Improving the Stability of EGFR Inhibitor Cobalt(III) Prodrugs.

Inorganic Chemistry
Marlene MathuberChristian 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...Continue Reading

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Methods Mentioned

BETA
xenograft
nuclear magnetic resonance
NMR
Fluorescence
FCS
flow cytometry
fluorescence microscopy
Assay

Software Mentioned

FACSDiva
Hyperquad2013
FluorEssence
GraphPad Prism
Diva
PSEQUAD
Chemstation
ImageJ

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