Abstract

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 (LC50). 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.

Details

Title
New hemisynthetic derivatives of sphaeropsidin phytotoxins triggering severe endoplasmic reticulum swelling in cancer cells
Author
Ingels, Aude 1 ; Scott, Robert 2 ; Hooper, Annie R. 2 ; van der Westhuyzen, Aletta E. 3 ; Wagh, Sachin B. 2 ; de Meester, Joséphine 3 ; Maddau, Lucia 4 ; Marko, Doris 5 ; Aichinger, Georg 5 ; Berger, Walter 6 ; Vermeersch, Marjorie 7 ; Pérez-Morga, David 7 ; Maslivetc, Vladimir A. 2 ; Evidente, Antonio 8 ; van Otterlo, Willem A. L. 3 ; Kornienko, Alexander 2 ; Mathieu, Véronique 1 

 Université Libre de Bruxelles, Department of Pharmacotherapy and Pharmaceutics, Chemistry and Biochemistry, Faculté de Pharmacie, Brussels, Belgium (GRID:grid.4989.c) (ISNI:0000 0001 2348 6355); Université Libre de Bruxelles, ULB Cancer Research Center, U-CRC, Brussels, Belgium (GRID:grid.4989.c) (ISNI:0000 0001 2348 6355) 
 Texas State University, Department of Chemistry and Biochemistry, San Marcos, USA (GRID:grid.264772.2) (ISNI:0000 0001 0682 245X) 
 University of Stellenbosch, Department of Chemistry and Polymer Science, Stellenbosch, South Africa (GRID:grid.11956.3a) (ISNI:0000 0001 2214 904X) 
 University of Sassari, Department of Agriculture, Section of Plant Pathology and Entomology, Sassari, Italy (GRID:grid.11450.31) (ISNI:0000 0001 2097 9138) 
 University of Vienna, Department of Food Chemistry and Toxicology, Faculty of Chemistry, Vienna, Austria (GRID:grid.10420.37) (ISNI:0000 0001 2286 1424) 
 Medical University of Vienna Center for Cancer Research, Vienna, Austria (GRID:grid.22937.3d) (ISNI:0000 0000 9259 8492) 
 Université Libre de Bruxelles (ULB), Electron Microscopy Laboratory, Center for Microscopy and Molecular Imaging (CMMI), Gosselies, Belgium (GRID:grid.4989.c) (ISNI:0000 0001 2348 6355) 
 National Research Council, Institute of Biomolecular Chemistry, Pozzuoli, Italy (GRID:grid.5326.2) (ISNI:0000 0001 1940 4177) 
Pages
14674
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3072089771
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.