{"title":"从海洋真菌中发现作为磷酸二酯酶 4 抑制剂的氧化对三联苯。","authors":"Jian Cai, Qian Zhou, Xin Qi, Furong Zhang, Jiafan Yang, Chunmei Chen, Kai Zhang, Zhexin Chen, Hai-Bin Luo, Yonghong Liu, Yi-You Huang, Xuefeng Zhou","doi":"10.1021/acs.jnatprod.4c00422","DOIUrl":null,"url":null,"abstract":"<p><p>Four new <i>p</i>-terphenyl derivatives, talaroterphenyls A-D (<b>1</b>-<b>4</b>), together with three biosynthetically related known ones (<b>5</b>-<b>7</b>), were obtained from the mangrove sediment-derived <i>Talaromyces</i> sp. SCSIO 41412. Compounds <b>1</b>-<b>3</b> are rare <i>p</i>-terphenyls, which are completely substituted on the central benzene ring by oxygen atoms; this is the first report of their isolation from natural sources. Their structures were elucidated through NMR spectroscopy, HRESIMS, and X-ray diffraction. Genome sequence analysis revealed that <b>1</b>-<b>7</b> were biosynthesized from tyrosine and phenylalanine, involving four key biosynthetic genes (<i>ttpB</i>-<i>ttpE</i>). These <i>p</i>-terphenyls (<b>1</b>-<b>7</b>) and 36 marine-derived terphenyl analogues (<b>8</b>-<b>43</b>) were screened for phosphodiesterase 4 (PDE4) inhibitory activities, and <b>1</b>-<b>5</b>, <b>14</b>, <b>17</b>, <b>23</b>, and <b>26</b> showed notable activities with IC<sub>50</sub> values of 0.40-16 μM. The binding pattern of <i>p</i>-terphenyl inhibitors <b>1</b>-<b>3</b> with PDE4 were explored by molecular docking analysis. Talaroterphenyl A (<b>1</b>), with a low cytotoxicity, showed obvious anti-inflammatory activity in LPS-stimulated RAW264.7 cells. Furthermore, in the TGF-β1-induced medical research council cell strain-5 (MRC-5) pulmonary fibrosis model, <b>1</b> could down-regulate the expression levels of FN1, COL1, and α-SMA significantly at concentrations of 5-20 μM. This study suggests that the oxidized <i>p</i>-terphenyl <b>1</b>, as a marine-derived PDE4 inhibitor, could be used as a promising antifibrotic agent.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery of Oxidized <i>p</i>-Terphenyls as Phosphodiesterase 4 Inhibitors from Marine-Derived Fungi.\",\"authors\":\"Jian Cai, Qian Zhou, Xin Qi, Furong Zhang, Jiafan Yang, Chunmei Chen, Kai Zhang, Zhexin Chen, Hai-Bin Luo, Yonghong Liu, Yi-You Huang, Xuefeng Zhou\",\"doi\":\"10.1021/acs.jnatprod.4c00422\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Four new <i>p</i>-terphenyl derivatives, talaroterphenyls A-D (<b>1</b>-<b>4</b>), together with three biosynthetically related known ones (<b>5</b>-<b>7</b>), were obtained from the mangrove sediment-derived <i>Talaromyces</i> sp. SCSIO 41412. Compounds <b>1</b>-<b>3</b> are rare <i>p</i>-terphenyls, which are completely substituted on the central benzene ring by oxygen atoms; this is the first report of their isolation from natural sources. Their structures were elucidated through NMR spectroscopy, HRESIMS, and X-ray diffraction. Genome sequence analysis revealed that <b>1</b>-<b>7</b> were biosynthesized from tyrosine and phenylalanine, involving four key biosynthetic genes (<i>ttpB</i>-<i>ttpE</i>). These <i>p</i>-terphenyls (<b>1</b>-<b>7</b>) and 36 marine-derived terphenyl analogues (<b>8</b>-<b>43</b>) were screened for phosphodiesterase 4 (PDE4) inhibitory activities, and <b>1</b>-<b>5</b>, <b>14</b>, <b>17</b>, <b>23</b>, and <b>26</b> showed notable activities with IC<sub>50</sub> values of 0.40-16 μM. The binding pattern of <i>p</i>-terphenyl inhibitors <b>1</b>-<b>3</b> with PDE4 were explored by molecular docking analysis. Talaroterphenyl A (<b>1</b>), with a low cytotoxicity, showed obvious anti-inflammatory activity in LPS-stimulated RAW264.7 cells. Furthermore, in the TGF-β1-induced medical research council cell strain-5 (MRC-5) pulmonary fibrosis model, <b>1</b> could down-regulate the expression levels of FN1, COL1, and α-SMA significantly at concentrations of 5-20 μM. This study suggests that the oxidized <i>p</i>-terphenyl <b>1</b>, as a marine-derived PDE4 inhibitor, could be used as a promising antifibrotic agent.</p>\",\"PeriodicalId\":47,\"journal\":{\"name\":\"Journal of Natural Products \",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2024-07-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Natural Products \",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.jnatprod.4c00422\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/6/29 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Natural Products ","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1021/acs.jnatprod.4c00422","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/6/29 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Discovery of Oxidized p-Terphenyls as Phosphodiesterase 4 Inhibitors from Marine-Derived Fungi.
Four new p-terphenyl derivatives, talaroterphenyls A-D (1-4), together with three biosynthetically related known ones (5-7), were obtained from the mangrove sediment-derived Talaromyces sp. SCSIO 41412. Compounds 1-3 are rare p-terphenyls, which are completely substituted on the central benzene ring by oxygen atoms; this is the first report of their isolation from natural sources. Their structures were elucidated through NMR spectroscopy, HRESIMS, and X-ray diffraction. Genome sequence analysis revealed that 1-7 were biosynthesized from tyrosine and phenylalanine, involving four key biosynthetic genes (ttpB-ttpE). These p-terphenyls (1-7) and 36 marine-derived terphenyl analogues (8-43) were screened for phosphodiesterase 4 (PDE4) inhibitory activities, and 1-5, 14, 17, 23, and 26 showed notable activities with IC50 values of 0.40-16 μM. The binding pattern of p-terphenyl inhibitors 1-3 with PDE4 were explored by molecular docking analysis. Talaroterphenyl A (1), with a low cytotoxicity, showed obvious anti-inflammatory activity in LPS-stimulated RAW264.7 cells. Furthermore, in the TGF-β1-induced medical research council cell strain-5 (MRC-5) pulmonary fibrosis model, 1 could down-regulate the expression levels of FN1, COL1, and α-SMA significantly at concentrations of 5-20 μM. This study suggests that the oxidized p-terphenyl 1, as a marine-derived PDE4 inhibitor, could be used as a promising antifibrotic agent.
期刊介绍:
The Journal of Natural Products invites and publishes papers that make substantial and scholarly contributions to the area of natural products research. Contributions may relate to the chemistry and/or biochemistry of naturally occurring compounds or the biology of living systems from which they are obtained.
Specifically, there may be articles that describe secondary metabolites of microorganisms, including antibiotics and mycotoxins; physiologically active compounds from terrestrial and marine plants and animals; biochemical studies, including biosynthesis and microbiological transformations; fermentation and plant tissue culture; the isolation, structure elucidation, and chemical synthesis of novel compounds from nature; and the pharmacology of compounds of natural origin.
When new compounds are reported, manuscripts describing their biological activity are much preferred.
Specifically, there may be articles that describe secondary metabolites of microorganisms, including antibiotics and mycotoxins; physiologically active compounds from terrestrial and marine plants and animals; biochemical studies, including biosynthesis and microbiological transformations; fermentation and plant tissue culture; the isolation, structure elucidation, and chemical synthesis of novel compounds from nature; and the pharmacology of compounds of natural origin.