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Molecules 2017, 22(7), 1018; doi:10.3390/molecules22071018

Synthesis and In Vitro Anti-Influenza Virus Evaluation of Novel Sialic Acid (C-5 and C-9)-Pentacyclic Triterpene Derivatives

1
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
2
Institut Parisien de Chimie Moléculaire, CNRS UMR 8232, Université Pierre & Marie Curie-Paris 6, 4 Place Jussieu, Paris 75005, France
3
School of Pharmacy, Jining Medical University, Rizhao 276826, China
Dedicated to Professor Lihe Zhang on the Occasion of His 80th Birthday.
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 16 May 2017 / Revised: 16 June 2017 / Accepted: 16 June 2017 / Published: 22 June 2017
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Abstract

The emergence of drug resistant variants of the influenza virus has led to a great need to identify novel and effective antiviral agents. In our previous study, a series of sialic acid (C-2 and C-4)-pentacyclic triterpene conjugates have been synthesized, and a five-fold more potent antiviral activity was observed when sialic acid was conjugated with pentacyclic triterpene via C-4 than C-2. It was here that we further reported the synthesis and anti-influenza activity of novel sialic acid (C-5 and C-9)-pentacyclic triterpene conjugates. Their structures were confirmed by ESI-HRMS, 1H-NMR, and 13C-NMR spectroscopic analyses. Two conjugates (26 and 42) showed strong cytotoxicity to MDCK cells in the CellTiter-Glo assay at a concentration of 100 μM. However, they showed no significant cytotoxicity to HL-60, Hela, and A549 cell lines in MTT assay under the concentration of 10 μM (except compound 42 showed weak cytotoxicity to HL-60 cell line (10 μM, ~53%)). Compounds 20, 28, 36, and 44 displayed weak potency to influenza A/WSN/33 (H1N1) virus (100 μM, ~20–30%), and no significant anti-influenza activity was found for the other conjugates. The data suggested that both the C-5 acetylamide and C-9 hydroxy of sialic acid were important for its binding with hemagglutinin during viral entry into host cells, while C-4 and C-2 hydroxy were not critical for the binding process and could be replaced with hydrophobic moieties. The research presented herein had significant implications for the design of novel antiviral inhibitors based on a sialic acid scaffold. View Full-Text
Keywords: pentacyclic triterpene; sialic acid; influenza virus; structure-activity relationship (SAR) pentacyclic triterpene; sialic acid; influenza virus; structure-activity relationship (SAR)
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MDPI and ACS Style

Han, X.; Si, L.-L.; Shi, Y.-Y.; Fan, Z.-B.; Wang, S.-X.; Tian, Z.-Y.; Li, M.; Sun, J.-Q.; Jiao, P.-X.; Ran, F.-X.; Zhang, Y.-M.; Zhou, D.-M.; Xiao, S.-L. Synthesis and In Vitro Anti-Influenza Virus Evaluation of Novel Sialic Acid (C-5 and C-9)-Pentacyclic Triterpene Derivatives
. Molecules 2017, 22, 1018.

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