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

ABSTRACT: 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.

SUBMITTER: Dessi A 

PROVIDER: S-EPMC7248964 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature