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.

Abstract

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.

• Authors: Tadashi Honda, Frank G Favaloro Jr, Tomasz Janosik, Yukiko Honda, Nanjoo Suh, Michael B Sporn, Gordon W Gribble
• Journal: Organic & biomolecular chemistry (Org Biomol Chem) Vol. 1 Issue 24 Pg. 4384-91 (Dec 21 2003) ISSN: 1477-0520 [Print] England
• PMID: 14685310 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid
• Anti-Inflammatory Agents, Non-Steroidal
• Antineoplastic Agents
• Nitriles
• Phenanthrenes
• Thioglycolates
• Nitric Oxide
• Oleanolic Acid
• Interferon-gamma

Topics

• Administration, Oral
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemical synthesis, chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Interferon-gamma (chemistry)
• Macrophages (drug effects, metabolism)
• Mice
• Models, Chemical
• Molecular Structure
• Nitric Oxide (antagonists & inhibitors, biosynthesis)
• Nitriles (chemical synthesis, chemistry, pharmacology)
• Oleanolic Acid (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Peritonitis (chemically induced, drug therapy)
• Phenanthrenes (chemical synthesis, chemistry, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship
• Thioglycolates (chemistry)