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Issue 24, 2003

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

Author affiliations

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-γ (IFN-γ) in mouse macrophages. One of these compounds, (±)-(4aβ,8aβ,10aα)-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 in vivo study using mouse peritoneal inflammation induced by thioglycollate and IFN-γ. 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 (4aβ,8aβ,10aα)-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.

Graphical abstract: 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

Article information


Submitted
01 Jul 2003
Accepted
10 Oct 2003
First published
31 Oct 2003

Org. Biomol. Chem., 2003,1, 4384-4391
Article type
Paper

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

T. Honda, F. G. Favaloro, Jr., T. Janosik, Y. Honda, N. Suh, M. B. Sporn and G. W. Gribble, Org. Biomol. Chem., 2003, 1, 4384 DOI: 10.1039/B307491A

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