芦荟大黄素α-氨基膦酸酯衍生物的设计合成及抗乙肝病毒活性研究  

Study on the design, synthesis and anti-hepatitis B virus activity of aloe emodin α-aminophosphonate derivatives

作　　者：李俊莹 黄慧冬 蓝富 梁丹丹 庞会锋 李钊全 王春苗[1] 侯华新[1] Li Junying;Huang Huidong;Lan Fu;Liang Dandan;Pang Huifeng;Li Zhaoquan;Wang Chunmiao;Hou Huaxin(Pharmaceutical College,Guangxi Medical University,Nanning 530021,China)

机构地区：[1]广西医科大学药学院,南宁530021

出　　处：《广西医科大学学报》2020年第4期634-639,共6页Journal of Guangxi Medical University

基　　金：国家自然科学基金资助项目(No.81460561)。

摘　　要：目的:设计合成芦荟大黄素α-氨基膦酸酯类衍生物并评价其抗乙肝病毒(HBV)的活性。方法:以芦荟大黄素为先导化合物,利用药效团拼合原理,经氧化、缩合、加成反应合成芦荟大黄素α-氨基膦酸酯衍生物,衍生物结构均经高分辨质谱(HRMS)、核磁共振氢谱(1H-NMR)和核磁共振碳谱(13C-NMR)确证;采用MTT法测定目标化合物对HepG2.2.15细胞的生长抑制作用,酶联免疫吸附测定法(ELISA)测定目标化合物体外抗HBV的活性。结果:成功合成了5个芦荟大黄素α-氨基膦酸酯衍生物,衍生物均具有一定的抗HBV活性,尤其是对HBeAg分泌的抑制。其中衍生物3b、3c对HBeAg的抑制率最高,分别是拉米夫定的1.5倍和先导化合物芦荟大黄素的4.3倍;衍生物3d对HBsAg的抑制率为15.22%,3e的抑制率为23.67%,明显高于先导化合物芦荟大黄素(P<0.05)。结论:芦荟大黄素α-氨基膦酸酯衍生物具有一定的抗HBV活性,有希望成为新的抗HBV候选化合物。Objective: To design and synthesize the derivatives of aloe emodin α-aminophosphonates and to evaluate its anti-hepatitis B virus(HBV)activity.Methods: Using aloe emodin as the lead compound,the aloe emodin α-aminophosphonate derivatives were synthesized by oxidation,condensation,and addition reaction based on the pharmacophore combination principle.The structures of the derivatives were confirmed by high resolution mass spectrum(HRMS),NMR hydrogen spectrum(1 H-NMR),and13 C-NMR.The growth inhibition effect of target compound on HepG2.2.15 cells was determined by MTT,and the anti-HBV activity of the target compound in vitro was determined by enzyme-linked immunoassay(ELISA).Results: Five aloe emodinα-aminophosphonate derivatives were successfully synthesized.All of the derivatives have certain anti-HBV activity,especially on the inhibition of HBeAg secretion.The inhibition rate of derivatives 3 b and 3 c on HBeAg was the highest,which was 1.5 times that of lamivudine and 4.3 times that of aloe emodin.The inhibition rate of derivatives 3 d on HBsAg was 15.22%,and the inhibition rate of 3 e was 23.67%,which was significantly higher than that of aloe emodin(P<0.05).Conclusion: Aloe emodin α-aminophosphonate derivatives have certain anti-HBV activity and are expected to become new anti-HBV candidate compounds.

关 键 词：芦荟大黄素 Α-氨基膦酸酯 合成 抗乙肝病毒活性 

分 类 号：TQ460.1[化学工程—制药化工]