Novel synthetic oleanane and ursane triterpenoids with various enone functionalities in ring A as inhibitors of nitric oxide production in mouse macrophages.

Abstract

We initially randomly synthesized about 60 oleanane and ursane triterpenoids as potential anti-inflammatory and cancer chemopreventive agents. Preliminary screening of these derivatives for inhibition of production of nitric oxide induced by interferon-gamma in mouse macrophages revealed that 3-oxooleana-1, 12-dien-28-oic acid (B-15) showed significant activity (IC(50) = 5.6 microM). On the basis of the structure of B-15, 19 novel olean- and urs-12-ene triterpenoids with a 1-en-3-one functionality having a substituent at C-2 in ring A have been designed and synthesized. Among them, 3-oxooleana-1,12-diene derivatives with carboxyl, methoxycarbonyl, and nitrile groups at C-2 showed higher activity than the lead compound B-15. In particular, 2-carboxy-3-oxooleana-1, 12-dien-28-oic acid (3) had the highest activity (IC(50) = 0.07 microM) in this group of triterpenoids. The potency of 3 was similar to that of hydrocortisone (IC(50) = 0.01 microM), although 3 does not act through the glucocorticoid receptor. Interesting structure-activity relationships of these novel synthetic triterpenoids are also discussed.

• Authors: T Honda, G W Gribble, N Suh, H J Finlay, B V Rounds, L Bore, F G Favaloro Jr, Y Wang, M B Sporn
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 43 Issue 9 Pg. 1866-77 (May 04 2000) ISSN: 0022-2623 [Print] United States
• PMID: 10794703 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Indicators and Reagents
• Receptors, Glucocorticoid
• Recombinant Proteins
• Nitric Oxide
• Interferon-gamma

Topics

• Animals
• Drug Design
• Female
• In Vitro Techniques
• Indicators and Reagents
• Interferon-gamma (antagonists & inhibitors, pharmacology)
• Macrophages (drug effects, metabolism)
• Magnetic Resonance Spectroscopy
• Mice
• Nitric Oxide (antagonists & inhibitors, biosynthesis)
• Receptors, Glucocorticoid (drug effects)
• Recombinant Proteins
• Spectrophotometry, Infrared
• Spectrophotometry, Ultraviolet
• Structure-Activity Relationship