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Biochem Pharmacol. 2013 Sep 1;86(5):632-44. doi: 10.1016/j.bcp.2013.06.021. Epub 2013 Jun 28.

A Penicillium sp. F33 metabolite and its synthetic derivatives inhibit acetyl-CoA:1-O-alkyl-sn-glycero-3-phosphocholine acetyltransferase (a key enzyme in platelet-activating factor biosynthesis) and carrageenan-induced paw edema in mice.

Author information

1
Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.

Abstract

Acetyl-CoA:1-O-alkyl-sn-glycero-3-phosphocholine (lyso-PAF) acetyltransferase is a key enzyme in the biosynthesis of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (PAF) in inflammatory cells. Substances which inhibit this enzyme are of therapeutic interest. In this study, we screened for new inhibitors of lyso-PAF acetyltransferase with anti-inflammatory effects. In a metabolite from Penicillium sp. F33, we isolated an acetyltransferase inhibitor identified as dihydrofumigatin (2-methoxy-1,3,4-trihydroxy-5-methylbenzene) from high resolution mass spectrometer and NMR data. Dihydrofumigatin had strong acetyltransferase inhibitory activity, but was not stable in aqueous solution. Thus, we chemically synthesized its oxidized form fumigatin (3-hydroxy-2-methoxy-5-methyl-1,4-benzoquinone) and derivatives thereof, and evaluated their inhibitory effects. Strong inhibitory activity was observed for saturated fatty acid esters of fumigatin; the order of inhibition was 3-decanoyloxy-2-methoxy-5-methyl-1,4-benzoquinone (termed FUD-7, IC₅₀ = 3 μM)>2-methoxy-5-methyl-3-tetradecanoyloxy-1,4-benzoquinone (termed FUD-8, IC₅₀ = 20 μM)>3-hexanoyloxy-2-methoxy-5-methyl-1,4-benzoquinone (IC₅₀ = 139 μM). Interestingly, these compounds also significantly suppressed the gene expression of lyso-PAF acetyltransferase/LPCAT2 in mouse bone marrow-derived macrophages stimulated by lipopolysaccharide (LPS). We further evaluated the effect of these substances on anti-inflammatory activity in vivo using the carrageenan-induced mouse paw edema test. FUD-7 and FUD-8 at 2.5 mg/kg showed significant, 47.9-51.7%, inhibition stronger than that of prednisolone at 10 mg/kg (41.9%). These results suggest that FUD-7 and FUD-8 are potent inhibitors with anti-inflammatory activity.

KEYWORDS:

1,4-diacetoxy-2-methoxy-5-methyl-3-tetradecanoyloxybenzene; 1-O-alkyl-sn-glycero-3-phosphocholine; 1-hexadecyl-2-N-methylcarbamyl-sn-glycero-3-phosphocholine; 2-methoxy-5-methyl-1,3,4-triacetoxybenzene; 2-methoxy-5-methyl-3-octadecanoyloxy-1,4-benzoquinone; 2-methoxy-5-methyl-3-tetradecanoyloxy-1,4-benzoquinone; 3,4-dihydroxy-1,2-dimethoxy-5-methylbenzene; 3-acetoxy-2-methoxy-5-methyl-1,4-benzoquinone; 3-decanoyloxy-2-methoxy-5-methyl-1,4-benzoquinone; 3-hexanoyloxy-2-methoxy-5-methyl-1,4-benzoquinone; 3-hydroxy-2-methoxy-5-methyl-1,4-benzoquinone (fumigatin); BMDMs; Carrageenan-induced edema; DART; FUD-1; FUD-2; FUD-3; FUD-4; FUD-5; FUD-6; FUD-7; FUD-8; FUD-9; Fumigatin; HPLC; HRMS; LPCAT2; LPS; Lyso-PAF acetyltransferase; NDGA; PAF; PAF biosynthesis; Platelet activating factor; TCA; TLC; bone marrow-derived macrophages; c-PAF; direct analysis in real time; high resolution mass spectrometer; high-performance liquid chromatography; lipopolysaccharide; lyso-PAF; lysophosphatidylcholine acyltransferase 2; nordihydroguaiaretic acid; platelet-activating factor, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine; thin layer chromatography; trichloroacetic acid

PMID:
23817078
DOI:
10.1016/j.bcp.2013.06.021
[Indexed for MEDLINE]

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