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

T. Honda, B. V. Rounds, L. Bore, H. J. Finlay, F. G. Favaloro, N. Suh, Y. Wang, M. B. Sporn, G. W. Gribble

Research output: Contribution to journalArticle

206 Scopus citations

Abstract

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-γ 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 (IC50 = 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) (IC50 = 1 μM 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-γ-induced mouse peritonitis.

Original languageEnglish (US)
Pages (from-to)4233-4246
Number of pages14
JournalJournal of medicinal chemistry
Volume43
Issue number22
DOIs
StatePublished - Nov 2 2000
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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