8,8′-亚甲基双黄芩素的合成及其抗肿瘤作用机制  

Synthesis and antitumor mechanism of 8,8'-methylene bis baicalein

作　　者：陈帅[1] 许晓燕[2,3,4] 罗森 汤依娜[1,4] 王笳[1] 袁崇均 余梦瑶[2,3,4] CHEN Shuai;XU Xiaoyan;LUO Sen;TANG Yina;WANG Jia;YUAN Chongjun;YU Mengyao(Institute of Pharmacy,Sichuan Academy of Chinese Medical Sciences,Sichuan Chengdu 610041,China;Institute of Fungus Medicinal Materials,Sichuan Academy of Chinese Medical Sciences,Sichuan Chengdu 610041,China;Laboratory for Systematic Research and Development of Fungus Medicinal Materials of Sichuan Province Administration of Traditional Chinese Medicine,Sichuan Chengdu 610041,China;Sichuan Provincial Key Laboratory of Quality and Innovation Research of Chinese Materia Medica,Sichuan Chengdu 610041,China)

机构地区：[1]四川省中医药科学院中药药学研究所,四川成都610041 [2]四川省中医药科学院菌类药材研究所,四川成都610041 [3]四川省中医药管理局菌类药材系统研究与开发实验室,四川成都610041 [4]中药材品质及创新中药研究四川省重点实验室,四川成都610041

出　　处：《中国医院药学杂志》2023年第18期2043-2050,共8页Chinese Journal of Hospital Pharmacy

基　　金：四川省省级科研院所基本科研业务费项目(编号:2023JDKY0027);四川省科技厅重点研发项目(编号:2020YFS0370)。

摘　　要：目的:以黄芩素为先导化合物合成双黄酮化合物8,8′-亚甲基双黄芩素(MBB),并探讨其抗肿瘤活性和作用机制。方法:通过傅-克反应合成MBB,并根据红外、紫外、质谱、核磁等数据确定此化合物的结构。采用MTT法,测定MBB对HCT116、A549、MCF-7、HepG2、NCI-N87的增殖抑制IC_(50)。利用H22荷瘤小鼠模型,评价MBB抑制H22肿瘤生长的作用。采用Annexin V-FITC/PI双染法,研究MBB对HCT116细胞的凋亡诱导作用。采用基于PI染色的流式细胞术,测定MBB对HCT116细胞周期的影响。运用DCFH-DA法,检测MBB对HCT116细胞ROS生成的作用。结果:成功合成MBB,并对其结构进行表征。MBB对HCT116、A549、MCF-7、HepG2、NCI-N87的增殖抑制IC_(50)分别为1.19,15.36,7.72,2.13,2.64μg·mL^(-1),并在25 mg·kg^(-1)和50 mg·kg^(-1)剂量下能够显著抑制H22肿瘤生长(P<0.05),抗肿瘤活性优于先导化合物黄芩素。MBB可剂量、时间依赖性地诱导HCT116细胞发生细胞凋亡,阻滞细胞周期,促进胞内ROS生成。结论:基于傅-克反应以黄芩素为先导化合物合成了MBB,其具有较强体内、体外抗肿瘤作用,其作用机制与诱导细胞凋亡,阻滞细胞周期,促进胞内ROS生成有关。OBJECTIVE To synthesis the bisflavone compound 8,8'-methylene bis baicalein(MBB)by using baicalein as a lead compound and investigate its antitumor activity and mechanism.METHODS MBB was synthesized by Friedel-Crafts alkylation,and its structure was determined by IR,UV,MS and NMR.The proliferation inhibition IC_(50)of MBB on HCT116,A549,MCF-7,HepG2 and NCI-N87 was determined by MTT method.The H22 tumor-bearing mouse model was used to evaluate the inhibitory effect of MBB on tumor growth.Apoptosis induction by MBB in HCT116 cells was investigated by annexin V-FITC/PI double staining.The effect of MBB on the cell cycle of HCT116 cells was determined by flow cytometry based on PI staining.The effect of MBB on ROS generation in HCT116 cells was examined by DCFH-DA assay.RESULTS MBB was successfully synthesized and its structure was characterized.The proliferation inhibition IC_(50)of MBB on HCT116,A549,MCF-7,HepG2 and NCI-N87 was 1.19,15.36,7.72,2.13,2.64μg·mL^(-1),respectively.And it could significantly inhibit the growth of H22 tumor at the dose of 25 mg·kg^(-1)and 50 mg·kg^(-1)(P<0.05).Its antitumor effect was superior to the lead compound baicalein.MBB could induce apoptosis,arrest cell cycle and promote intracellular ROS generation in HCT116 cells in a dose-and time-dependent manner.CONCLUSION Based on the Friedel-Crafts alkylation,MBB was synthesized by using baicalein as a lead compound.It has strong anti-tumor effect both in vivo and in vitro,and its mechanism is related to induction of apoptosis,cell cycle arrest and promotion of intracellular ROS production.

关 键 词：8 8′-亚甲基双黄芩素 肿瘤 细胞凋亡 细胞周期 活性氧 

分 类 号：R28[医药卫生—中药学] R914[医药卫生—中医学]