{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:08:46Z","timestamp":1785434926614,"version":"3.56.0"},"reference-count":33,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82373748"],"award-info":[{"award-number":["82373748"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82373748"],"award-info":[{"award-number":["82373748"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Shandong Provincial Natural Science Foundation","doi-asserted-by":"publisher","award":["ZR2025LSW047"],"award-info":[{"award-number":["ZR2025LSW047"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81973198"],"award-info":[{"award-number":["81973198"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82111540166"],"award-info":[{"award-number":["82111540166"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["81973198"],"award-info":[{"award-number":["81973198"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82111540166"],"award-info":[{"award-number":["82111540166"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Mar. Drugs","Marine Drugs"],"abstract":"<jats:p>Marine-associated polar fungi are promising sources of structurally diverse natural products. To investigate polyketide metabolites from the Antarctic moss-derived fungus Penicillium sp. OUCMDZ-4014, HSQC NMR combined with DeepSAT analysis was used to prioritize fractions enriched in cyclic and aromatic polyketides, and chromane-like metabolites. Chromatographic separation yielded ten resorcylic acid lactone-derived aromatic polyketides, including RAL macrolides, ring-opened esters, and isocoumarins, among which compounds 4\u20137 were new. Their planar structures were established by HRESIMS and 1D\/2D NMR analyses. Their chemical structures including configurations were established by HRESIMS, 1D\/2D NMR, ECD calculations, 13C NMR calculations, and DP4+ analysis. Isocoumarins 7\u201310 displayed diverse levels of \u03b1-glucosidase inhibition, with compound 9 being the most active (IC50 = 47.0 \u00b1 3.83 \u03bcM). Kinetic analysis indicated noncompetitive inhibition by 9 and mixed-type inhibition by 10. Genome mining revealed a putative res biosynthetic gene cluster containing HR-PKS, NR-PKS, and tailoring-enzyme genes. Compound 1 underwent nonenzymatic conversion into 9 under culture-medium conditions, while trace conversion was also observed during concentration, revealing a chemical link between the RAL macrolide and isocoumarin scaffolds, and highlighting the contribution of post-biosynthetic chemical transformation to fungal polyketide diversification.<\/jats:p>","DOI":"10.3390\/md24080256","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T13:53:26Z","timestamp":1784901206000},"page":"256","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Resorcylic Acid Lactones and Isocoumarin Derivatives from the Marine-Associated Polar Fungus Penicillium sp. OUCMDZ-4014"],"prefix":"10.3390","volume":"24","author":[{"given":"Deng","family":"Yu","sequence":"first","affiliation":[{"name":"School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongtian","family":"Du","sequence":"additional","affiliation":[{"name":"School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuehan","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengze","family":"An","sequence":"additional","affiliation":[{"name":"School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyang","family":"Ding","sequence":"additional","affiliation":[{"name":"School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiapeng","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7591-3264","authenticated-orcid":false,"given":"Weiming","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China"},{"name":"Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Centre, Qingdao 266237, China"},{"name":"Key Laboratory of Marine Drugs, Ministry of Education of China, Ocean University of China, Qingdao 266003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8235-2952","authenticated-orcid":false,"given":"Yi","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China"},{"name":"Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Centre, Qingdao 266237, China"},{"name":"Key Laboratory of Marine Drugs, Ministry of Education of China, Ocean University of China, Qingdao 266003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1021\/acs.jnatprod.9b01285","article-title":"Natural Products as Sources of New Drugs over the Nearly Four Decades from 01\/1981 to 09\/2019","volume":"83","author":"Newman","year":"2020","journal-title":"J. Nat. Prod."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1039\/D2NP00083K","article-title":"Marine natural products","volume":"40","author":"Carroll","year":"2023","journal-title":"Nat. Prod. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1039\/c0np00061b","article-title":"Secondary metabolites of fungi from marine habitats","volume":"28","author":"Rateb","year":"2011","journal-title":"Nat. Prod. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Imhoff, J.F. (2016). Natural Products from Marine Fungi\u2014Still an Underrepresented Resource. Mar. Drugs, 14.","DOI":"10.3390\/md14010019"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Tian, Y., Li, Y.-L., and Zhao, F.-C. (2017). Secondary Metabolites from Polar Organisms. Mar. Drugs, 15.","DOI":"10.3390\/md15030028"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17803","DOI":"10.1039\/C8NJ02534G","article-title":"Resorcylic Acid Lactones (RALs) and Their Structural Congeners: Recent Advances in Their Biosynthesis, Chemical Synthesis and Biology","volume":"42","author":"Jana","year":"2018","journal-title":"New J. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1248\/cpb.56.1355","article-title":"8\u2032-Hydroxyzearalanone and 2\u2032-Hydroxyzearalanol: Resorcyclic Acid Lactone Derivatives from the Marine-Derived Fungus Penicillium sp","volume":"56","author":"Yang","year":"2008","journal-title":"Chem. Pharm. Bull."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3183","DOI":"10.1021\/jf500248z","article-title":"Antifouling and Fungicidal Resorcylic Acid Lactones from the Sea Anemone-Derived Fungus Cochliobolus lunatus","volume":"62","author":"Liu","year":"2014","journal-title":"J. Agric. Food Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"39870","DOI":"10.1039\/C5RA02203G","article-title":"Structure, Absolute Configuration, and Conformational Study of Resorcylic Acid Derivatives and Related Congeners from the Fungus Penicillium brocae","volume":"5","author":"Zhang","year":"2015","journal-title":"RSC Adv."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5121","DOI":"10.1128\/AEM.00478-08","article-title":"Genes for the Biosynthesis of the Fungal Polyketides Hypothemycin from Hypomyces subiculosus and Radicicol from Pochonia chlamydosporia","volume":"74","author":"Reeves","year":"2008","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4530","DOI":"10.1021\/ja100060k","article-title":"Enzymatic Synthesis of Resorcylic Acid Lactones by Cooperation of Fungal Iterative Polyketide Synthases Involved in Hypothemycin Biosynthesis","volume":"132","author":"Zhou","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Noor, A.O., Almasri, D.M., Bagalagel, A.A., Abdallah, H.M., Mohamed, S.G.A., Mohamed, G.A., and Ibrahim, S.R.M. (2020). Naturally Occurring Isocoumarins Derivatives from Endophytic Fungi: Sources, Isolation, Structural Characterization, Biosynthesis, and Biological Activities. Molecules, 25.","DOI":"10.3390\/molecules25020395"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"24","DOI":"10.2174\/1872208316666220512122439","article-title":"Antidiabetic Agents from Fungi with Special Reference to \u03b1-Glucosidase Inhibitors","volume":"17","author":"Deshmukh","year":"2023","journal-title":"Recent Pat. Biotechnol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"106555","DOI":"10.1016\/j.fitote.2025.106555","article-title":"Isocoumarin and Pyranone Derivatives Isolated from the Mangrove-Associated Fungus Exserohilum rostratum NS-KS-3 as \u03b1-Glucosidase Inhibitors","volume":"183","author":"Bian","year":"2025","journal-title":"Fitoterapia"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"9957","DOI":"10.1039\/C5OB01713K","article-title":"Dereplication of Natural Products Using Minimal NMR Data Inputs","volume":"13","author":"Williams","year":"2015","journal-title":"Org. Biomol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1021\/acs.jnatprod.1c00841","article-title":"Dereplication of Fungal Metabolites by NMR-Based Compound Networking Using MADByTE","volume":"85","author":"Egan","year":"2022","journal-title":"J. Nat. Prod."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s13321-023-00738-4","article-title":"DeepSAT: Learning Molecular Structures from Nuclear Magnetic Resonance Data","volume":"15","author":"Kim","year":"2023","journal-title":"J. Cheminform."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/s41579-018-0121-1","article-title":"Fungal Secondary Metabolism: Regulation, Function and Drug Discovery","volume":"17","author":"Keller","year":"2019","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"27396","DOI":"10.1038\/srep27396","article-title":"Penicimenolides A\u2013F, Resorcylic Acid Lactones from Penicillium sp., Isolated from the Rhizosphere Soil of Panax notoginseng","volume":"6","author":"An","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6928","DOI":"10.1002\/ejoc.201001237","article-title":"Curvularin-Type Metabolites from the Fungus Curvularia sp. Isolated from a Marine Alga","volume":"2010","author":"Dai","year":"2010","journal-title":"Eur. J. Org. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5085","DOI":"10.1002\/ejoc.200800522","article-title":"Apralactone A and a New Stereochemical Class of Curvularins from the Marine-Derived Fungus Curvularia sp","volume":"2008","author":"Greve","year":"2008","journal-title":"Eur. J. Org. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10783","DOI":"10.1021\/ja4041362","article-title":"Thioesterase Domains of Fungal Nonreducing Polyketide Synthases Act as Decision Gates during Combinatorial Biosynthesis","volume":"135","author":"Xu","year":"2013","journal-title":"J. Am. Chem. Soc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5398","DOI":"10.1073\/pnas.1301201110","article-title":"Rational Reprogramming of Fungal Polyketide First-Ring Cyclization","volume":"110","author":"Xu","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"12354","DOI":"10.1073\/pnas.1406999111","article-title":"Diversity-Oriented Combinatorial Biosynthesis of Benzenediol Lactone Scaffolds by Subunit Shuffling of Fungal Polyketide Synthases","volume":"111","author":"Xu","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1021\/np970200x","article-title":"New Macrocyclic Lactones from a Penicillium Species","volume":"60","author":"Barrow","year":"1997","journal-title":"J. Nat. Prod."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1021\/cb500043g","article-title":"Insights into the Biosynthesis of 12-Membered Resorcylic Acid Lactones from Heterologous Production in Saccharomyces cerevisiae","volume":"9","author":"Xu","year":"2014","journal-title":"ACS Chem. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"26412","DOI":"10.1039\/C6RA02566H","article-title":"Isocoumarins and Benzofurans from the Mangrove Endophytic Fungus Talaromyces amestolkiae Possess \u03b1-Glucosidase Inhibitory and Antibacterial Activities","volume":"6","author":"Chen","year":"2016","journal-title":"RSC Adv."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"W46","DOI":"10.1093\/nar\/gkad344","article-title":"antiSMASH 7.0: New and Improved Predictions for Detection, Regulation, Chemical Structures and Visualisation","volume":"51","author":"Blin","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e110","DOI":"10.1093\/nar\/gkz654","article-title":"A Deep Learning Genome-Mining Strategy for Biosynthetic Gene Cluster Prediction","volume":"47","author":"Hannigan","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"W309","DOI":"10.1093\/nar\/gkh379","article-title":"AUGUSTUS: A Web Server for Gene Finding in Eukaryotes","volume":"32","author":"Stanke","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Eddy, S.R. (2011). Accelerated Profile HMM Searches. PLoS Comput. Biol., 7.","DOI":"10.1371\/journal.pcbi.1002195"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"D427","DOI":"10.1093\/nar\/gky995","article-title":"The Pfam Protein Families Database in 2019","volume":"47","author":"Mistry","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4350","DOI":"10.1093\/bioinformatics\/btaa213","article-title":"DNA Features Viewer: A Sequence Annotation Formatting and Plotting Library for Python","volume":"36","author":"Zulkower","year":"2020","journal-title":"Bioinformatics"}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/24\/8\/256\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T13:54:36Z","timestamp":1784901276000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/24\/8\/256"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,24]]},"references-count":33,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["md24080256"],"URL":"https:\/\/doi.org\/10.3390\/md24080256","relation":{},"ISSN":["1660-3397"],"issn-type":[{"value":"1660-3397","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,24]]}}}