对HeLa细胞的IC_(50)值为17.25±0.06μmol/L,优于先导化合物和顺铂;化合物2a对人宫颈正常细胞(H8)毒性较低,IC_(50)值为78.70±1.91μmol/L。分子对接结果表明:化合物2a能较好地与MDM2蛋白结合。
Chalcone belongs to the flavonoid class of compounds,and their natural compounds or synthetic analogues have a wide range of anticancer activities.This article is based on the structure of trans chalcone and uses the principle of pharmacophore assembly to design a series of novel morpholine chalcone derivatives as potential drugs for the treatment of cervical cancer,including 8 novel chalcone derivatives(2a~2h).Compounds 2a~2h were synthesized through the Claisen Schmidt reaction and analyzed by ^(1)H NMR,^(13)C NMR and HR-MS(ESI)was used for structural characterization.Human cervical cancer cells(HeLa,SiHa,C33-A)and human normal cervical cells(H8)were selected as in vitro models.The anti proliferative activity of the target compound was determined using the CCK-8 method,and candidate compounds were selected.The binding ability of the candidate compounds to MDM2 protein in mice was studied using molecular docking technology.The results showed that most compounds had varying degrees of anti proliferative activity against cervical cancer cells,with compound 2a showing more prominent activity.The IC_(50)value for HeLa cells was 17.25±0.06μmol/L,which was superior to the lead compound and cisplatin;Compound 2a has low toxicity to human cervical normal cells(H8),with an IC_(50)value of 78.70±1.91μmol/L.The molecular docking results indicate that compound 2a can bind well to MDM2 protein.
作者
邓欣怡
侯代亮
海尼木·夏木西
木合布力·阿布力孜
DENG Xinyi;HOU Dailiang;Hainimu XIAMUXI;Mourboul ABLISE(College of Pharmacy,Xinjiang Medical University,Urumqi 830011,China)
出处
《合成化学》
2026年第3期159-165,共7页
Chinese Journal of Synthetic Chemistry
基金
19期大学生创新训练计划项目(S202410760042)
新疆医科大学博士科研启动基金项目(2019-16)。
关键词
查尔酮
药物分子设计
化学合成
宫颈癌
MDM2蛋白
chalcone
drug molecular design
chemical synthesis
cervical carcinoma
MDM2 protein
