胆酸二聚体化合物的设计、合成及抑制肝细胞凋亡研究  

Design, synthesis and efficacy of bile acid oligomers in inhibiting glycochenodeoxycholic acid-induced hepatocyte apoptosis

作　　者：牛伟萍 牛伟晓 张国宁[1] 朱梅[1] 何红伟[1] 王菊仙[1] NIU Wei-ping;NIU Wei-xiao;ZHANG Guo-ning;ZHU Mei;HE Hong-wei;WANG Ju-xian(Organic Synthesis Chamber,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China)

机构地区：[1]中国医学科学院北京协和医学院医药生物技术研究所合成室,北京100050

出　　处：《中国医药生物技术》2020年第4期370-377,共8页Chinese Medicinal Biotechnology

基　　金：国家自然科学基金(81703366、81673497);中国医学科学院医学科学创新基金(2016-I2M-3-014);“重大新药创制”国家科技重大专项(2019ZX09201001-003)。

摘　　要：目的通过设计合成胆酸二聚体化合物及评价其体外抑制肝细胞凋亡活性,发现新型治疗慢性肝病的候选化合物。方法以熊去氧胆酸、鹅去氧胆酸和奥贝胆酸为起始原料,经亲电取代、脱水缩合、氢化等反应制备目标化合物。通过测定半胱氨酸天冬氨酸蛋白酶3、7的活性水平评价目标化合物体外抑制肝细胞凋亡的活性。结果合成胆酸二聚体化合物24个,体外活性结果表明部分目标化合物具有较好的抑制肝细胞凋亡活性,12个化合物(1a、1e、1h、2a、2c、2e、2f、2g、3a、3c、3d、5a)在20μmol/L浓度下抑制肝细胞凋亡的活性优于阳性对照物牛磺熊去氧胆酸(40.94%)。化合物1a、1e、2a和5a的抑制率分别为75.60%、88.56%、83.25%和105.24%,是阳性对照的2倍。结论熊去氧胆酸和鹅去氧胆酸二聚体具有抑制肝细胞凋亡的活性,奥贝胆酸二聚体无抑制肝细胞凋亡的活性;连接胆酸骨架的连接链长度对活性有明显的影响,其中具有较短连接链(N,N’-二甲基乙二胺、四甲基乙二胺、乙二醇二甲醚)的化合物(1a、1e、2a)的活性优于具有较长连接链(N,N’-二甲基-1,8-辛二胺、2,5,8,11,14,17-六氧十八烷)的化合物(1g、3e)的活性。Objective To design, synthesize and evaluate the efficacy of bile acid oligomers in inhibiting glycochenodeoxycholic acid-induced hepatocyte apoptosis in vitro to provide candidate compounds for the development of drugs for chronic liver disease. Methods Oligomers of bile acids(ursodeoxycholic acid, chenodeoxycholic acid, and obeticholic acid) were synthesized by electrophilic substitution, condensation reaction, hydrogenation, etc. The inhibitory effects of target compounds were evaluated on glycochenodeoxycholic acid-induced hepatocyte apoptosis by measuring caspase3/7 level in vitro. Results Most of the synthesized bile acid oligomers displayed inhibitory activity against hepatocyte apoptosis. Among synthesized compounds, 12 target compounds(1 a, 1 e, 1 h, 2 a, 2 c, 2 e, 2 f, 2 g, 3 a, 3 c, 3 d, 5 a) were more potent than positive control tauroursodeoxycholic(40.94%). Especially, compounds 1 a, 1 e, 2 a, and 5 a exhibited substantial antiapoptotic activity, with inhibition rates of 75.60%, 88.56%, 83.25% and 105.24%, respectively. Conclusion Ursodeoxycholic acid oligomers and chenodeoxycholic acid oligomers, instead of obeticholic acid oligomers, exhibit potent inhibitory effect. Compounds with shorter linker(1 a, 1 e, 2 a) exhibit more obvious activity than that of compounds with longer linker(1 g, 3 e).

关 键 词：合成 抑制肝细胞凋亡 熊去氧胆酸 鹅去氧胆酸 奥贝胆酸 

分 类 号：R914[医药卫生—药物化学] R965[医药卫生—药学]