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 |
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Authors: | Yasuhiro Yamazaki Kengo Yasuda Tensei Matsuyama Takuya Ishihara Ryoko Higa Taira Sawairi Masahiko Yamaguchi Masahiro Egi Shuji Akai Toshio Miyase Akira Ikari Masao Miwa Junko Sugatani |
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Institution: | 1. Department of Pharmaco-Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan;2. Department of Synthetic Organic Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan;3. Institute for Environmental Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan |
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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. |
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Keywords: | PAF platelet-activating factor 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine c-PAF 1-hexadecyl-2-N-methylcarbamyl-sn-glycero-3-phosphocholine lyso-PAF 1-O-alkyl-sn-glycero-3-phosphocholine LPCAT2 lysophosphatidylcholine acyltransferase 2 HPLC high-performance liquid chromatography HRMS high resolution mass spectrometer DART direct analysis in real time TLC thin layer chromatography TCA trichloroacetic acid LPS lipopolysaccharide BMDMs bone marrow-derived macrophages NDGA nordihydroguaiaretic acid FUD-1 3 4-dihydroxy-1 2-dimethoxy-5-methylbenzene FUD-2 2-methoxy-5-methyl-1 3 4-triacetoxybenzene FUD-3 1 4-diacetoxy-2-methoxy-5-methyl-3-tetradecanoyloxybenzene FUD-4 3-hydroxy-2-methoxy-5-methyl-1 4-benzoquinone (fumigatin) FUD-5 3-acetoxy-2-methoxy-5-methyl-1 4-benzoquinone FUD-6 3-hexanoyloxy-2-methoxy-5-methyl-1 4-benzoquinone FUD-7 3-decanoyloxy-2-methoxy-5-methyl-1 4-benzoquinone FUD-8 2-methoxy-5-methyl-3-tetradecanoyloxy-1 4-benzoquinone FUD-9 2-methoxy-5-methyl-3-octadecanoyloxy-1 4-benzoquinone |
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