Synthetic oleanane and ursane triterpenoids with modified rings A and C: Aseries of highly active inhibitors of nitric oxide production in mouse macrophages

We have designed and synthesized 16 new olean- and urs-1-en-3-one triterpen oids with various modified rings C as potential antiinflammatory and cancer chemopreventive agents and evaluated their inhibitory activities against p roduction of nitric oxide induced by interferon-gamma in mouse macrophages. This investigation revealed that 9(11)-en-12-one and 12-en-11-one function alities in ring C increase the potency by about 2-10 times compared with th e original 12-ene, Subsequently, we have designed and synthesized novel ole an- and urs-1-en-3-one derivatives with nit;rile and carboxyl groups at. C- 2 in ring A and with 9(11)-en-12-one and 12-en-11-one functionalities in ri ng C. Among them, we have found that methyl 2-cyano-3, 12-dioxoolcana-1,9(1 1)-dien-28-oate (26), 2-cyano-3, 12-dioxooleana-1,9(11)-dien-28-oic acid (C DDO) (28), and methyl 2-carboxy-3,12-dioxooleana-1,9(11)-dien-28-oate (29) have extremely high potency (IC50 = 0.1 nM level). Their potency is similar to that of dexamethasone although they do not act through the glucocortico id receptor. Overall, the combination of modified rings A and C increases t he potency by about 10 000 times compared with the lead compound, 3-oxoolea na-1,12-dien-28-oic acid (8) (IC50 = 1 muM level). The selected oleanane tr iterpenoid, CDDO (26), was found to be a potent, multifunctional agent in v arious in vitro assays and to show antiinflammatory activity against thiogl ycollate-interferon-gamma -induced mouse peritonitis.