New hemisynthetic derivatives of sphaeropsidin phytotoxins triggering severe endoplasmic reticulum swelling in cancer cells

• Published in: Scientific reports Vol. 14; no. 1; pp. 14674 - 18
• Main Authors: Ingels, Aude, Scott, Robert, Hooper, Annie R., van der Westhuyzen, Aletta E., Wagh, Sachin B., de Meester, Joséphine, Maddau, Lucia, Marko, Doris, Aichinger, Georg, Berger, Walter, Vermeersch, Marjorie, Pérez-Morga, David, Maslivetc, Vladimir A., Evidente, Antonio, van Otterlo, Willem A. L., Kornienko, Alexander, Mathieu, Véronique
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.06.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154; 631/67; Abietanes - chemistry; Abietanes - pharmacology; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic drugs; Apoptosis; Apoptosis - drug effects; Biochemistry; Cancer; Cancer research; Cell death; Cell Line, Tumor; Diterpene; Diterpenes - chemistry; Diterpenes - pharmacology; Endoplasmic reticulum; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Endoplasmic reticulum swelling; ER stress; Humanities and Social Sciences; Humans; Iso-pimarane; Lipophilic; Medical research; Microscopy; Mode of action; multidisciplinary; Multidrug resistance; Natural product; Natural products; Phytopathogenic fungi; Phytotoxins; Proteasomes; Science; Science (multidisciplinary); Sphaeropsidin; Sphaeropsidin; Diterpene; ER stress; Natural product; Iso-pimarane; Endoplasmic reticulum swelling; Cancer
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-65335-3

Sphaeropsidins are iso -pimarane diterpenes produced by phytopathogenic fungi that display promising anticancer activities. Sphaeropsidin A, in particular, has been shown to counteract regulatory volume increase, a process used by cancer cells to avoid apoptosis. This study reports the hemi-synthesis of new lipophilic derivatives obtained by modifications of the C15,C16-alkene moiety. Several of these compounds triggered severe ER swelling associated with strong proteasomal inhibition and consequently cell death, a feature that was not observed with respect to mode of action of the natural product. Significantly, an analysis from the National Cancer Institute sixty cell line testing did not reveal any correlations between the most potent derivative and any other compound in the database, except at high concentrations (LC 50 ). This study led to the discovery of a new set of sphaeropsidin derivatives that may be exploited as potential anti-cancer agents, notably due to their maintained activity towards multidrug resistant models.