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Étude théorique des interactions entre dérivés du cisplatine et composés soufrés d'intérêt biologique

Abstract : The study of the reactions between thiolates and derivatives of cisplatin are key to improving the understanding of the behaviour of this anticancer drug. These reactions, namely thiolations (replacement of a ligand by a thiolate) or bidentations (replacement of another ligand by a second group of the considered thiolate), are involved in the mechanisms which give rise to the destruction of cancer cells. They are also involved in the development of resistance mechanisms towards the treatment. We have used quantum chemistry methods (Møller-Plesset perturbation theory at degree 2 (MP2) completed by large basis functions set) to build a robust theoretical study of the reactions between cisplatin (and its main hydrolyzed products) and some thiolates of biological interest, such as cysteine and glutathione. Kinetic and thermodynamic data obtained for both thiolations and bidentations shed light on the nature of the preferred chemical pathways. Our Raman spectroscopy measurements show that only two thiolations actually occur, possibly due to bidentation reactions eventually taking place after each thiolation. In addition, the S,N bidentation is shown to be preferred with respect to the S,O bidentation. Also, the lability scale of the ligands was found to be almost systematically H2O > Cl– ≈ NH3(trans) > NH3(cis) > OH–, the difference between ammine ligands being induced by a significant trans-labilization by thiolates, due to the trans effect inherent in the planar square structure of platinum (II) complexes.
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Thibault Minervini. Étude théorique des interactions entre dérivés du cisplatine et composés soufrés d'intérêt biologique. Chimie théorique et/ou physique. Université Bourgogne Franche-Comté, 2019. Français. ⟨NNT : 2019UBFCD014⟩. ⟨tel-02548600⟩

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