Improving the Stability of EGFR Inhibitor Cobalt(III) Prodrugs
- Author(s)
- Marlene Mathuber, Hemma Schueffl, Orsolya Dömötör, Claudia Karnthaler, Éva A Enyedy, Petra Heffeter, Bernhard K Keppler, Christian R Kowol
- Abstract
Although tyrosine kinase inhibitors (TKIs) have revolutionized cancer therapy in the past two decades, severe drawbacks such as strong adverse effects and drug resistance limit their clinical application. Prodrugs represent a valuable approach to overcoming these disadvantages by administration of an inactive drug with tumor-specific activation. We have recently shown that hypoxic prodrug activation is a promising strategy for a cobalt(III) complex bearing a TKI of the epidermal growth factor receptor (EGFR). The aim of this study was the optimization of the physicochemical properties and enhancement of the stability of this compound class. Therefore, we synthesized a series of novel derivatives to investigate the influence of the electron-donating properties of methyl substituents at the metal-chelating moiety of the EGFR inhibitor and/or the ancillary acetylacetonate (acac) ligand. To understand the effect of the different methylations on the redox properties, the newly synthesized complexes were analyzed by cyclic voltammetry and their behavior was studied in the presence of natural low-molecular weight reducing agents. Furthermore, it was proven that reduction to cobalt(II) resulted in a lower stability of the complexes and subsequent release of the coordinated TKI ligand. Moreover, the stability of the cobalt(III) prodrugs was investigated in blood serum as well as in cell culture by diverse cell and molecular biological methods. These analyses revealed that the complexes bearing the methylated acac ligand are characterized by distinctly enhanced stability. Finally, the cytotoxic activity of all new compounds was tested in cell culture under normoxic and various hypoxic conditions, and their prodrug nature could be correlated convincingly with the stability data. In summary, the performed chemical modifications resulted in new cobalt(III) prodrugs with strongly improved stabilities together with retained hypoxia-activatable properties.
- Organisation(s)
- Department of Inorganic Chemistry
- External organisation(s)
- University of Szeged, University of Vienna, Medizinische Universität Wien, Research Cluster Translational Cancer Therapy Research
- Journal
- Inorganic Chemistry
- Volume
- 59
- Pages
- 17794-17810
- No. of pages
- 17
- ISSN
- 0020-1669
- DOI
- https://doi.org/10.1021/acs.inorgchem.0c03083
- Publication date
- 12-2020
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 104003 Inorganic chemistry, 301904 Cancer research
- Keywords
- ASJC Scopus subject areas
- Inorganic Chemistry, Physical and Theoretical Chemistry
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/e463e041-fc28-46bd-b15d-9291d05a5dbb