2-Methyl-2-(2-methylpropenyl)-2,3-dihydronaphtho[2,3-b]furan-4,9-dione (NFD-37) is a synthetic furonaphthoquinone compound. In the present study, the NFD-37 compound was found to inhibit prostaglandin (PG) E-2 production in lipopolysaccharide (LPS)-stimulated macrophages RAW 264.7. NFD-37 compound exhibited a preferred inhibition on enzyme activity of cyclooxygenase (COX)-2 over COX-1. Further, NFD-37 compound attenuated LPS-induced synthesis of both mRNA and protein of COX-2, and suppressed LPS-induced COX-2 promoter activity in the macrophages, indicating that the furonaphthoquinone compound could down-regulate LPS-induced COX-2 expression at the transcription level. Even though COX-2 promoter behaves as a sophisticated biosensor for host defense, nuclear factor (NF)-kappa B activation has been evidenced to play a major mechanism for LPS-induced COX-2 expression in macrophages. NFD-37 compound exhibited a dose-dependent inhibitory effect on LPS-induced phosphorylation of inhibitory kappa B alpha (I kappa B alpha) protein, and subsequently inhibited I kappa B alpha degradation, DNA binding activity of NF-kappa B complex as well as NF-kappa B transcriptional activity in macrophages RAW 264.7. In another experiment, NFD-37 compound inhibited both COX-2 promoter activity and GST-I kappa B alpha phosphorylation elicited by an expression vector encoding I kappa B kinase beta. Taken together, NFD-37 compound inhibited enzyme activity of COX-2 but also suppressed COX-2 expression depending on NF-kappa B activation, and thus could provide an invaluable tool to investigate pharmacological potential in the excess PG-related disorders. (c) 2005 Elsevier Inc. All rights reserved.