新型小檗碱衍生物的合成及其体外降糖活性
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摘要
为提高小檗碱的水溶性以及降糖活性,对其C-9位进行了结构修饰,合成了6个9-O-小檗碱酯类衍生物(3a～3f),其中3b～3d和3f为新化合物,其结构经~1H NMR,IR和HR-MS (ESI)表征。选用人肝癌细胞(HepG2)建立胰岛素抵抗模型(HepG2-IR),通过MTT法研究了3a～3f的体外降糖活性。结果表明:3a～3f均具有不同程度的降糖活性,其中化合物3a(IC_(50)=0. 044±0. 97 mg·L~(-1))在低浓度0. 08 mg·L~(-1)时,对HepG2-IR细胞葡萄糖消耗量为3. 5 mM,优于小檗碱(2. 75 mM)。
In order to improve the water solubility and hypoglycemic activity of berberine,six berberine derivatives( 3a ～ 3f) were synthesized by structural modifications. Among them,3b ～ 3d and 3f were new compounds. The structures were characterized by ~1H NMR,IR and HR-MS( ESI). The in vitro hypoglycemic activities of 3a ～ 3f in establishing insulin resistance model( HepG2-IR) by Human hepatoma cell( HepG2) were determined by MTT method. The results showed that 3a ～ 3f had different levels of hypoglycemic activity,compound 3a( IC50= 0. 044 + 0. 68 mg·L~(-1)) consumed 3. 5 mM glucose for HepG2-IR cells at low concentration of 0. 08 mg·L~(-1),which was better than berberine( 2. 75 mM).
In order to improve the water solubility and hypoglycemic activity of berberine,six berberine derivatives( 3a ～ 3f) were synthesized by structural modifications. Among them,3b ～ 3d and 3f were new compounds. The structures were characterized by ~1H NMR,IR and HR-MS( ESI). The in vitro hypoglycemic activities of 3a ～ 3f in establishing insulin resistance model( HepG2-IR) by Human hepatoma cell( HepG2) were determined by MTT method. The results showed that 3a ～ 3f had different levels of hypoglycemic activity,compound 3a( IC50= 0. 044 + 0. 68 mg·L~(-1)) consumed 3. 5 mM glucose for HepG2-IR cells at low concentration of 0. 08 mg·L~(-1),which was better than berberine( 2. 75 mM).
引文
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[2] BIAN X,HE L,YANG G. Synthesis and antihyperglycemic evaluation of various protoberberine derivatives[J]. Bioorganic&medicinal chemistry letters,2006,16(5):1380-1383.
[3]朱家颖,岑晓凤,陈星.黄连生物碱降糖活性协同作用研究[J].时珍国医国药,2010,21(9):2282-2284.
[4] CHENG Z,PANG T,GU M,et al. Berberine-stimulated glucose uptake in l6 myotubes involves both ampk and p38 mapk[J]. Biochimica et Biophysica Acta(BBA)-General Subjects, 2006, 1760(11):1682-1689.
[5]陈洪源,明智强,谢佳乐.小檗碱降血糖机制的研究进展[J].食品与药品,2008,10(2):69-71.
[6]殷峻,陈名道,杨颖,等.小檗碱对大鼠脂代谢的影响[J].上海第二医科大学学报,2003,S1:28-30.
[7]邢宇,刘鑫,林园,等.小檗碱药理作用及其临床应用研究进展[J].中国药理学与毒理学杂志,2017,31(06):491-502.
[8] LI Y H,LI Y,YANG P,et al. Design,synthesis,and cholesterol-lowering efficacy for prodrugs of berberrubine[J]. Bioorg Med Chem,2010,18(17):6422-6428.
[9]陈竹. 9-O-小檗碱糖苷同系物的合成及降糖药理活性[D].重庆:西南大学,2011.
[10] BIAN X L,HE L C,YANG G D. Synthesis and antihyperglycemic evaluation of various protoberberine derivatives[J]. Bioorg Med Chem Lett,2006,16:1380-1383.
[11] ZHANG S,WANG X,YIN W,et al. Synthesis and hypoglycemic activity of 9-O-(lipophilic group substituted)berberine derivatives[J]. Bioorganic&Medicinal Chemistry Letters,2016,26(19):4799-4803.
[12] KIM S H,LEE S J,LEE J H,et al. Antimicrobial activity of 9-O-acyl-and 9-O-alkyl berberrubine derivatives[J]. Planta medica,2002,68(3):277-281.
[13]刘丽贤,袁晓,高英.微波辐射合成小檗红碱的工艺研究[J].天然产物研究与开发,2014,26(3):427-430.
[14]杨勇,雷志英,周细国.小檗红碱的化学与药理[J].现代生物医学进展,2013,(5):977-979.