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Synthèse et étude du mécanisme d’action cytotoxique de complexes organométalliques d’iridium à ligand arène

Abstract : The development of novel transition metal complexes with cytotoxic properties as potential anticancerdrugs is of increasing interest. Half-sandwich complexes of iridium(III) including various coligands are currently investigated to this purpose but their molecular mechanism of action is still poorly understood. In this line, we have introduced a series of ten complexes including phenyloxazoline derivatives as chelating ligands and showed that their cytotoxicity on HeLa cells was partly linked to their ability to raise intracellular H2O2 levels, presumably by catalysis and depletion of intracellular NADH. Amongst this series, one complex in particular showed excellent properties both in vitro and in live cells, we undertook to further characterize the cellular response upon exposure to this complex. Several cell lines and biological techniques were employed to unveil some putative mechanisms of cellular response. We also demonstrated using mass spectrometry that half-sandwich complexes are able to form covalent adducts with some amino-acids’ side chain. A convenient strategy to get insight into the mechanism of action of metal-based drugs is to append a fluorescent reporter group which enables their intracellular tracking and the analysis of their subcellular distribution. To this end, we designed a half-sandwich iridium complex comprising a modified phenyloxazoline ligand to which was appended a BODIPYentity, also chosen to address the drug to membrane-rich organelles. This complex was able to form fluorescent adducts with a subset of proteins upon treatment of live cells. To identify these binding partners, we synthesized a half-sandwich iridium complex comprising a bio-orthogonal reactive function ready to perform chemoselective (“click”) ligations with relevant molecules (fluorophore,biotin). This new complex will allow us to get unbiased insight into its intracellular behaviour and interm identify its protein targets, providing a new entry to the development of half-sandwich iridium based anticancer drugs.
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Submitted on : Tuesday, July 19, 2022 - 2:29:51 PM
Last modification on : Tuesday, August 2, 2022 - 4:30:42 AM

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  • HAL Id : tel-03727628, version 1

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Robin Ramos. Synthèse et étude du mécanisme d’action cytotoxique de complexes organométalliques d’iridium à ligand arène. Chimie de coordination. Sorbonne Université, 2021. Français. ⟨NNT : 2021SORUS463⟩. ⟨tel-03727628⟩

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