氮杂环马蹄金素衍生物的合成及抗HBV活性
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摘要
目的:对苗药马蹄金的活性成分马蹄金素[N-(N-苯甲酰基-L-苯丙氨酰基)-O-乙酰基-L-苯丙氨醇,MTS]进行结构修饰,以期获得抗乙肝病毒(HBV)活性更好、毒性更低目标分子。方法:以MTS为先导化合物,设计合成一系列含氮杂环取代的MTS衍生物并对其进行抗HBV活性测试。结果:合成了新的MTS衍生物共计6个,经体外活性筛选结果显示有3个衍生物具有抗HBV活性。结论:化合物4b、6b、6c显示较好的抗HBV活性,说明含氮杂环取代的苗药马蹄金的活性成分MTS衍生物值得深入研究。
Objective:To develop new anti-hepatitis B virus(HBV) agents with high anti-HBV activity from Matijin-Su [N-(N-benzoyl-L-phenylalanyl)-O-acetyl-L-phenylalanol, MTS], isolated from Miao Ethnomedicine Matijin(Dichondra repens Forst). Methods: A series of MTS derivatives with nitrogen-containing heterocycles were designed, synthesized and evaluated for their anti-HBV activity in HepG2 2.2.15 cells. Results: Six new derivatives of MTS were synthesized and three compounds exhibited anti-HBV activity. Conclusion: Derivative 4 b, 6 b and 6 c have good anti-HBV activity,which means that the MTS derivatives with nitrogen-containing heterocycles are worth of further research.
Objective:To develop new anti-hepatitis B virus(HBV) agents with high anti-HBV activity from Matijin-Su [N-(N-benzoyl-L-phenylalanyl)-O-acetyl-L-phenylalanol, MTS], isolated from Miao Ethnomedicine Matijin(Dichondra repens Forst). Methods: A series of MTS derivatives with nitrogen-containing heterocycles were designed, synthesized and evaluated for their anti-HBV activity in HepG2 2.2.15 cells. Results: Six new derivatives of MTS were synthesized and three compounds exhibited anti-HBV activity. Conclusion: Derivative 4 b, 6 b and 6 c have good anti-HBV activity,which means that the MTS derivatives with nitrogen-containing heterocycles are worth of further research.
引文
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[2] Ward H,Tang L,Poonia B,et al.Treatment of hepatitis B virus:an update[J].Future Microbiol,2016,11(12):1581-1597.
[3] Orlando R,Foggia M,Maraolo AE,et al.Prevention of hepatitis B virus infection:from the past to the future[J].Eur J Clin Microbiol Infect Dis,2015,34 (6):1059-1070.
[4] 刘玉明,梁光义,徐必学.苗族药马蹄金化学成分的研究[J].天然产物研究与开发,2003,15(1):15-17.
[5] 梁光义,刘玉明,徐必学.苯丙氨醇类化合物作为制备治疗乙肝药品的应用及其制备方法[P].中国:02160309.X,2002-12-19.
[6] Xu BX,Huang ZM,Liu CX,et al.Synthesis and anti-hepatitis B virus activities of Matijing-Su derivatives[J].Bioorg Med Chem,2009,17(8):3118-3125.
[7] Qiu JY,Xu BX,Huang ZM,et al.Synthesis and biological evaluation of Matijing-Su derivatives as potent anti-HBV agents[J].Bioorg Med Chem,2011,19(18):5352-5360.
[8] Hu ZX,An Q,Li KF,et al.Identification,Synthesis,and Strategy for Minimization of Potential Impurities in the Preclinical Anti-HBV Drug Y101[J].Org Process Res Dev,2013,17(9):1156-1167.
[9] Fan HR,Li RX,Gu Y,et al.Quantitation of bentysrepinine (Y101) in rat plasma by liquid chromatography tandem mass spectrometry:Application to pharmacokinetic study[J].J Chromatogr B,2012,889-890(6):103-109.
[10] 樊慧蓉,慈小燕,李薇,等.抗乙肝候选新药替芬泰的体外转运机制研究[J].药学学报,2016,51(8):1233-1239.
[11] Akhtar J,Khan AA,Ali Z,et al.Structure-activity relationship (SAR) study and design strategies of nitrogen-containing heterocyclic moieties for their anticancer activities[J].Eur J Med Chem,2017,125:143-189.
[12] Korba BE,Gerin JL.Use of a standardized cell culture assay to assess activities of nucleoside analogs against hepatitis B virus replication[J].Antiviral Res,1992,19(1):55-70.