土槿乙酸C-18醇酯衍生物的合成及其体外免疫抑制活性研究
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摘要
目的:将土瑾乙酸C-18位进行结构改造,筛选出具有高效、低毒、水溶性好等优点的新型免疫抑制化合物。方法:将C-18位还原为醇羟基,通过缩合酰化反应引入苯环、呋喃环、吡啶环羧酸,得到土槿乙酸C-18醇酯衍生物。经MTT法对小鼠T、B淋巴细胞的免疫抑制活性和对小鼠正常脾细胞毒性体外细胞实验筛选。结果:合成得到10个未见文献报道的土瑾乙酸C-18醇酯衍生物B1-B10,所合成的目标化合物均经~1H-NMR, ~(13)C-NMR, HR-ESI进行结构确定,并测定了其体外免疫抑制活性,结果显示其中衍生物B2、B6、B7对T淋巴细胞增殖抑制活性强于土槿乙酸,衍生物B6、B7对B淋巴细胞抑制活性明显强于土槿乙酸。尤其是大多数化合物对正常细胞作用很弱,远低于阳性对照药,呈现高效低毒特性。结论:土槿乙酸C-18醇酯衍生物,引入呋喃环,抑制T、B淋巴细胞增殖活性明显增加,引入具有共轭体系的呋喃环时活性更佳,并且毒性降低。
Objective: To obtain immunosuppressive compounds with high efficiency, low toxicity and good water solubility by modifying Pseudolaric acid B at the C-18 site. Methods: The carboxylic acid group at the C-18 position of pseudolaric acid B was reduced to the corresponding alcohol. The alcohol which was further converted through condensation acylation reaction into the esters of pseudolaric acid B with the benzene ring,furan ring,and pyridine ring carboxylic acid. The immunosuppressive activity of these compounds in mouse T and B lymphocytes and the normal spleen cytotoxicity were tested by MTT assay in vitro.Results: Ten C-18 alcoholic hydroxylesters derivatives of pseudolaric acid B weresynthesized, which were not reported in the literature.The structures of these compounds were confirmed by spectropic analysis of HR-ESI-MS,~1H-NMR and~(13)C-NMR,and the immunocompetence of all the synthesized compounds was tested.The results showed that among the derivatives,the B2, B6 and B7 were better than pseudolaric acids B on the immunosuppressive activity in T lymphocyte proliferation while B6 and B7 on B lymphocytes inhibitory activity were significantly stronger thanpseudolaric acids B.Particularly, most compounds had very weak effects on normal cells,which were much lower than the positive control drugs, showing high efficiency and low toxicity.Conclusion: The C-18 alcoholic hydroxylesters derivatives of pseudolaric acid B which were introduced into the furan ring, shows better inhibiting effect in proliferation of T and B lymphocytes,but the activity of the furan ring with conjugated system is higher, and the toxicity could be decreased.
Objective: To obtain immunosuppressive compounds with high efficiency, low toxicity and good water solubility by modifying Pseudolaric acid B at the C-18 site. Methods: The carboxylic acid group at the C-18 position of pseudolaric acid B was reduced to the corresponding alcohol. The alcohol which was further converted through condensation acylation reaction into the esters of pseudolaric acid B with the benzene ring,furan ring,and pyridine ring carboxylic acid. The immunosuppressive activity of these compounds in mouse T and B lymphocytes and the normal spleen cytotoxicity were tested by MTT assay in vitro.Results: Ten C-18 alcoholic hydroxylesters derivatives of pseudolaric acid B weresynthesized, which were not reported in the literature.The structures of these compounds were confirmed by spectropic analysis of HR-ESI-MS,~1H-NMR and~(13)C-NMR,and the immunocompetence of all the synthesized compounds was tested.The results showed that among the derivatives,the B2, B6 and B7 were better than pseudolaric acids B on the immunosuppressive activity in T lymphocyte proliferation while B6 and B7 on B lymphocytes inhibitory activity were significantly stronger thanpseudolaric acids B.Particularly, most compounds had very weak effects on normal cells,which were much lower than the positive control drugs, showing high efficiency and low toxicity.Conclusion: The C-18 alcoholic hydroxylesters derivatives of pseudolaric acid B which were introduced into the furan ring, shows better inhibiting effect in proliferation of T and B lymphocytes,but the activity of the furan ring with conjugated system is higher, and the toxicity could be decreased.
引文
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[2]李晓翠,苗爱东,张洪峰,等.土荆皮的研究进展[J].现代中西医结合杂志, 2014, 23(29):3301
[3]李珠莲,陈科,潘德济,等.土槿皮新二萜成分的研究Ⅲ.土槿甲酸苷和土槿乙酸苷的分离及化学结构测定[J].化学学报, 1985, 43(8):786
[4] Li T,Wang W,Zhao J H,et al. Pseudolaric acid B inhibits T-cell mediated immune response in vivo viap38MAPK signal cascades and PPARγactivation[J]. Life Sciences,2015, 121:88
[5]李覃,董小青,王翼腾,等.土槿乙酸抑制接触性超敏反应的药效学研究及机制探讨[J].中国药理学通报,2014, 30(11):1552
[6]孟爱国,刘春艳.土槿乙酸诱导人胃癌AGS细胞凋亡机制的研究[J].肿瘤,2010, 30(6):495
[7] Ma G Y, Li C, Li X C.Selective inhibition of human leukemia cell growth and induction of cell cycle arrest and apoptosis by pseudolaric acid B[J]. J Cancer Res ClinOncol, 2010, 136(9):1333
[8] Gan L S,Yang S P, Fan C Q. Lignans and Their Degraded Derivatives from Sarcostemmaacidum[J]. J Natural Products,2005, 68(2):221
[9]司徒镇强,吴军正.细胞培养[M].西安:世界图书出版公司西安公司,2004:379