{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:16:53Z","timestamp":1791245813327,"version":"4.1.0"},"reference-count":47,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003566","name":"Ministry of Oceans and Fisheries","doi-asserted-by":"publisher","award":["KOPRI PE26160"],"award-info":[{"award-number":["KOPRI PE26160"]}],"id":[{"id":"10.13039\/501100003566","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Curvularins, a class of macrocyclic lactones, have cytotoxic, antimicrobial, and anti-inflammatory properties. Curvularin, a 12-membered macrolactone, was used as a scaffold to design and synthesize structurally modified analogues to investigate structure\u2013activity relationships and improve biological efficacy. Three series of curvularin-based analogues, Cur-5H-OMe, Cur-4P-OMe, and Cur-OMe, were synthesized with the same core structure but different substituent sizes and positions. Nine representative derivatives were evaluated for anti-inflammatory, anticancer, antibacterial, and antifungal activities. In LPS-stimulated RAW 264.7 macrophages, most compounds inhibited nitric oxide (NO) production in a concentration-dependent manner but exhibited cytotoxicity at high concentrations. Cytotoxicity assays against HaCaT cells and human cancer cell lines (HCT116, HeLa, and A375) revealed limited selectivity toward cancer cells. Antimicrobial evaluation indicated selective activity against the Gram-positive bacteria, Staphylococcus aureus. Compound 23 exhibited superior antibacterial potency compared with kanamycin and notable antifungal activity against Candida albicans. This study provides a versatile synthetic platform and identifies key structural features of curvularin derivatives, demonstrating their potential as anti-inflammatory and antimicrobial lead compounds.<\/jats:p>","DOI":"10.3390\/molecules31061061","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T15:54:53Z","timestamp":1774281293000},"page":"1061","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synthesis and Biological Evaluation of Curvularin-Type Derivatives with Potential Anti-Inflammatory, Anticancer, and Antimicrobial Activities"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-7952-9363","authenticated-orcid":false,"given":"Kyung Hee","family":"Kim","sequence":"first","affiliation":[{"name":"Division of Life Sciences, Korea Polar Research Institute, Incheon 21990, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tai Kyoung","family":"Kim","sequence":"additional","affiliation":[{"name":"CRYOTECH Inc., 2F-211-3, 71 Mieumsandan 5-ro 41beon-gil, Gangseo-gu, Busan 46744, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2409-9968","authenticated-orcid":false,"given":"Ju-Mi","family":"Hong","sequence":"additional","affiliation":[{"name":"Division of Life Sciences, Korea Polar Research Institute, Incheon 21990, Republic of Korea"},{"name":"Department of Marine Sciences, Incheon National University, Incheon 22012, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin A","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Life Sciences, Korea Polar Research Institute, Incheon 21990, Republic of Korea"},{"name":"Department of Marine Sciences, Incheon National University, Incheon 22012, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Ju","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Life Sciences, Korea Polar Research Institute, Incheon 21990, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6746-7447","authenticated-orcid":false,"given":"Jin-Hyoung","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Life Sciences, Korea Polar Research Institute, Incheon 21990, Republic of Korea"},{"name":"Department of Polar Science, University of Science and Technology, Daejeon 34113, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4415-1778","authenticated-orcid":false,"given":"Joung Han","family":"Yim","sequence":"additional","affiliation":[{"name":"Division of Life Sciences, Korea Polar Research Institute, Incheon 21990, Republic of Korea"},{"name":"CRYOTECH Inc., 2F-211-3, 71 Mieumsandan 5-ro 41beon-gil, Gangseo-gu, Busan 46744, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5776-7582","authenticated-orcid":false,"given":"Il-Chan","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Life Sciences, Korea Polar Research Institute, Incheon 21990, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9576-2179","authenticated-orcid":false,"given":"Se Jong","family":"Han","sequence":"additional","affiliation":[{"name":"Division of Life Sciences, Korea Polar Research Institute, Incheon 21990, Republic of Korea"},{"name":"Department of Polar Science, University of Science and Technology, Daejeon 34113, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1007\/s00300-024-03296-z","article-title":"Sea ice as habitat for microalgae, bacteria, virus, fungi, meio- and macrofauna: A review of an extreme environment","volume":"47","author":"Gradinger","year":"2024","journal-title":"Polar Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s40168-020-00826-9","article-title":"Structure and function of the Arctic and Antarctic marine microbiota as revealed by metagenomics","volume":"8","author":"Cao","year":"2020","journal-title":"Microbiome"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Dickinson, I., Goodall-Copestake, W., Thorne, M.A., Schlitt, T., Avila-Jimenez, M.L., and Pearce, D.A. (2016). Extremophiles in an Antarctic marine ecosystem. Microorganisms, 4.","DOI":"10.3390\/microorganisms4010008"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Fu, Z., Gong, X., Hu, Z., Wei, B., and Zhang, H. (2024). Unveiling biosynthetic potential of an Arctic marine-derived strain Aspergillus sydowii MNP-2. BMC Genom., 25.","DOI":"10.1186\/s12864-024-10501-0"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1007\/s13659-024-00433-3","article-title":"Chemistry and biology of marine-derived Trichoderma metabolites","volume":"14","author":"Song","year":"2024","journal-title":"Nat. Prod. Bioprospect."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Arrieche, D., Cabrera-Pardo, J.R., San-Martin, A., Carrasco, H., and Taborga, L. (2023). Natural products from Chilean and Antarctic marine fungi and their biomedical relevance. Mar. Drugs, 21.","DOI":"10.3390\/md21020098"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1007\/s42770-023-01011-4","article-title":"The hidden rainbow: The extensive biotechnological potential of Antarctic fungi pigments","volume":"54","author":"Cavalcante","year":"2023","journal-title":"Braz. J. Microbiol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Jod\u0142owska, I., and Bia\u0142kowska, A.M. (2024). Cold-adapted fungi: Goldmine of biomolecules applicable in industry. Appl. Sci., 14.","DOI":"10.3390\/app142411950"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1515\/biol-2018-0002","article-title":"Secondary metabolites of Antarctic fungi antagonistic to aquatic pathogenic bacteria","volume":"13","author":"Zhao","year":"2018","journal-title":"Open Life Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s00792-024-01339-1","article-title":"Antarctic marine sediment as a source of filamentous fungi-derived antimicrobial and antitumor compounds of pharmaceutical interest","volume":"28","author":"Camacho","year":"2024","journal-title":"Extremophiles"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ha, T.M., Kim, D.C., Sohn, J.H., Yim, J.H., and Oh, H. (2020). Anti-inflammatory and protein tyrosine phosphatase 1B inhibitory metabolites from the Antarctic marine-derived fungal strain Penicillium glabrum SF-7123. Mar. Drugs, 18.","DOI":"10.3390\/md18050247"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Hang, S., Lu, H., and Jiang, Y. (2024). Marine-derived metabolites act as promising antifungal agents. Mar. Drugs, 22.","DOI":"10.3390\/md22040180"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Deng, W., Du, H., Liu, D., and Ma, Z. (2022). Editorial: The role of natural products in chronic inflammation. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.901538"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"nwac206","DOI":"10.1093\/nsr\/nwac206","article-title":"Natural products and drug discovery","volume":"9","author":"Newman","year":"2022","journal-title":"Natl. Sci. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ahmad, M., Tahir, M., Hong, Z., Zia, M.A., Rafeeq, H., Ahmad, M.S., Rehman, S.U., and Sun, J. (2024). Plant and marine-derived natural products: Sustainable pathways for future drug discovery and therapeutic development. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1497668"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Ha, T.M., Ko, W., Lee, S.J., Kim, Y.C., Son, J.Y., Sohn, J.H., Yim, J.H., and Oh, H. (2017). Anti-inflammatory effects of curvularin-type metabolites from a marine-derived fungal strain Penicillium sp. SF-5859 in lipopolysaccharide-induced RAW264.7 macrophages. Mar. Drugs, 15.","DOI":"10.3390\/md15090282"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1039\/B701677H","article-title":"Amide bond formation: Beyond the myth of coupling reagents","volume":"38","author":"Valeur","year":"2009","journal-title":"Chem. Soc. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1246\/cl.1975.1045","article-title":"A convenient method for the synthesis of carboxylic esters","volume":"4","author":"Mukaiyama","year":"1975","journal-title":"Chem. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7227","DOI":"10.1021\/acs.joc.9b00776","article-title":"A unified synthetic approach to optically pure curvularin-type metabolites","volume":"84","author":"Allu","year":"2019","journal-title":"J. Org. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2801","DOI":"10.1039\/C4OB00331D","article-title":"Total synthesis of monosporascone and dihydromonosporascone","volume":"12","author":"Punch","year":"2014","journal-title":"Org. Biomol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5740","DOI":"10.1002\/anie.200600787","article-title":"Selective construction of carbocyclic eight-membered rings by ring-closing metathesis of acyclic precursors","volume":"45","author":"Michaut","year":"2006","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2199","DOI":"10.1021\/cr0200872","article-title":"Synthesis of oxygen- and nitrogen-containing heterocycles by ring-closing metathesis","volume":"104","author":"Deiters","year":"2004","journal-title":"Chem. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1021\/cr9002424","article-title":"Ruthenium-based heterocyclic carben-coordinated olefin metathesis catalyst","volume":"110","author":"Vougioukalakis","year":"2010","journal-title":"Chem. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"114000","DOI":"10.1016\/j.phytochem.2024.114000","article-title":"Curvularin derivatives from the marine mangrove derived fungus Penicillium sumatrense MA-325","volume":"220","author":"Wang","year":"2024","journal-title":"Phytochemistry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1007\/s12010-009-8591-2","article-title":"Isolation and difference in anti-Staphylococcus aureus bioactivity of curvularin derivates from fungus Eupenicillium sp","volume":"159","author":"Xie","year":"2009","journal-title":"Appl. Biochem. Biotechnol."},{"key":"ref_26","first-page":"119","article-title":"Curvularin derivatives from hydrothermal vent sediment fungus Penicillium sp. HL-50 guided by molecular networking and their anti-inflammatory activity","volume":"23","author":"Yu","year":"2025","journal-title":"Chin. J. Nat. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6259","DOI":"10.1080\/14786419.2024.2377313","article-title":"Mauritone A, a new polyketide from a fungal-bacterial symbiont Aspergillus spelaeus GXIMD 04541\/Sphingomonas echinoides GXIMD 04532","volume":"39","author":"Yang","year":"2025","journal-title":"Nat. Prod. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1021\/cb200353m","article-title":"Using the heat-shock response to discover anticancer compounds that target protein homeostasis","volume":"7","author":"Santagata","year":"2012","journal-title":"ACS Chem. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"143","DOI":"10.31616\/asj.2019.0285","article-title":"The anti-inflammatory and cytoprotective efficiency of curvularin, a fungal macrolactone against lipopolysaccharide-induced inflammatory response in nucleus pulposus cells: An in vitro study","volume":"15","author":"Banala","year":"2021","journal-title":"Asian Spine J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1271\/bbb.70094","article-title":"A concise synthetic approach to \u03b2,\u03b3-dehydrocurvularin: Synthesis of (\u00b1)-di-O-methyl-\u03b2,\u03b3-dehydrocurvularin","volume":"71","author":"Miyagi","year":"2007","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1080\/00397911.2021.1979043","article-title":"Stereoselective total synthesis of (-)-curvularin","volume":"52","author":"Krishna","year":"2022","journal-title":"Synth. Commun."},{"key":"ref_32","first-page":"163","article-title":"10,11-Dehydrocurvularin attenuates inflammation by suppressing NLRP3 inflammasome activation","volume":"21","author":"Zhao","year":"2023","journal-title":"Chin. J. Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1002\/cmdc.200800022","article-title":"Inhibitors of inducible NO synthase expression: Total synthesis of (S)-curvularin and its ring homologues","volume":"3","author":"Elzner","year":"2008","journal-title":"ChemMedChem"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.4155\/fmc.12.93","article-title":"Macrocycles in new drug discovery","volume":"4","author":"Mallinson","year":"2012","journal-title":"Future Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3283","DOI":"10.1016\/j.bmcl.2018.09.016","article-title":"Methyl-containing pharmaceuticals: Methylation in drug design","volume":"28","author":"Sun","year":"2018","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1007\/s13205-021-02877-7","article-title":"NF-\u03baB inhibitory, antimicrobial and antiproliferative potentials of compounds from Hawaiian fungus Aspergillus polyporicola FS910","volume":"11","author":"Wang","year":"2021","journal-title":"3 Biotech"},{"key":"ref_37","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 fungus Curvularia sp","volume":"2008","author":"Greve","year":"2008","journal-title":"Eur. J. Org. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Chang, C.F., Ke, C.Y., Wu, Y.C., and Chuang, T.H. (2015). Structure-Activity Relationship of Synthetic 2-Phenylnaphthalenes with Hydroxyl Groups that Inhibit Proliferation and Induce Apoptosis of MCF-7 Cancer Cells. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0141184"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7234","DOI":"10.1021\/jm050567w","article-title":"Cellular apoptosis and cytotoxicity of phenolic compounds: A quantita-tive structure-activity relationship study","volume":"48","author":"Selassie","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e202500761","DOI":"10.1002\/cbdv.202500761","article-title":"New curvularin and norlignanolide derivatives from cocultures of marine mangrove endophytic fungus Penicillium brocae MA-231 and phytopathogen Curvularia spicifera QA-26","volume":"22","author":"Zhang","year":"2025","journal-title":"Chem. Biodivers."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2327","DOI":"10.1021\/acs.jnatprod.4c00489","article-title":"Sucurchalasins A and B, sulfur-containing heterodimers of a cytochalasan and a macrolide from the endophytic fungus Aspergillus spelaeus GDGJ-286","volume":"87","author":"Zhou","year":"2024","journal-title":"J. Nat. Prod."},{"key":"ref_42","first-page":"204","article-title":"Secondary metabolites of Curvularia oryzae MTCC 2605","volume":"3","author":"Busi","year":"2009","journal-title":"Rec. Nat. Prod."},{"key":"ref_43","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_44","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1080\/10286020.2022.2117168","article-title":"Alternarialone A, a new curvularin-type metabolite from the mangrove-derived fungus Alternaria longipes","volume":"25","author":"Huo","year":"2023","journal-title":"J. Asian Nat. Prod. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1021\/acs.jnatprod.6b00785","article-title":"Metabolites from the endophytic fungus Curvularia sp. M12 act as motility inhibitors against Phytophthora capsici zoospores","volume":"80","author":"Mondol","year":"2017","journal-title":"J. Nat. Prod."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Cadelis, M.M., Li, S.A., van de Pas, S.J., Grey, A., Mulholland, D., Weir, B.S., Copp, B.R., and Wiles, S. (2023). Antimicrobial natural products from plant pathogenic fungi. Molecules, 28.","DOI":"10.3390\/molecules28031142"},{"key":"ref_47","first-page":"1563","article-title":"Antimycobacterial and cytotoxicity activity of synthetic and natural compounds","volume":"30","author":"Galetti","year":"2007","journal-title":"Qu\u00edmica Nova"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/6\/1061\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T08:03:18Z","timestamp":1774339398000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/6\/1061"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,23]]},"references-count":47,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["molecules31061061"],"URL":"https:\/\/doi.org\/10.3390\/molecules31061061","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,23]]}}}