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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2017-06, Vol.22 (7), p.1018
• Main Authors: Han, Xu, Si, Long-Long, Shi, Yong-Ying, Fan, Zi-Bo, Wang, Shou-Xin, Tian, Zhen-Yu, Li, Man, Sun, Jia-Qi, Jiao, Ping-Xuan, Ran, Fu-Xiang, Zhang, Yong-Min, Zhou, De-Min, Xiao, Su-Long
• Format: Article
• Language: English
• Subjects: Acids; Animals; Antiviral activity; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Baby foods; Binding; Carbon-13 Magnetic Resonance Spectroscopy; Cell Line, Tumor; Cell lines; Chemical Sciences; Conjugates; Cytotoxicity; Dogs; Drug resistance; Hemagglutinin Glycoproteins, Influenza Virus - chemistry; Hemagglutinins; Humans; Hydrophobicity; Influenza; Influenza A; Influenza A Virus, H1N1 Subtype - drug effects; influenza virus; Madin Darby Canine Kidney Cells; N-Acetylneuraminic Acid - chemistry; NMR; Nuclear magnetic resonance; pentacyclic triterpene; Proton Magnetic Resonance Spectroscopy; sialic acid; Spectrometry, Mass, Electrospray Ionization; structure-activity relationship (SAR); Triterpenes - chemical synthesis; Triterpenes - chemistry; Triterpenes - pharmacology; Viruses
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules22071018

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 C-NMR spectroscopic analyses. Two conjugates ( and ) 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 showed weak cytotoxicity to HL-60 cell line (10 μM, ~53%)). Compounds , , , and 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.