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

• Published in: Organic & biomolecular chemistry 2003-12, Vol.1 (24), p.4384-4391
• Main Authors: Honda, Tadashi, Favaloro, Jr, Frank G, Janosik, Tomasz, Honda, Yukiko, Suh, Nanjoo, Sporn, Michael B, Gribble, Gordon W
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Interferon-gamma - chemistry; Macrophages - drug effects; Macrophages - metabolism; Mice; Models, Chemical; Molecular Structure; Nitric Oxide - antagonists & inhibitors; Nitric Oxide - biosynthesis; Nitriles - chemical synthesis; Nitriles - chemistry; Nitriles - pharmacology; Oleanolic Acid - analogs & derivatives; Oleanolic Acid - chemical synthesis; Oleanolic Acid - chemistry; Oleanolic Acid - pharmacology; Peritonitis - chemically induced; Peritonitis - drug therapy; Phenanthrenes - chemical synthesis; Phenanthrenes - chemistry; Phenanthrenes - pharmacology; Stereoisomerism; Structure-Activity Relationship; Thioglycolates - chemistry
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/b307491a

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.