Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4′-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Molecules Année : 2020

Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4′-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors

Résumé

The 3,3 ,5,5-tetrachloro-2-iodo-4,4-bipyridine structure is proposed as a novel chemical scaffold for the design of new transthyretin (TTR) fibrillogenesis inhibitors. In the frame of a proof-of-principle exploration, four chiral 3,3 ,5,5-tetrachloro-2-iodo-2-substituted-4,4-bipyridines were rationally designed and prepared from a simple trihalopyridine in three steps, including a Cu-catalysed Finkelstein reaction to introduce iodine atoms on the heteroaromatic scaffold, and a Pd-catalysed coupling reaction to install the 2-substituent. The corresponding racemates, along with other five chiral 4,4-bipyridines containing halogens as substituents, were enantioseparated by high-performance liquid chromatography in order to obtain pure enantiomer pairs. All stereoisomers were tested against the amyloid fibril formation (FF) of wild type (WT)-TTR and two mutant variants, V30M and Y78F, in acid mediated aggregation experiments. Among the 4,4-bipyridine derivatives, interesting inhibition activity was obtained for both enantiomers of the 3,3 ,5,5-tetrachloro-2-(4-hydroxyphenyl)-2-iodo-4,4-bipyridine. In silico docking studies were carried out in order to explore possible binding modes of the 4,4-bipyridine derivatives into the TTR. The gained results point out the importance of the right combination of H-bond sites and the presence of iodine as halogen-bond donor. Both experimental and theoretical evidences pave the way for the utilization of the iodinated 4,4-bipyridine core as template to design new promising inhibitors of TTR amyloidogenesis.
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Dates et versions

hal-02592133 , version 1 (15-05-2020)

Identifiants

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Alessandro Dessì, Paola Peluso, Roberto Dallocchio, Robin Weiss, Giuseppina Andreotti, et al.. Rational Design, Synthesis, Characterization and Evaluation of Iodinated 4,4′-Bipyridines as New Transthyretin Fibrillogenesis Inhibitors. Molecules, 2020, 25 (9), pp.2213. ⟨10.3390/molecules25092213⟩. ⟨hal-02592133⟩
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