Shi Yongying, Si Longlong, Han Xu, Fan Zibo, Wang Shouxin, Li Man, Sun Jiaqi, Zhang Yongmin, Zhou Demin, Xiao Sulong
State Key Laboratory of Natural and Biomimetic Drugs , School of Pharmaceutical Sciences , Peking University , Beijing 100191 , China . Email:
School of Pharmacy , Jining Medical University , Rizhao 276826 , China.
Medchemcomm. 2017 Jun 2;8(7):1531-1541. doi: 10.1039/c7md00245a. eCollection 2017 Jul 1.
Sialic acid derivatives, analogs, and their conjugates are important pharmacophores. Modification of the C-4 hydroxyl group of sialic acid can lead to derivatives, such as zanamivir, with potent anti-influenza activities. Herein, we described the synthesis of C-4-modified sialic acid derivatives conjugation with naturally derived pentacyclic triterpenes, which are active ingredients of traditional Chinese medicine, and the evaluation of their anti-influenza virus activity in MDCK cells. Interestingly, a set of configurational isomers was obtained during the de--acetylation reaction of two pentacyclic triterpene-sialic acid conjugates under Zemplén conditions, and a mechanism was proposed. Owing to the attachment of the Neu5Ac2en moiety, all synthesized conjugates displayed lower hydrophobicity than their parent compounds. In comparison with ursane- and lupane-type triterpenes, oleanane-type triterpene-functionalized Neu5Ac2en conjugates were most promising. The insertion of a (1,2,3-triazol-4-yl)-methyl between the amide bond and Neu5Ac2en caused a substantial decrease in activity. Compound exhibited the highest inhibitory activity (IC = 8.3 μM) and selectivity index (SI = 22.7). Further studies involving hemagglutination inhibition and neuraminidase inhibition suggested that compound inhibited virus-induced hemagglutination with no effect on the enzymatic activity of neuraminidase, indicating that the antiviral activity appeared to be mediated interaction with hemagglutinin at the initial stage of viral infection.
唾液酸衍生物、类似物及其缀合物是重要的药效基团。对唾液酸的C-4羟基进行修饰可得到具有强效抗流感活性的衍生物，如扎那米韦。在此，我们描述了与天然来源的五环三萜（中药的活性成分）缀合的C-4修饰唾液酸衍生物的合成，以及它们在MDCK细胞中抗流感病毒活性的评估。有趣的是，在Zemplén条件下，两种五环三萜-唾液酸缀合物的脱乙酰化反应过程中得到了一组构型异构体，并提出了一种机制。由于Neu5Ac2en部分的连接，所有合成的缀合物的疏水性均低于其母体化合物。与乌苏烷型和羽扇豆烷型三萜相比，齐墩果烷型三萜官能化的Neu5Ac2en缀合物最具前景。在酰胺键和Neu5Ac2en之间插入(1,2,3-三唑-4-基)-甲基导致活性大幅降低。化合物表现出最高的抑制活性（IC = 8.3 μM）和选择性指数（SI = 22.7）。进一步的血凝抑制和神经氨酸酶抑制研究表明，化合物抑制病毒诱导的血凝，但对神经氨酸酶的酶活性没有影响，这表明抗病毒活性似乎是在病毒感染初期通过与血凝素的相互作用介导的。
