HCV protease inhibitory, cytotoxic and apoptosis-inducing effects of oleanolic acid derivatives.
OBJECTIVE
To evaluate oleanolic acid derivatives on liver disease related bioactivities, 29 oleanolic acid derivatives of several series were tested for their inhibitory activity on hepatitis C viral protease and for their cytotoxic effects on Hep G2 cells.


RESULTS
The amino derivatives showed potent cytotoxicity, among which, the beta-amino isomer exhibited more distinct cytotoxicity than the alpha-isomer. The cytotoxicity of hemiesters and hemiamides varied as the chain lengths varied. The oxalic and malonic hemiesters showed weaker cytototoxicity than oleanolic acid, while those with longer chain lengths showed higher cytotoxicity. Contrary to the cytotoxic activity, the free amino derivatives showed little inhibitory activity on HCV protease. All the hemiesters and hemiamides showed high activity against HCV protease.


CONCLUSIONS
The findings that addition of amino-group enhanced the cytotoxicity and that introduction of acidic group increased the inhibition on HCV protease may be useful for further design and synthesis of triterpene derivatives as drug candidates for liver diseases.
Ma
Chao-Mei
CM
Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, Japan. mchaomei@hotmail.com
Wu
Xiu-Hong
XH
Masao
Hattori
H
Wang
Xi-Jun
XJ
Kano
Yoshihiro
Y
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008113:Liver Neoplasms / Q000188:drug therapy; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009828:Oleanolic Acid; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases