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Synthesis of novel pentacyclic triterpene-Neu5Ac2en derivatives and investigation of their in vitro anti-influenza entry activity

Abstract

Sialic acid (Neu5Ac) derivatives, analogs and their conjugates are important pharmacophores. Modification of C-4 of sialic acid can lead to derivatives with potent anti-influenza activities, such as Zanamivir. Herein, we described the synthesis of novel C-4 modified sialic acid derivatives by conjugation with naturally derived pentacyclic triterpenes, an active ingredient of traditional Chinese medicine, and the evaluation of their in vitro anti-influenza A/WSN/33 (H1N1) virus entry activity in the MDCK cells. Interestingly, a set of configurational isomers was obtained during the de-O-acetylation reaction of two pentacyclic triterpene-sialic acid conjugates under Zemplén conditions and a mechanism was proposed. Due to the attachment of Neu5Ac2en moiety, all synthesized conjugates showed lower hydrophobicity (AlogP) than their parent compounds. Compared with ursane- and lupane-type pentacyclic triterpenes, oleanane-type pentacyclic triterpene functionalized Neu5Ac2en conjugates were the most promising, and they demonstrated higher activity and selectivity comparable to the reference compound curcumin, a small-molecule entry inhibitor targeting the influenza hemagglutinin. The insertion of a (1,2,3-triazol-4-yl) methyl between the amide bond and Neu5Ac2en caused a substantial decrease in activity. Compound 15a showed the highest inhibitory activity (IC50 = 8.3 μM) and selectivity index (SI = 22.7). Further studies involving hemagglutination inhibition and neuraminidase inhibition suggested that compound 15a inhibited virus-induced hemagglutination with no effect on the neuraminidase enzymatic activity, indicating that the antiviral activity appears to be mediated by interaction with hemagglutinin at the initial stage of viral infection.

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Publication details

The article was received on 11 May 2017, accepted on 30 May 2017 and first published on 02 Jun 2017


Article type: Research Article
DOI: 10.1039/C7MD00245A
Citation: Med. Chem. Commun., 2017, Accepted Manuscript
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    Synthesis of novel pentacyclic triterpene-Neu5Ac2en derivatives and investigation of their in vitro anti-influenza entry activity

    Y. Shi, L. Si, X. Han, Z. Fan, S. Wang, M. Li, J. Sun, Y. Zhang, D. Zhou and S. Xiao, Med. Chem. Commun., 2017, Accepted Manuscript , DOI: 10.1039/C7MD00245A

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