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

J Med Chem. 2000 May 4;43(9):1866-77. doi: 10.1021/jm000008j.


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.

Publication types

  • 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.

MeSH terms

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


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