2. Academic Validation
  3. Metalloporphyrin-Catalyzed Oxidation of Sunitinib and Pazopanib, Two Anticancer Tyrosine Kinase Inhibitors: Evidence for New Potentially Toxic Metabolites

Metalloporphyrin-Catalyzed Oxidation of Sunitinib and Pazopanib, Two Anticancer Tyrosine Kinase Inhibitors: Evidence for New Potentially Toxic Metabolites

  • J Med Chem. 2018 Sep 13;61(17):7849-7860. doi: 10.1021/acs.jmedchem.8b00812.
Marie-Noëlle Paludetto 1 2 3 4,  Christian Bijani 1,  Florent Puisset 2 3 4,  Vania Bernardes-Génisson 1 3,  Cécile Arellano 2 3,  Anne Robert 1
Affiliations

Affiliations

  • 1 Laboratoire de Chimie de Coordination du CNRS (LCC-CNRS) , Université de Toulouse , 205 route de Narbonne, BP 44099 , 31077 Toulouse , Cedex 4, France.
  • 2 Centre de Recherches en Cancérologie de Toulouse (CRCT), INSERM UMR1037 , Université de Toulouse , 2 avenue Hubert Curien, CS53717 , 31037 Toulouse , Cedex 1, France.
  • 3 Université Paul Sabatier , 31400 Toulouse , France.
  • 4 Pharmacie , Institut Claudius Regaud, IUCT-O , 31037 Toulouse , Cedex 1, France.
PMID: 30102538 DOI: 10.1021/acs.jmedchem.8b00812
Abstract

Oxidation of two tyrosine kinase inhibitors (TKIs) sunitinib and pazopanib, using a chemical catalytic system able to mimic the Cytochrome P450 type oxidation, allowed us to prepare putative reactive/toxic metabolites of these Anticancer drugs. Among these metabolites, aromatic aldehyde derivatives were unambiguously characterized. Such biomimetic oxidation of TKI-type drugs was essential to facilitate the identification of low amounts of aldehydes generated from these TKIs when incubated with human liver microsomes (HLM), which are classical models of human hepatic metabolism. These TKI derivative aldehydes quickly react in vitro with amines. A similar reaction is expected to occur in vivo and may be at the origin of the potentially severe hepatotoxicity of these TKIs.

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