Synthesis, structure-activity relationships and biological evaluation of dehydroandrographolide and andrographolide derivatives as novel anti-hepatitis B virus agents
Synthesis, structure-activity relationships and biological evaluation of dehydroandrographolide and andrographolide derivatives as novel anti-hepatitis B virus agents
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新型抗乙型肝炎病毒药物脱氢穿心莲内酯及穿心莲内酯衍生物的合成、构效关系及生物学评价
DOI：
10.1016/j.bmcl.2014.03.060
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发表时间：
2014-05-15
影响因子：
2.7
通讯作者：
Chen, Ji-Jun
中科院分区：
文献类型：
--
作者：
Chen, Hao;Ma, Yun-Bao;Chen, Ji-Jun
从穿心莲中分离得到的两种天然二萜类化合物脱水穿心莲内酯和穿心莲内酯具有抗HBV DNA复制的活性，其IC_（50）值分别为22.58和54.07 μ M，SI值分别为8.7和3.7。在此基础上，合成了48个脱氢穿心莲内酯和穿心莲内酯衍生物，并对其抗HBV活性进行了评价，得到了一系列具有较低细胞毒性的衍生物，其中14个抗HBsAg分泌衍生物，19个抗HBeAg分泌衍生物和38个抗HBV DNA复制衍生物。有趣的是，化合物4e不仅可以抑制HBsAg和HBeAg的分泌，而且可以抑制HBV DNA的复制，SI值为20.3、125.0和104.9。其中化合物2c抑制HBV DNA复制的活性最强，SI值大于165.1，最佳logP值为1.78，最佳logD值为1.78。揭示了该类衍生物的构效关系，为进一步开发抗HBV药物提供了理论指导。(C)2014爱思唯尔有限公司版权所有。
Dehydroandrographolide and andrographolide, two natural diterpenoids isolated from Andrographis paniculata possessed activity against HBV DNA replication with IC50 values of 22.58 and 54.07 mu M and low SI values of 8.7 and 3.7 in our random assay. Consequently, 48 derivatives of dehydroandrographolide and andrographolide were synthesized and evaluated for their anti-HBV properties to yield a series of active derivatives with lower cytotoxicity, including 14 derivatives against HBsAg secretion, 19 derivatives against HBeAg secretion and 38 derivatives against HBV DNA replication. Interestingly, compound 4e could inhibit not only HBsAg and HBeAg secretions but also HBV DNA replication with SI values of 20.3, 125.0 and 104.9. Furthermore, the most active compound 2c with SI value higher than 165.1 inhibiting HBV DNA replication was revealed with the optimal logP value of 1.78 and logD values. Structureactivity relationships (SARs) of the derivatives were disclosed for guiding the future research toward the discovery of new anti-HBV drugs. (C) 2014 Elsevier Ltd. All rights reserved.