HCV protease inhibitory, cytotoxic and apoptosis-inducing effects of oleanolic acid derivatives

Abstract

Purpose. 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 as well as for their cytotoxic and apoptosis-inducing effects on Hep G2 cells. Results. The amino derivatives (17-19) showed potent cytotoxicity. The β-amino isomer (18) showed strong apoptosis-inducing effect and exhibited more distinct cytotoxicity than the α-isomer. The cytotoxicity of hemiesters and hemiamides varied as the chain lengths varied. The oxalic and malonic hemiesters (4 and 5) showed weaker cytototoxicity than oleanolic acid (1), while those with longer chain lengths (6-11) showed higher cytotoxicity. Contrary to the cytotoxic activity, the free amino derivatives (17-19) showed little inhibitory activity on HCV protease. All the hemiesters (4-11) and hemiamides (4-11) showed high activity against HCV protease. Conclusion. 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.