Design, synthesis, and biological evaluation of novel 2′-deoxy-2′-fluoro-2′-C-methyl 8-azanebularine derivatives as potent anti-HBV agents. Issue 11 (1st June 2019)

• Record Type: Journal Article
• Authors: Yang, Wu; Peng, Youmei; Wang, Jingwen; Song, Chuanjun; Yu, Wenquan; Zhou, Yubing; Jiang, Jinhua; Wang, Qingduan; Wu, Jie; Chang, Junbiao
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 11(2019)
• Page Start: 1291
• Page End: 1297
• Publication Date: 2019-06-01
• Subjects: 2′-Deoxy-2′-fluoro-2′-C-methyl 8-azanebularine analogues -- Anti-HBV activity -- Nucleoside reverse transcriptase inhibitor (NRTI) -- Lamivudine-resistant HBV mutants -- Viral DNA replication; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.04.005
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: This work describes the synthesis of new 2′-fluoro-2′- C -methyl 8-azanebularine nucleoside derivatives with moderate to good in vitro anti-HBV activity.2g can efficiently inhibit the wild-type and lamivudine-resistant HBV DNA replication. Abstract: Hepatitis B virus (HBV) is a global health problem requiring more efficient and better tolerated anti-HBV agent. In this paper, a series of novel 2′-deoxy-2′-fluoro-2′- C -methyl-β-d -arabinofuranosyl 8-azanebularine analogues (1 and2a) and N 4 -substituted 8-azaadenosine derivatives(2b-g) were designed, synthesized and screened for in vitro anti-HBV activity. Two concise and practical synthetic routes were developed toward the structural motif construction of 2′-deoxy-2′-fluoro-2′- C -methyl-β-d -arabinofuranosyl 8-azainosine from the ribonolactone3 under mild conditions. The in vitro anti-HBV screening results showed that these 8-azanebularine analogues had a significant inhibitory effect on the expression of HBV antigens and HBV DNA at a concentration of 20 μM. Among them, halogen-substituted 8-azaadenosine derivative2g displayed activities comparable to that of 3TC. In particular, 2g retained excellent activity against lamivudine-resistant HBV mutants.