A Series of Oleanolic Acid Derivatives as Anti-Hepatitis B Virus Agents: Design, Synthesis, and in Vitro and in Vivo Biological Evaluation.

Wenqiang Yan,Shun Gu,Bi Li,Xin Xu,Haimin Lei,Bing Xu,Jian Ren,Penglong Wang,Chenze Zhang,Fuhao Chu,Miao Liang

doi:10.3390/molecules21040402

Wenqiang Yan, Shun Gu + Show 9 more

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https://doi.org/10.3390/molecules21040402

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Abstract

A series of oleanolic acid derivatives were synthesized by diverse reactions, including the introduction of conjugated alkadiene and epoxy ring moieties formed by means of photosensitized oxidation. Eosin Y was used as photosensitizer during this process. Next the cytotoxicity of the products was evaluated on HepG2.2.15 cells to determine the appropriate treatment concentration for the subsequent experiments. Most of the OA derivatives exhibited anti-HBV antigens secretion activity in HepG2.2.15 cells. Among the tested compounds, OA-4 (3.13 µg/mL) showed significant activity against the secretion of HBsAg, HBeAg, and HBV DNA replication with inhibitory ratios of 90.52% ± 1.78%, 31.55% ± 3.65%, and 94.57% ± 3.11% after 6 days, respectively. Besides, OA-4 was further investigated in a duck model with DHBV infection. When OA-4 was administered at a dosage of 500 mg/kg, the results revealed a significant inhibitory effects of DHBV at 19.94% ± 2.87%, 28.80% ± 3.62% and 29.25% ± 2.65% at days 5, 10, and 3 after the cessation of OA-4 treatment, respectively. It’s worth noting that OA-4 is superior to lamivudine in the inhibition of rebound of viral replication rate. The structure–activity relationships of OA derivatives had been preliminary discussed, which should be useful to explore further novel anti-HBV agents.

Highlights

Hepatitis B virus (HBV) infection is a serious worldwide public health problem which often leads to acute and chronic consequences in humans such as cirrhosis and hepatocellular carcinoma (HCC) [1,2,3]
As shown in Scheme 1, OA-1 was synthesized by the treatment of anhydrous OA with
The mixture was kept illuminated for 10 h to give OA-3 and OA-2, whose structures

Summary

Introduction

Hepatitis B virus (HBV) infection is a serious worldwide public health problem which often leads to acute and chronic consequences in humans such as cirrhosis and hepatocellular carcinoma (HCC) [1,2,3]. Millions of the HBV patients will eventually succumb to the infection sequence due to high recurrence, drug resistance and side effects, including influenza-like illness, myalgia, reduction of neutrophilic granulocytes and Molecules 2016, 21, 402; doi:10.3390/molecules21040402 www.mdpi.com/journal/molecules. The continued development of new antimicrobial agents with different of antiviral targets and inhibition of viral load rebound is essential. The continued development of new antimicrobial agents with different antiviral. Attempts to discover new lead targets on andthe inhibition viral loadofrebound is essential. Compounds has already drawn considerable attention [9,10,11].

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