Chemical modification of oleanene type triterpenes and their inhibitory activity against HIV-1 protease dimerization.
Oleanolic acid derivatives with different lengths of 3-O-acidic acyl chains were synthesized and evaluated for their inhibitory activity against HIV-1 protease. The lengths of the acidic chains were optimized to 6 and 8 carbons. Changing a 3-ester bond to an amide bond or dimerization of the triterpenes retained their inhibitory activity against HIV-1 protease. Introduction of an additional acidic chain to C-28 of oleanolic acid increased the inhibitory activity appreciably, though a derivative with only one acidic chain linked at C-28 also showed potent activity against HIV-1 protease. The inhibitory mechanism was proved directly by size exclusion chromatography to be inhibition of dimerization of the enzyme polypeptides. The ester bonds of the triterpene derivatives were found to be stable to lipase under mild alkaline conditions.
Chao-Ma
Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, Japan.
Nakamura
N
N
Hattori
M
M
D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D019281:Dimerization; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D008049:Lipase / Q000037:antagonists & inhibitors; D008745:Methylation; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000138:chemical synthesis* / Q000494:pharmacology
D017320:HIV Protease Inhibitors; D014315:Triterpenes; D009828:Oleanolic Acid; D008049:Lipase