title: A Series of Oleanolic Acid Derivatives as Anti-Hepatitis B Virus Agents: Design, Synthesis, and in Vitro and in Vivo Biological Evaluation.
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.
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. ywq3226925@163.com.
authors.forename: Wenqiang
authors.initials: W
authors.lastname: Yan
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. zcz920418@163.com.
authors.forename: Chenze
authors.initials: C
authors.lastname: Zhang
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. libimegan@163.com.
authors.forename: Bi
authors.initials: B
authors.lastname: Li
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. xu.xin@vip.126.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. mimi1111202@sina.com.
authors.forename: Miao
authors.initials: M
authors.lastname: Liang
authors.affiliation: Department of Pharmacology, Xuanwu Hospital of Capital Medical University, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing 100053, China. gszy2003@163.com.
authors.forename: Shun
authors.initials: S
authors.lastname: Gu
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. chufhao@163.com.
authors.forename: Fuhao
authors.initials: F
authors.lastname: Chu
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. weichenxubing@126.com.
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. renjian2008333@163.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Ren
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. wpl581@126.com.
authors.forename: Penglong
authors.initials: P
authors.lastname: Wang
authors.affiliation: School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China. leihaimin@126.com.
authors.forename: Haimin
authors.initials: H
authors.lastname: Lei
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D004372:Ducks / Q000821:virology; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000188:drug therapy* / Q000821:virology; D006513:Hepatitis B e Antigens / Q000187:drug effects; D006515:Hepatitis B virus / Q000187:drug effects / Q000472:pathogenicity; D006801:Humans; D009828:Oleanolic Acid / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D006513:Hepatitis B e Antigens; D009828:Oleanolic Acid
keywords: anti-hepatitis B virus; eosin Y; epoxy ring; oleanolic-acid derivatives; virus recrudescence