NOVEL TRITERPENOIDS SUPPRESS INDUCIBLE NITRIC-OXIDE SYNTHASE (INOS) AND INDUCIBLE CYCLOOXYGENASE (COX-2) IN MOUSE MACROPHAGES

We have synthesized more than 80 novel triterpenoids, all derivatives of oleanolic and ursolic acid, as potential anti-inflammatory and chem opreventive agents, These triterpenoids have been tested for their abi lity to suppress the de novo formation of two enzymes, inducible nitri c oxide synthase (iNOS) and inducible cyclooxygenase (COX-2), using IF N-gamma-stimulated primary mouse macrophages or lipopolysaccharide (LP S)activated RAW 264.7 macrophages as assay systems, Two synthetic olea nanes, 3,12-dioxoolean-1-en-28-oic acid (TP-69) and 3,11-dioxoolean-1, 12-dien-28-oic acid (TP-72), were highly active inhibitors of de novo formation of both iNOS and COX-2, Both TP-69 and TP-72 blocked the inc rease in iNOS or COX-2 mRNA induced by IFN-gamma or LPS. In addition, TP-72 suppressed NF-kappa B activation in primary macrophages treated with the combination of IFN-gamma and LPS or IFN-gamma and tumor necro sis factor, The 3-alpha(axial)-epimer of ursolic acid suppressed de no vo formation of COX-2, in contrast to naturally occurring 3-beta(equat orial)-ursolic acid. Inhibitory effects of TP-69 or TP-72 on iNOS form ation were not blocked by the glucocorticoid receptor antagonist RU-48 6, indicating that these triterpenoids do not act through the glucocor ticoid receptor, nor does TP-72 act as an iNOS or COX-2 enzyme inhibit or when added to RAW cells in which synthesis of these two enzymes in response to LPS has already been induced, It may be possible to develo p triterpenoids as useful agents for chemoprevention of cancer or othe r chronic diseases with an inflammatory component.