药学学报, 2022, 57(4): 1095-1105
引用本文:
黄维杰, 况安香, 邵晓霜, 曾晓萍, 梁光义, 孟雪玲, 徐必学. 氟代马蹄金素二肽模拟物的合成及其抗HBV活性初探[J]. 药学学报, 2022, 57(4): 1095-1105.
HUANG Wei-jie, KUANG An-xiang, SHAO Xiao-shuang, ZENG Xiao-ping, LIANG Guang-yi, MENG Xue-ling, XU Bi-xue. Synthesis and anti-HBV activity of fluorinated dipeptidomimetics of Matijin-Su[J]. Acta Pharmaceutica Sinica, 2022, 57(4): 1095-1105.

氟代马蹄金素二肽模拟物的合成及其抗HBV活性初探
黄维杰1,2,4, 况安香1,2,3, 邵晓霜1,2,3, 曾晓萍1,2, 梁光义1,2, 孟雪玲1,2, 徐必学1,2*
1. 贵州医科大学省部共建药用植物功效与利用国家重点实验室, 贵州 贵阳 550014;
2. 贵州省中国科学院天然产物化学重点实验室/贵州省天然药物工程研究中心, 贵州 贵阳 550014;
3. 贵州中医药大学, 贵州贵阳 550025;
4. 贵州医科大学药学院, 贵州 贵阳 550025
摘要:
为拓展马蹄金素(MTS)二肽衍生物结构多样性,以获得新型抗乙肝病毒活性目标分子,本文采用生物电子等排体替换法,将MTS二肽衍生物中容易水解的酰胺键以含有三氟甲基取代的甲氨基单元替换,设计合成了新型氟代MTS二肽模拟物。所有目标化合物均通过1H NMR、13C NMR、19F NMR、HRMS或ESI-MS进行了结构确证,通过单晶X射线衍射测定了化合物10'的晶体结构,并以HepG2 2.2.15细胞模型对其进行了体外抗乙肝病毒(HBV)测试,结果显示所有目标化合物对HBV DNA的复制均有抑制作用,14e14f14k的IC50值分别为0.37、0.29、0.79 μmol·L-1
关键词:    马蹄金素二肽模拟物      三氟甲基      合成      抗HBV活性     
Synthesis and anti-HBV activity of fluorinated dipeptidomimetics of Matijin-Su
HUANG Wei-jie1,2,4, KUANG An-xiang1,2,3, SHAO Xiao-shuang1,2,3, ZENG Xiao-ping1,2, LIANG Guang-yi1,2, MENG Xue-ling1,2, XU Bi-xue1,2*
1. State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China;
2. The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences/Guizhou Provincial Engineering Research Center for Natural Drugs, Guiyang 550014, China;
3. Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China;
4. School of Pharmacy, Guizhou Medical University, Guiyang 550025, China
Abstract:
To expand the structural diversity of Matijin-Su (MTS) derivatives and explore novel anti-HBV activity compounds, a series of fluorinated dipeptidomimetics of MTS were designed and synthesized by using trifluoromethyl substituted methylamine unit as bioisostere to replace the amide bond of the MTS derivatives. The structures of all target compounds were confirmed by 1H NMR, 13C NMR, 19F NMR, HRMS, or ESI-MS, and the crystal structure of 10ʹ was determined by X-ray single crystal diffraction. Their inhibitory activity against hepatitis B virus (HBV) in vitro were evaluated using HepG2 2.2.15 cell model. The results showed that all target compounds had inhibitory effect on HBV DNA replication, the IC50 of 14e, 14f, and 14k were 0.37, 0.29, and 0.79 μmol·L-1, respectively.
Key words:    dipeptidomimetics of Matijin-Su    trifluoromethyl    synthesis    anti-HBV activity   
收稿日期: 2021-11-19
DOI: 10.16438/j.0513-4870.2021-1657
基金项目: 国家自然科学基金资助项目(81760623);贵州省高层次创新人才培养计划项目(黔科合平台人才[2016]5678).
通讯作者: 徐必学,Tel:86-851-83807713,E-mail:bixue_xu@126.com
Email: bixue_xu@126.com
相关功能
PDF(1343KB) Free
打印本文
0
作者相关文章
黄维杰  在本刊中的所有文章
况安香  在本刊中的所有文章
邵晓霜  在本刊中的所有文章
曾晓萍  在本刊中的所有文章
梁光义  在本刊中的所有文章
孟雪玲  在本刊中的所有文章
徐必学  在本刊中的所有文章

参考文献:
[1] Liu YM, Liang GY, Xu BX. Studies on the chemical constituents from Dichondra repens Forst[J]. Nat Prod Res Dev (天然产物研究与开发), 2003, 15:15-17.
[2] Xu BX, Huang ZM, Liu CX, et al. Synthesis and anti-hepatitis B virus activities of Matijing-Su derivatives[J]. Bioorg Med chem, 2009, 17:3118-3125.
[3] 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, 19:5352-5360.
[4] Liang GP, Cao PX, Yang XX, et al. Synthesis and anti-hepatitis B virus activities of nitric oxide-releasing derivatives of Matijin-Su[J]. Chin J Org Chem (有机化学), 2014, 34:973-979.
[5] Yuan J, Liu QC, Xu GC, et al. Synthesis and anti-hepatitis B virus activities of Matijin-Su derivatives with potential for hepatic targeting[J]. Chin J Org Chem (有机化学), 2015, 35:2176-2183.
[6] Xu GC, Liu QC, Yuan J, et al. Synthesis and anti-hepatitis B virus activities of galactopyranosyl derivatives of Matijin-Su[J]. Chin J Org Chem (有机化学), 2016, 36:1617-1625.
[7] Liu Y, Lu W, Liu QC, et al. Synthesis and anti-HBV activity evaluation of Matijin-Su derivatives containing gallic acid moiety[J]. Acta Pharm Sin (药学学报), 2017, 52:1140-1145.
[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 Proc Res Dev, 2013, 17:1156-1167.
[9] Fan H, Hu Z, Li R, et al. Metabolite identification of bentysrepinine (Y101), a novel anti-HBV agent in rats using a five-step strategy based on a combined workflow with two different platforms of liquid chromatography-tandem mass spectrometry[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2017, 1040:118-128.
[10] Mei YC, Yang BW. Application of amide bioisosteres in the optimization of lead compounds[J]. Prog Chem (化学进展), 2016, 28:1406-1416.
[11] Sani M, Volonterio A, Zanda M. The trifluoroethylamine function as peptide bond replacement[J]. ChemMedChem. 2007, 2:1693-1700.
[12] Gauthier JY, Chauret N, Cromlish W, et al. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K[J]. Bioorg Med Chem Lett, 2008, 18:923-928.
[13] Ireland RE, Norbeck DW. Application of the Swern oxidation to the manipulation of highly reactive carbonyl compounds[J]. J Org Chem, 1985, 50:2198-2200.
[14] Meyer SD, Schreiber SL. Acceleration of the Dess-Martin oxidation by water[J]. J Org Chem, 1994, 59:7549-7552.
[15] Zeng C, Kerrigan SA, Katzenellenbogen JA, et al. Efficient synthesis of (2R,3S)-2-amino-3-(benzyloxy)-4,4,4-trifluorobutanoic acid (4,4,4-trifluoro-OBn-d-allothreonine)[J]. Tetrahedron Lett, 2010, 51:5361-5363.
[16] Giovani S, Penzo M, Butini S, et al. Plasmodium falciparum subtilisin-like protease 1:discovery of potent difluorostatone-based inhibitors[J]. RSC Adv, 2015, 5:22431-22448.
[17] Li YX, Kinami K, Hirokami Y, et al. Gem-difluoromethylated and trifluoromethylated derivatives of DMDP-related iminosugars:synthesis and glycosidase inhibition[J]. Org Biomol Chem, 2016, 14:2249-2263.
[18] Andrés JM, Pedrosa R, Pérez-Encabo A. Diastereoselective synthesis of β-amino-α-(trifluoromethyl) alcohols from homochiral α-dibenzylamino aldehydes[J]. Eur J Org Chem, 2004, 7:1558-1566.
[19] Rioton S, Orliac A, Antoun Z, et al. Stereoselective rearrangement of (trifluoromethyl) prolinols to enantioenriched 3-substituted 2-(trifluoromethyl) piperidines[J]. Org Lett, 2015, 17:2916-2919.
[20] Wang PL, Liu QC, Wang CY, et al. Inhibitory effect of tifentai on HBV-DNA in cultured cell line HepG2-2.2.15in vitro[J]. Pharm J Chin PLA (解放军药学学报), 2015, 31:1-3.
[21] Wada Y, Harayama Y, Kamimura D, et al. The synthetic and biological studies of discorhabdins and related compounds[J]. Org Biomol Chem, 2011, 9, 4959-4976.