Synthesis and antiviral effects of isosteviol-derived analogues against the hepatitis B virus

Dose‐dependent pharmacokinetics and tentative identification of urine metabolites from an isosteviol derivative with anti‐hepatitis B activity in rats

“…Compound 1 was synthesized (≥ 97.0% purity) from isosteviol as described in a previous report (Huang et al, ). Diclofenac sodium was purchased from Sigma‐Aldrich (St Louis, MO, USA) and was used as an internal standard.…”

“…Isosteviol, an ent ‐beyerane diterpenoid that possesses various biological activities, is obtained through the acid hydrolysis of stevioside (Figure ), a glycoside from Stevia rebaudiana (Bertoni) Bertoni (Compositae) (Ceunen & Geuns, ). Compound 1 ( ent ‐16‐oxobeyeran‐19‐ N ‐methylureido), a derivative of isosteviol (Figure ), showed potent activity against hepatitis B virus (HBV) in cell culture (Huang et al, ). In addition to compound 1 , several semisynthetic isosteviol derivatives possessing antiviral (Akihisa et al, ; Huang et al, ), anti‐inflammatory (Chang et al, ; Chou et al, ), antitumor (Ukiya et al, ) and α ‐glucosidase inhibitory (Wu et al, ) activities were synthesized.…”

“…In addition to compound 1 , several semisynthetic isosteviol derivatives possessing antiviral (Akihisa et al, ; Huang et al, ), anti‐inflammatory (Chang et al, ; Chou et al, ), antitumor (Ukiya et al, ) and α ‐glucosidase inhibitory (Wu et al, ) activities were synthesized. The anti‐HBV activity of 1 in Huh7 cells was achieved through inhibition of viral gene expression, reductions in levels of encapsidated viral DNA intermediates and inhibition of the host cell's Toll‐like receptor 2 (TLR 2)/nuclear factor (NF)‐ κ B signaling pathway (Huang et al, ). This mechanism of action is distinct from those of typical HBV reverse‐transcriptase/polymerase inhibitors.…”

“…Several studies associated HBV DNA and viral proteins (including HBV X) with the development of hepatocellular carcinoma (Hung et al, ; Li et al, ; Liu et al, ; Xu, Zhou, Wang, & Qiao, ), and the size of the viral load was also found to be correlated with outcomes of HBV infection (Chen, Chang, Huang, Wen, & Lin, ; Chisari, Isogawa, & Wieland, ; Liu et al, ). Thus, inhibition of viral gene expression, a reduction in levels of encapsidated viral DNA intermediates and inhibition of the host cell's TLR 2/NF‐ κ B signaling pathway exhibited by compound 1 (Huang et al, ) offer yet another potential arsenal in the fight against HBV infections. HBV infections still pose significant health risks with an estimated three‐quarters of the global population exposed; hence, the search continues for new anti‐HBV agents that offer different modes of action with possibly fewer side‐effects and contraindications than the currently used nucleoside/nucleotide analogues and interferon.…”

Isosteviol Derivative Inhibits Osteoclast Differentiation and Ameliorates Ovariectomy-Induced Osteoporosis

“…Isosteviol derivatives exert a variety of biological effects, including anti-hypertension, anti-inflammation, anti-diarrhea, anti-cancer, anti-viral, and anti-bacterial activity 12 – 16 . NC-8, an isosteviol derivative, has been demonstrated to effectively inhibit the secretion of hepatitis B virus (HBV) surface antigens and HBV core antigens and inhibit the host TLR2/NF-κB signaling pathway 14 . However, the effect of NC-8 on RANKL activity through the ERK, p38, and NF-κB pathways has not been identified in the existing literature.…”