2. Academic Validation
  3. Synthesis and biological evaluation of novel pentacyclic triterpene α-cyclodextrin conjugates as HCV entry inhibitors

Synthesis and biological evaluation of novel pentacyclic triterpene α-cyclodextrin conjugates as HCV entry inhibitors

  • Eur J Med Chem. 2016 Nov 29:124:1-9. doi: 10.1016/j.ejmech.2016.08.020.
Sulong Xiao 1,  Qi Wang 2,  Longlong Si 3,  Xiaoshu Zhou 3,  Yongmin Zhang 4,  Lihe Zhang 3,  Demin Zhou 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: slxiao@bjmu.edu.cn.
  • 2 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China; Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
  • 3 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
  • 4 Institut Parisien de Chimie Moléculaire, CNRS UMR 8232, Université Pierre & Marie Curie-Paris 6, 4 Place Jussieu, 75005, Paris, France.
  • 5 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China. Electronic address: deminzhou@bjmu.edu.cn.
PMID: 27565552 DOI: 10.1016/j.ejmech.2016.08.020
Abstract

Hepatitis C virus (HCV) entry is a key target for the treatment of chronic HCV Infection. In our continuing efforts to identify novel potential anti-HCV entry inhibitors, a series of water-soluble triazole-bridged α-cyclodextrin-pentacyclic triterpene conjugates were easily synthesized with moderate to good yields. These novel compounds were fully identified and characterized by 1D and 2D NMR spectroscopy and ESI-HRMS. The anti-HCV entry activities were determined based on HCVpp/VSVGpp entry assays. The best results were found for compounds 15 and 18, which displayed the most promising anti-HCV entry activities with average IC50 values of 1.18 μM and 0.25 μM, respectively. In addition, the in vitro cytotoxicity activity of the two compounds against MDCK cells showed no toxicity at 100 μM. Five different binding assays were set up to identify the action mechanism. The results showed that the compounds exert their inhibitory activity at the post-binding step and subsequently prevent virus entry.

Keywords

Click chemistry; HCV entry inhibitor; Pentacyclic triterpene; α-Cyclodextrin.

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