Monoaryl derivatives as transthyretin fibril formation inhibitors: Design, synthesis, biological evaluation and structural analysis.

Published on Sep 15, 2020in Bioorganic & Medicinal Chemistry3.073
· DOI :10.1016/J.BMC.2020.115673
Lidia Ciccone9
Estimated H-index: 9
(UniPi: University of Pisa),
Susanna Nencetti18
Estimated H-index: 18
(UniPi: University of Pisa)
+ 6 AuthorsElisabetta Orlandini20
Estimated H-index: 20
(UniPi: University of Pisa)
Source
Abstract
Abstract Transthyretin (TTR) is a s-sheet-rich homotetrameric protein that transports thyroxine (T4) and retinol both in plasma and in cerebrospinal fluid. TTR also interacts with amyloid-β, playing a protective role in Alzheimer’s disease. Dissociation of the native transthyretin (TTR) tetramer is widely accepted as the critical step in TTR amyloids fibrillogenesis, and is responsible for extracellular deposition of amyloid fibrils. Small molecules, able to bind in T4 binding sites and stabilize the TTR tetramer, are interesting tools to treat and prevent systemic ATTR amyloidosis. We report here the synthesis, in vitro evaluation and three-dimensional crystallographic analyses of new monoaryl-derivatives in complex with TTR. Of the derivatives reported here, the best inhibitor of TTR fibrillogenesis, 1d, exhibits an activity similar to diflunisal.
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