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Synthèse de double donneurs de monoxyde d’azote, évaluation de leur cytotoxicté et de leur activité pharmacologique

Abstract : This work describes the synthesis of different families of nitritc oxide (NO) donor compounds based on amidoximes as well as the biological evaluation of their NO release ability. Firstly, the synthesis of hybrid NO double donors possessing jointly an amidoxime function and an S-nitrosothiol function has been considered. During these trials, a molecule having two amidoxime functions linked by a disulfide bond was developed, with a view to its subsequent reduction into free thiol followed by a nitrosation by the cells enzymes. The following part of this work has been devoted to the development of different types of NO donors consisting solely of amidoximes. Various mono-, bis- and poly-amidoximes have been synthesized and characterized. All the amidoximes that are soluble in the physiological medium have been tested and were shown to be cytocompatible with human smooth muscle cells. The NO release capabilities and the kinetics of these releases were evaluated. Finally, the biological studies aimed to evaluate the release of NO showed that two aromatic mono-amidoximes allowed providing high quantities of NO on both rat liver microsomes and on human smooth cells. Lastly, the aromatic/aliphatic bis-amidoxime presents a similar ability to release NO on cells as the aromatic mono-amidoximes but at a twice lower concentration, which shows that this molecule is the most powerful among all NO donor compounds tested during this study.
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Tanya Sahyoun. Synthèse de double donneurs de monoxyde d’azote, évaluation de leur cytotoxicté et de leur activité pharmacologique. Chimie organique. Université de Lorraine, 2019. Français. ⟨NNT : 2019LORR0140⟩. ⟨tel-02499250⟩

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