Synthesis and biological evaluation of nucleoside analogues than contain silatrane on the basis of the structure of acyclovir (ACV) as novel inhibitors of hepatitis B virus (HBV)

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 5; pp. 1310 - 1314
• Main Authors: Han, Anyue, Li, Lingna, Qing, Kuiyou, Qi, Xiaolu, Hou, Leping, Luo, Xintong, Shi, Shaohua, Ye, Faqing
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-03-2013
• Subjects: ACV; Acyclovir - analogs & derivatives; Acyclovir - pharmacology; Animals; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; chemistry; cytotoxicity; DNA; Female; flow cytometry; HBV transgenic mouse; Hep G2 Cells; Hepatitis B - drug therapy; hepatitis B antigens; Hepatitis B virus; Hepatitis B virus - drug effects; HepG2.2.15 cell; herpes simplex; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; nucleosides; Organosilicon Compounds - chemical synthesis; Organosilicon Compounds - chemistry; Organosilicon Compounds - pharmacology; public health; Purine Nucleosides - chemical synthesis; Purine Nucleosides - chemistry; Purine Nucleosides - pharmacology; quantitative polymerase chain reaction; Random Allocation; Silatrane; T-lymphocytes; transgenic animals; viruses; HepG2.2.15 cell; 3TC; Silatrane; HBeAg; HBsAg; HSV; MTT; FCM; HBV transgenic mouse; ACV; qPCR; Hepatitis B virus; HBV; GAPDH; ELISA
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.12.097

In this study, we used the combination principle to design and synthesize nucleoside analogues that contain silatrane on the basis of the structure of ACV. We found that the compounds were effective inhibitors of HBV, both in vitro and in vivo.
Hepatitis B virus (HBV) infection causes major public health problems worldwide. Acyclovir (ACV) is mainly used to inhibit herpes simplex virus (HSV) rather than HBV. In this study, we used the combination principle to design and synthesize nucleoside analogues that contain silatrane on the basis of the structure of ACV. We found that the compounds were effective inhibitors of HBV, both in vitro and in vivo. All of the compounds showed suppressive activity on the expression of HBV surface antigen (HBsAg) and HBV e antigen (HBeAg) in the HepG2.2.15 cell line with low cytotoxicity. One of compounds was studied in HBV transgenic mice model, and the test results showed its ability to reduce the levels of HBsAg, HBeAg and HBV DNA by ELASE and qPCR. Furthermore, significant improvement of T lymphocyte was observed after treatment, as evaluated by flow cytometry (FCM).