We have designed and synthesized 16 new olean- and urs-1-en-3-one triterpenoids with various modified rings C as potential antiinflammatory and cancer chemopreventive agents and evaluated their inhibitory activities against production of nitric oxide induced by interferon-gamma in mouse macrophages. This investigation revealed that 9(11)-en-12-one and 12-en-11-one functionalities in ring C increase the potency by about 2-10 times compared with the original 12-ene. Subsequently, we have designed and synthesized novel olean- and urs-1-en-3-one derivatives with nitrile and carboxyl groups at C-2 in ring A and with 9(11)-en-12-one and 12-en-11-one functionalities in ring C. Among them, we have found that methyl 2-cyano-3, 12-dioxooleana-1,9(11)-dien-28-oate (25), 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) (26), and methyl 2-carboxy-3,12-dioxooleana-1,9(11)-dien-28-oate (29) have extremely high potency (IC(50) = 0.1 nM level). Their potency is similar to that of dexamethasone although they do not act through the glucocorticoid receptor. Overall, the combination of modified rings A and C increases the potency by about 10 000 times compared with the lead compound, 3-oxooleana-1,12-dien-28-oic acid (8) (IC(50) = 1 microM level). The selected oleanane triterpenoid, CDDO (26), was found to be a potent, multifunctional agent in various in vitro assays and to show antiinflammatory activity against thioglycollate-interferon-gamma-induced mouse peritonitis.

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The previously reported inhibitor of nitric oxide production CDDO is further modified to form derivative (VI) which is found to be an alternative agent to CDDO. -(HONDA, TADASHI; ROUNDS, BARBIEANN V.; BORE, LOTHAR; FAVALORO JR., FRANK G.; GRIBBLE, GORDON W.; SUH, NANJOO; WANG, YONGPING; SPORN, MICHAEL B.; Bioorg. Med. Chem. Lett. 9 (1999) 24, 3429-3434; Dep. Chem., Dartmouth Coll., Hanover, NH 03755, USA; EN)

Design and Synthesis of 2-Cyano-3,12-dioxoolean-1,9-dien-28-oic Acid, a Novel and Highly Active Inhibitor of Nitric Oxide Production in Mouse Macrophages.-Several new derivatives with electronwithdrawing substituents at the C-2 position of 3-oxoolean-1-en-28-oic acid are prepared and tested as inhibitors of the production of nitric oxide induced by interferon-γ in mouse macrophages. Among the compounds prepared, (VII) is the most effective one. The potency of (VII) is similar to that of dexamethasone though it does not act through the glucocorticoid receptor. -(HONDA, T.; ROUNDS, B. V.; GRIBBLE, G. W.; SUH, N.; WANG, Y.; SPORN, M. B.; Bioorg. Med.

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