{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T04:04:36Z","timestamp":1792037076956,"version":"4.4.0"},"reference-count":68,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T00:00:00Z","timestamp":1769472000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"French Ministry"},{"DOI":"10.13039\/100007586","name":"Aix Marseille University","doi-asserted-by":"crossref","award":["A.T.E.R 2018-2019"],"award-info":[{"award-number":["A.T.E.R 2018-2019"]}],"id":[{"id":"10.13039\/100007586","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Canc\u00e9rop\u00f4le Provence Alpes C\u00f4te d\u2019Azur","award":["Gefluc TAUXX80S 2019-2020"],"award-info":[{"award-number":["Gefluc TAUXX80S 2019-2020"]}]},{"name":"CNRS"},{"name":"Institute of Radical Chemistry"},{"name":"Institute of Neurophysiology"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Glioblastoma is one of the most highly aggressive types of brain tumor in adults. With limited treatment options, current therapies remain insufficient due to its invasiveness and immune evasion, highlighting the urgent need for new treatments. Bifunctional molecules targeting multiple aspects of the disease could be promising to overcome drug resistance and tumor heterogeneity. Metformin has demonstrated protective effects against brain tumors but requires high doses for efficacy, making it of great interest for molecular optimization. In this context, we synthesized a series of nine metformin\u2013phenolic molecules, combining the metformin guanidine framework with phenolic acids, which have well-established properties in inhibiting cancer cell migration and adhesion. Their impact on cytotoxicity, reactive oxygen species inhibition, and signaling pathways was investigated for glioma cell lines and stem cells. Two of these hybrids, 5a and 5h, particularly enhanced cytotoxicity in glioblastoma cells, selectively targeting cancer cells while sparing healthy ones. Their mechanism of action differed significantly from metformin. Unlike metformin, which mainly triggers metabolic stress, the hybrids broadly inhibit RTK\u2013MAPK\u2013PI3K signaling, leading to cell cycle arrest and apoptosis. The results suggest that these compounds could offer a more effective and synergistic approach for glioblastoma treatment.<\/jats:p>","DOI":"10.3390\/ijms27031259","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T11:35:42Z","timestamp":1769513742000},"page":"1259","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Bifunctional Metformin\u2013Phenolic Hybrids with Improved Anticancer and Antioxidant Properties: Evaluation on Glioma Cells"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0381-4179","authenticated-orcid":false,"given":"Caroline","family":"Delehedde","sequence":"first","affiliation":[{"name":"Aix Marseille Universit\u00e9, CNRS, Institut de Chimie Radicalaire (ICR), UMR 7273, SMBSO, 13397 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4885-1122","authenticated-orcid":false,"given":"Mathieu","family":"Chocry","sequence":"additional","affiliation":[{"name":"Aix Marseille Universit\u00e9, CNRS, Institut de Chimie Radicalaire (ICR), UMR 7273, SMBSO, 13397 Marseille, France"},{"name":"Aix Marseille Universit\u00e9, CNRS, Institut de Neurophysiopathologie (INP), UMR 7051, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Aix Marseille Universit\u00e9, CNRS, Institut de Chimie Radicalaire (ICR), UMR 7273, SMBSO, 13397 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Asteian","sequence":"additional","affiliation":[{"name":"Aix Marseille Universit\u00e9, CNRS, Institut de Chimie Radicalaire (ICR), UMR 7273, SMBSO, 13397 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9914-786X","authenticated-orcid":false,"given":"Maxime","family":"Robin","sequence":"additional","affiliation":[{"name":"Aix Marseille Universit\u00e9, CNRS, Institut de Chimie Radicalaire (ICR), UMR 7273, SMBSO, 13397 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9369-5689","authenticated-orcid":false,"given":"Ludovic","family":"Leloup","sequence":"additional","affiliation":[{"name":"Aix Marseille Universit\u00e9, CNRS, Institut de Neurophysiopathologie (INP), UMR 7051, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathieu","family":"Cassien","sequence":"additional","affiliation":[{"name":"Aix Marseille Universit\u00e9, CNRS, Institut de Chimie Radicalaire (ICR), UMR 7273, SMBSO, 13397 Marseille, France"},{"name":"Yelen Analytics, 13820 Ensu\u00e8s-la-Redonne, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3267-5352","authenticated-orcid":false,"given":"Anne","family":"Mercier","sequence":"additional","affiliation":[{"name":"Aix Marseille Universit\u00e9, CNRS, Institut de Chimie Radicalaire (ICR), UMR 7273, SMBSO, 13397 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7255-7591","authenticated-orcid":false,"given":"Marcel","family":"Culcasi","sequence":"additional","affiliation":[{"name":"Aix Marseille Universit\u00e9, CNRS, Institut de Chimie Radicalaire (ICR), UMR 7273, SMBSO, 13397 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6509-4210","authenticated-orcid":false,"given":"Herv\u00e9","family":"Kovacic","sequence":"additional","affiliation":[{"name":"Aix Marseille Universit\u00e9, CNRS, Institut de Neurophysiopathologie (INP), UMR 7051, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9207-0780","authenticated-orcid":false,"given":"Sylvia","family":"Pietri","sequence":"additional","affiliation":[{"name":"Aix Marseille Universit\u00e9, CNRS, Institut de Chimie Radicalaire (ICR), UMR 7273, SMBSO, 13397 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1007\/s12035-020-01892-8","article-title":"Tumor Development and Angiogenesis in Adult Brain Tumor: Glioblastoma","volume":"57","author":"Ahir","year":"2020","journal-title":"Mol. 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