Synthetic oleanane and ursane triterpenoids with modified rings A and C: a series of highly active inhibitors of nitric oxide production in mouse macrophages.
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.
Honda
T
T
Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, USA.
Rounds
B V
BV
Bore
L
L
Finlay
H J
HJ
Favaloro
F G
FG
Suh
N
N
Wang
Y
Y
Sporn
M B
MB
Gribble
G W
GW
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D007371:Interferon-gamma; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010538:Peritonitis / Q000139:chemically induced / Q000473:pathology; D013329:Structure-Activity Relationship; D013864:Thioglycolates; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D013864:Thioglycolates; D014315:Triterpenes; D009569:Nitric Oxide; D009828:Oleanolic Acid; C017487:2-mercaptoacetate; D007371:Interferon-gamma