Efficient synthesis of (-)- and (+)-tricyclic compounds with enone functionalities in rings A and C. A novel class of orally active anti-inflammatory and cancer chemopreventive agents.
Novel tricyclic compounds with enone functionalities in rings A and C [tricyclic-bis-enone (TBE) compounds] were designed on the basis of the structure of a synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO)(1), which is a promising drug candidate for prevention and/or treatment of cancer and inflammatory diseases whose pathogenesis may involve excessive production of nitric oxide (NO) and/or prostaglandins. A series of TBE compounds in racemic form shows high inhibitory activity against production of NO induced by interferon-[gamma](IFN-[gamma]) in mouse macrophages. One of these compounds, (+/-)-(4a[small beta],8a[small beta],10a[small alpha])-1,2,4a,6,8a,9,10,10a-octahydro-1,1,4a,8a-tetramethyl-2,6-dioxophenanthrene-3,7-dicarbonitrile ((+/-)-3), is orally active at 15 mg kg(-1)(single administration) in a preliminary study using mouse peritoneal inflammation induced by thioglycollate and IFN-[gamma]. Therefore, we desired to synthesize optically active TBE compounds for a comparison of the biological potency of both enantiomers. We now describe the synthesis of both enantiomers of (4a[small beta],8a[small beta],10a[small alpha])-1,2,4a,6,8a,9,10,10a-octahydro-1,1,4a,8a-tetramethyl-2,6-dioxophenanthrene-3-carbonitrile (2) and 3 from commercially available simple compounds. Interestingly, (+)-3 having the same configuration as the CDDO antipode shows about 10 times higher inhibitory activity than (-)-3 on NO production in mouse macrophages. In contrast, (-)-3 inhibits proliferation of MCF-7 breast cancer cells, whereas (+)-3 does not.
Honda
Tadashi
T
Department of Chemistry, Dartmouth College, 6128 Burke Laboratory, Hanover, New Hampshire 03755, USA. th9@dartmouth.edu
Favaloro
Frank G
FG
Janosik
Tomasz
T
Honda
Yukiko
Y
Suh
Nanjoo
N
Sporn
Michael B
MB
Gribble
Gordon W
GW
D000284:Administration, Oral; 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; D007371:Interferon-gamma / Q000737:chemistry; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010538:Peritonitis / Q000139:chemically induced / Q000188:drug therapy; D010616:Phenanthrenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013864:Thioglycolates / Q000737:chemistry
C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D009570:Nitriles; D010616:Phenanthrenes; D013864:Thioglycolates; D009569:Nitric Oxide; D009828:Oleanolic Acid; D007371:Interferon-gamma