Novel synthetic oleanane and ursane triterpenoids with various enone functionalities in ring A as inhibitors of nitric oxide production in mouse macrophages.
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.
Honda
T
T
Department of Chemistry, Dartmouth College, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Gribble
G W
GW
Suh
N
N
Finlay
H J
HJ
Rounds
B V
BV
Bore
L
L
Favaloro
F G
FG
Wang
Y
Y
Sporn
M B
MB
D000818:Animals; D015195:Drug Design; D005260:Female; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D011965:Receptors, Glucocorticoid / Q000187:drug effects; D011994:Recombinant Proteins; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D011965:Receptors, Glucocorticoid; D011994:Recombinant Proteins; D009569:Nitric Oxide; D007371:Interferon-gamma