白杨素苯并咪唑衍生物合成及其体外抗肿瘤活性的研究  

A Study on Synthesis of Chrysinbenzimidazole Derivatives and Its Anti-tumor Activity in vitro

作　　者：聂少林 王海洋 许泽峰 邓湘萍 王哲[1] 曹轩[1] 唐国涛[1] NIE Shaolin;WANG Haiyang;XU Zefeng;DENG Xiangping;WANG Zhe;CAO Xuan;TANG Guotao(Institute of Pharmacy and Pharmacology,Hunan Province Cooperative Innovation Center for Molecular/Target New Drug Study,University of South China,Hengyang,Hunan,421001,China;z The Second Hospital of Zhuzhou City,Pharmacy de-partment,Zhuzhou,Hunan,412005,China)

机构地区：[1]南华大学药物药理研究所/湖南省分子靶标新药研究协同创新中心,湖南衡阳421001 [2]株洲市二医院药剂科,湖南株洲412005

出　　处：《肿瘤药学》2018年第4期531-536,共6页Anti-Tumor Pharmacy

摘　　要：目的合成一系列白杨素苯并咪唑衍生物并研究其体外抗肿瘤活性。方法以白杨素为起始原料,通过醚化反应引入苯并咪唑衍生物,合成9个白杨素苯并咪唑衍生物3~11。采用MTT法检测化合物3~11对人源性胃癌细胞MGC-803,乳腺癌细胞MCF-7、肝癌细胞Hep G-2和鼠源性胃癌细胞MFC的体外抗增殖活性。流式细胞仪检测化合物10作用24 h后细胞的凋亡和周期情况。结果合成的白杨素苯并咪唑衍生物均用1H NMR,MS确证。相比于乳腺癌细胞MCF-7和肝癌细胞Hep G-2,化合物3~11对胃癌细胞MGC-803的抗增殖活性更好。化合物4、6、7、9、10、11对胃癌细胞MGC-803的抗增殖活性优于白杨素,化合物7、10、11对胃癌细胞MGC-803和胃癌细胞MFC的抗增殖活性优于阳性对照药5-氟尿嘧啶,其中化合物10对鼠源性胃癌细胞MFC的IC 50值为(25.72±3.95)μM。用不同浓度的化合物10处理后细胞凋亡率明显增加,G0/G1期细胞逐渐增多,而S期和G2/M期细胞逐渐减少。结论化合物10抗肿瘤细胞增殖活性最强,能以剂量依赖方式诱导MFC细胞凋亡,并使细胞停滞于G0/G1期。化合物10可作为抗肿瘤候选药物进一步优化和评价。Objective A series of chrysin benzimidazole derivatives were synthesised and evaluated for their anti-tumor activity in vitro. Methods In this study, benzimidazole derivatives were introduced into chrysin by the etherification reaction with chrysin as raw material, synthesizing 9 chrysin benzimidazole derivatives 3-23. The anti-proliferative activity of chrysin benzimidazole derivatives 3-23 against MGC-803 cells, MCF-7 cells and HepG2 cells was studied by MTT colorimetric assay. Cell apoptosis and cell cycle distribution was inves- tigated by flow cytometry after treatment with compound 10 at different concentrations for 24 h. Results All of the synthetic compounds gave satisfactory analytical and spectroscopic data confirmed by 1H NMR and MS, which were in full accordance with their depicted structures. On the whole, the compounds showed better growth inhibition in MGC-803 cells compared with breast cancer cell MCF-7 and hepatoma carcinoma cell HepG-2. Compound 4, 6, 7, 9, 10 and 11 showed better inhibitory activities than chrysin. What＇ s more, compounds 7, 10 and 11 showed better inhibitory activity against gastric cancer cell MGC-803 and MFC than the positive control 5-Fu. The ICs0 value range of compound 10 against MFC cells was （25.72 ＋ 3.95） ~tM. Alter treatment with compound 10 at different concentrations for 24 h, the per- eentage of apoptotie cells and G0/G1 phase cells obviously increased but S and G2/M phase cells gradually decreased. Conclusion Com- pound 10 exhibited the most potent anti-proliferative activity, and induced apoptosis of MFC cells in a dose-dependent manner and caused the cell cycle to be arrested in the G0/G1 phase. It could be a potential antieaneer agent after further optimization and evaluation.

关 键 词：白杨素 苯并咪唑 合成 体外 抗肿瘤 

分 类 号：R73-34[医药卫生—肿瘤]