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Identification et optimisation de inhibiteurs d’arginase reposant sur des groupements chélateurs de métaux

Abstract : For over a century, arginase has been recognised as a metalloenzyme, which plays an essential role in the urea cycle. Nevertheless, the demonstration of its role in the homoeostasis of nitrogen monoxide, and consequently in cardiovascular and infectious pathologies, as well as in the immune escape of tumours, is much more recent. Along with these findings, the development of inhibitors has accelerated. These inhibitors are however limited in structural diversity, efficacy and pharmacokinetic parameters. To date, several clinical trials are underway, but no drug targeting arginase is available on the market. The initial work, presented here, was devoted to the identification of arginase inhibitors of innovative structures through the screening of commercial metal-chelating fragments. Two of the three hits obtained were invalidated following their preparation in the laboratory. Investigations carried out on one of the commercial compounds led to palladium impurities discovery. This research also identified two palladium complexes inhibitors of arginase. The third touch has been mechanically investigated and confirmation, through laboratory preparation, is underway. The second work is inspired by arginase inhibitor polyphenols. The most active of them have in common catechol moiety. Following an in vitro and in silico study of the activity of this moiety on arginase, the exploration of several extension pathways of the latter has led to the preparation of two series of nitrogen analogues of piceatannol. Three compounds were obtained with an activity close to piceatannol, however, the latter show an increased competitive character.
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Submitted on : Monday, June 7, 2021 - 4:41:20 PM
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Jason Muller. Identification et optimisation de inhibiteurs d’arginase reposant sur des groupements chélateurs de métaux. Médecine humaine et pathologie. Université Bourgogne Franche-Comté, 2020. Français. ⟨NNT : 2020UBFCE015⟩. ⟨tel-03252441⟩

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