{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T05:40:08Z","timestamp":1751866808759,"version":"3.41.0"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T00:00:00Z","timestamp":1751846400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Chem."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Endophytic fungi from desert plants are prolific producers of structurally unique stress-responsive metabolites. This study investigates the secondary metabolites of Phoma betae A. B. Frank (Didymellaceae), a desert plant endophytic fungus, aiming to discover novel bioactive compounds through advanced molecular networking strategies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A building blocks-based molecular network (BBMN) strategy was employed to screen the fungal extract. Target compounds were isolated using silica gel and ODS column chromatography, followed by semi-preparative HPLC purification. Structural elucidation was achieved through comprehensive NMR spectroscopy, mass fragmentation pathway analysis, and electronic circular dichroism (ECD) calculations. Cytotoxicity was evaluated against HeLa and A549 cancer cell lines using CCK-8 assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Three compounds were characterized:Phomaderide (3), a unique (6\/5\/4\/5\/6) spiro-cyclic dimer formed via stereoselective [2+2] photocycloaddition of two phaeosphaeride A (1) monomers. Its biosynthetic precursor phaeosphaeride A (1). A new hydroxylated analog, phaeosphaeride C (2). Compounds 2 and 3 exhibited moderate cytotoxicity against HeLa (IC<jats:sub>50<\/jats:sub> 29.97\u201339.15 \u03bcM) and A549 cells (IC<jats:sub>50<\/jats:sub> 30.47\u201358.33 \u03bcM).<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>This work highlights the metabolic versatility of extremophilic fungi, demonstrating Phoma betae's capacity to generate architecturally complex molecules. Phomaderide's unprecedented spiro-cyclic dimer scaffold positions it as a promising lead for anticancer drug discovery, with structural modifications (hydroxylation and dimerization) significantly influencing bioactivity. The BBMN strategy proved effective for targeted isolation of structurally related analogs from complex extracts.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fchem.2025.1583666","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T05:26:34Z","timestamp":1751865994000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Phomaderide, a unique (6\/5\/4\/5\/6) spiro-cyclic dimer from the desert plant endophytic fungus Phoma betae A. B. Frank (Didymellaceae)"],"prefix":"10.3389","volume":"13","author":[{"given":"Hao-Di","family":"Sun","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan-Duo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui-Qi","family":"Fang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Tong","family":"Hua","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gang","family":"Ding","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lan-Ping","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"9659","DOI":"10.1021\/jo301662e","article-title":"Total synthesis and biological activity of the proposed structure of phaeosphaeride A","volume":"77","author":"Chatzimpaloglou","year":"2012","journal-title":"J. Org. Chem."},{"key":"B2","doi-asserted-by":"publisher","first-page":"4043","DOI":"10.1021\/jo500545d","article-title":"Synthetic and biological studies of phaeosphaerides","volume":"79","author":"Chatzimpalogou","year":"2014","journal-title":"J. Org. Chem."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s00894-021-04687-3","article-title":"Molecular docking, spectroscopic, and quantum chemical studies on aromatic heterocycle tetrakis(4-pyridyl)cyclobutane regioisomers: potential membrane-permeable inhibitors. J. Mol. Model","volume":"94","author":"Haruna","year":"2021","journal-title":"3"},{"key":"B4","doi-asserted-by":"publisher","first-page":"19609","DOI":"10.1002\/anie.202103878","article-title":"Discovery of neuritogenic securinega alkaloids from flueggea suffruticosa by a building blocks-based molecular network strategy","volume":"60","author":"He","year":"2021","journal-title":"Angew. Chem. Int. Ed."},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodchem.2025.143590","article-title":"Novel enzymatic synthesis of 3-Hydroxybutyryl Naringin and its molecular identification and bioactive characterization. Food Chem","volume":"143590","author":"Kim","year":"2025","journal-title":"15"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.1021\/jo5025046","article-title":"Establishment of relative and absolute configurations of phaeosphaeride A: total synthesis of ent-phaeosphaeride A","volume":"80","author":"Kobayashi","year":"2015","journal-title":"J. Org. Chem."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1488","DOI":"10.1021\/acs.jnatprod.9b01148","article-title":"Bioactive seco-sativene sesquiterpenoids from an artemisia desertorum endophytic fungus, cochliobolus sativus","volume":"83","author":"Liu","year":"2020","journal-title":"J. Nat. Prod."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2024.102504","article-title":"Discovery and evolution of [4 + 2] cyclases. Curr opin chem biol","volume":"102504","author":"Liu","year":"2024","journal-title":"81"},{"key":"B9","doi-asserted-by":"publisher","first-page":"2238","DOI":"10.1021\/acs.jnatprod.3c00434","article-title":"Shielding effects of aromatic (indole) ring for structural analysis","volume":"86","author":"Liu","year":"2023","journal-title":"J. N. Prod."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodres.2025.115803","article-title":"Unveiling the formation capacity and characterization of pentacyclic triterpene-structured oleogels: role of the molecular configuration and oil profile. Food Res. Int","volume":"115803","author":"Liu","year":"2025","journal-title":"203"},{"key":"B11","doi-asserted-by":"publisher","first-page":"4067","DOI":"10.1021\/ol061556f","article-title":"Phaeosphaeride A, an inhibitor of STAT3-dependent signaling isolated from an endophytic fungus","volume":"8","author":"Maloney","year":"2006","journal-title":"Org. Lett."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1039\/c8np00022k","article-title":"Protein-protein interactions in polyketide synthase-nonribosomal peptide synthetase hybrid assembly lines","volume":"35","author":"Miyanaga","year":"2018","journal-title":"Nat. Prod. Rep."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/S0031-9422(00)90595-8","article-title":"Maoecrystal M: a naturally occurring symmetric ent-kaurane dimer from Rabdosia eriocalyx. PHYTOCHEMISTRY","volume":"725","author":"Shen","year":"1994","journal-title":"35"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202421472","article-title":"Quantitative Formation of octa-substituted cyclobutanes by the [2+2] photocycloaddition of stiff-stilbenes","author":"Sun","year":"2024","journal-title":"J. Angew. Chem. Int"},{"key":"B15","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1002\/pca.3092","article-title":"UPLC-Q-TOF-MS\/MS analysis of the guaiane sesquiterpenoids oxytropiols A\u2013J and detection of undescribed analogues from the locoweed endophytic fungus Alternaria oxytropis (Pleosporaceae)","volume":"33","author":"Tan","year":"","journal-title":"Phytochem. Anal."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.phytochem.2019.05.012","article-title":"Sesquiterpenoids and mycotoxin swainsonine from the locoweed endophytic fungus Alternaria oxytropis. PHYTOCHEMISTRY","volume":"154","author":"Tan","year":"2019","journal-title":"164"},{"key":"B17","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.phytochem.2022.113264","article-title":"Undescribed diphenyl ethers betaethrins A-I from a desert plant endophytic strain of the fungus Phoma betae A.B. Frank (Didymellaceae). phytochemistry","volume":"113264","author":"Tan","year":"","journal-title":"201"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.phytochem.2021.112969","article-title":"Phaeosphspirone (1\/1\u2032), a pair of unique polyketide enantiomers with an unusual 6\/5\/5\/6 tetracyclic ring from the desert plant endophytic fungus Phaeosphaeriaceae sp. PHYTOCHEMISTRY","volume":"112969","author":"Xu","year":"2022","journal-title":"194"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1039\/d2np00034b","article-title":"[2 + 2]-Cycloaddition-derived cyclobutane natural products: structural diversity, sources, bioactivities, and biomimetic syntheses","volume":"40","author":"Yang","year":"2023","journal-title":"Nat. Prod. Rep."},{"key":"B20","doi-asserted-by":"publisher","first-page":"e5144","DOI":"10.1002\/pro.5144","article-title":"Structural basis for substrate flexibility of the O-methyltransferase MpaG' involved in mycophenolic acid biosynthesis","volume":"33","author":"You","year":"2024","journal-title":"Protein Sci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1039\/C5OB02296G","article-title":"Antimalarial diterpenoid dimers of a new carbon skeleton from Aphanamixis grandifolia","volume":"14","author":"Zhang","year":"2016","journal-title":"Org. Biomol. Chem."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.phytochem.2021.112701","article-title":"Bioactive metabolites from the desert plant-associated endophytic fungus Chaetomium globosum (Chaetomiaceae). PHYTOCHEMISTRY","volume":"112701","author":"Zhang","year":"2021","journal-title":"185"},{"key":"B23","doi-asserted-by":"publisher","first-page":"10939","DOI":"10.1021\/acs.analchem.3c00744","article-title":"Building block extractor: an MS\/MS data mining tool for targeted discovery of natural products with specified features","volume":"95","author":"Zhu","year":"2023","journal-title":"J. Anal. Chem."}],"container-title":["Frontiers in Chemistry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2025.1583666\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T05:26:34Z","timestamp":1751865994000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2025.1583666\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,7]]},"references-count":23,"alternative-id":["10.3389\/fchem.2025.1583666"],"URL":"https:\/\/doi.org\/10.3389\/fchem.2025.1583666","relation":{},"ISSN":["2296-2646"],"issn-type":[{"value":"2296-2646","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,7]]}}}