School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.
Faculty of Naval Medicine, Second Military Medical University, Shanghai, 200433, China.
Med Chem. 2021;17(9):974-982. doi: 10.2174/1573406416999200818150053.
Schisandronic acid (SA), a triterpenoid from fruits of Schisandra sphenanthera, inhibited pan-genotypic HCV entry into human hepatocytes by interfering with virion-cell membrane fusion. It was a promising lead compound for the development of novel HCV entry inhibition agents.
The aim of the present study is to search for compounds with more potent anti-HCV and antitumor activities and explore SARs. A series of novel derivatives of SA were designed and synthesized and evaluated for in vitro, their anti-HCV and antitumor activities.
SA derivatives were synthesized by reduction, condensation, esterification or amidation. The anti-HCV activity of title compounds was tested by inhibition on HCVcc infection of Huh7 cells, and a preliminary MOA study was conducted by determining inhibition on HCVpp entry into Huh7 cells. The antitumor activity in vitro was determined by MTT methods.
In total, 24 novel derivatives were synthesized. Most of the compounds inhibited HCVcc infection. Compounds 5h and 6 showed the most potent anti-HCVcc activities and inhibition of HCVpp entry into Huh7 cells without obvious cytotoxicity. Most of the title compounds showed potent in vitro antitumor activities against Bel7404 and SMMC7721 tumor cell lines. Compounds 5j and 6 exhibited more potent antitumor activity than positive control SA and DOX.
Structural modification of SA could lead to the discovery of potent anti-HCV or antitumor agents. Compounds 5h, 5j and 6 were promising lead compounds for development of novel HCV entry inhibition or antitumor agents.
五味子酸（SA）是五味子果实中的一种三萜类化合物，通过干扰病毒-细胞膜融合抑制泛基因型 HCV 进入人肝细胞。它是开发新型 HCV 进入抑制剂的有前途的先导化合物。
本研究旨在寻找具有更强抗 HCV 和抗肿瘤活性的化合物，并探索构效关系。设计并合成了一系列新型 SA 衍生物，并对其进行了体外抗 HCV 和抗肿瘤活性评价。
通过还原、缩合、酯化或酰胺化合成 SA 衍生物。通过抑制 Huh7 细胞中 HCVcc 的感染来测试标题化合物的抗 HCV 活性，并通过测定对 HCVpp 进入 Huh7 细胞的抑制作用来进行初步的作用机制研究。体外抗肿瘤活性通过 MTT 法测定。
共合成了 24 种新型衍生物。大多数化合物抑制 HCVcc 感染。化合物 5h 和 6 表现出最强的抗 HCVcc 活性和抑制 HCVpp 进入 Huh7 细胞的作用，且无明显细胞毒性。大多数标题化合物对 Bel7404 和 SMMC7721 肿瘤细胞系表现出较强的体外抗肿瘤活性。化合物 5j 和 6 的抗肿瘤活性强于阳性对照 SA 和 DOX。
SA 的结构修饰可能会发现具有强抗 HCV 或抗肿瘤活性的化合物。化合物 5h、5j 和 6 是开发新型 HCV 进入抑制剂或抗肿瘤剂的有前途的先导化合物。
