1,8-二乙酰基大黄酸-(2-溴)-乙酯的合成及对骨肉瘤MG-63细胞的作用研究  

Synthesis of 1,8-diacetyl rhein(2-bromo)-ethyl ester and its role in osteosarcoma MG-63 cells

作　　者：田炜 粟正英 蓝富 李钊全 何盈萱 侯华新[1] 

机构地区：[1]广西医科大学药学院,广西南宁530021

出　　处：《中国药理学通报》2018年第1期55-60,共6页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 81460561)

摘　　要：目的设计并合成新的大黄酸衍生物1,8-二乙酰基大黄酸-(2-溴)-乙酯(大黄酸衍生物B),探讨其对骨肉瘤MG-63细胞的作用和机制。方法以大黄酸为原料合成了1,8-二乙酰基大黄酸-(2-溴)-乙酯,经UV、IR、NMR确定合成产物的结构,并利用HPLC测定其纯度。采用MTT法测定大黄酸和大黄酸衍生物B对骨肉瘤MG-63细胞的体外生长抑制作用;流式细胞仪检测细胞凋亡和细胞周期分布。结果经UV、IR、~1H NMR、^(13)C NMR进行分子结构表征,确证合成的目标化合物为1,8-二乙酰基大黄酸-(2-溴)-乙酯,纯度>98%。MTT结果表明,大黄酸和大黄酸衍生物B对骨肉瘤MG-63细胞的IC_(50)值分别为110.60、25.78μmol·L^(-1)。流式细胞仪检测细胞凋亡和周期结果表明,80μmol·L^(-1)的大黄酸和大黄酸衍生物B对骨肉瘤MG-63细胞的凋亡率分别为(6.87±0.53)%、(48.84±2.20)%,且主要将细胞周期阻滞在S期。结论合成化合物1,8-二乙酰基大黄酸-(2-溴)-乙酯的体外抗肿瘤活性明显优于大黄酸,且具有阻滞骨肉瘤MG-63细胞周期进程和促进其凋亡的作用。AimTo design and synthesize of a new rhein derivative 1,8-diacetyl rhein(2-bromo)-ethyl ester(rhein derivatives B)and explore its effect on osteosarcoma MG-63 cells and the related mechanism.Methods1,8-diacetyl rhein(2-bromo)-ethyl ester was synthesized from rhein and its structure was identified by UV,IR and NMR spectra.The purity of the synthetic product was determined by HPLC.The in vitro anti-proliferative activity of rhein and the synthetic product on osteosarcoma MG-63 cells were determined by MTT assay.Apoptosis and cell cycle distribution were detected by flow cytometry.Results The molecular structure of 1,8-diacetyl rhein(2-bromo)-ethyl ester was confirmed by UV,IR,~1H NMR and^(13)C NMR,and the purity was higher than 98%.The IC_(50)values of rhein and rhein derivatives B on osteosarcoma MG-63 cells were 110.60μmol·L^(-1)and 25.78μmol·L^(-1),respectively.The Resultsof flow cytometry showed that the apoptotic rates of rhein and rhein derivatives B at the concentration of 80μmol·L^(-1)were(6.87±0.53)%and(48.84±2.20)%,respectively,and the cell cycle was mainly arrested in S phase on MG-63 cells.Conclusions The anti-tumor activity of 1,8-diacetyl rhein-(2-bromo)-ethyl ester is superior to that of rhein in vitro,and the mechanisms may be associated with blocking the process of cell cycle of osteosarcoma MG-63 cells and initiating apoptosis.

关 键 词：大黄酸 合成 抗肿瘤活性 骨肉瘤细胞 细胞凋亡 细胞周期 

分 类 号：R284.1[医药卫生—中药学] R329.25[医药卫生—中医学]