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.
Highlights
Human transthyretin is a homotetrameric protein (55 kDa) made up of four subunits (A-B-C-D, Figure 1a), each composed of 127 aminoacids [1,2,3]
In the majority of the TTR:small molecule crystal structures reported to date [3], the molecule is bound to the T4 binding site, with the exception of polyphenol (−)-epigallocatechin gallate (EGCG)
Each T4 binding pocket is composed of a small inner cavity, and a large outer cavity, with three pairs of symmetric hydrophobic depressions named halogen binding pockets (Figure 3) where the iodine atoms of T4 are located
Summary
Human transthyretin (hTTR, prealbumin) is a homotetrameric protein (55 kDa) made up of four subunits (A-B-C-D, Figure 1a), each composed of 127 aminoacids [1,2,3]. TTR is involved in the transport of thyroid hormones (thyroxine (T4 ) and triiodothyronine (T3 )) (Figure 1b) in blood and cerebrospinal fluid. The tetrameric assembly of TTR contains a central hydrophobic channel with two symmetrical funnel-shaped T4 binding pockets located at the energetically weaker dimer-dimer A-B/C-D interface [4], the other. A-C/B-D interface being stabilized by interstrand hydrogen bonds (HBs). (b) structures of thyroxine (T4 ), triiodothyronine (T3 ), tafamidis and other ATTR drug candidates under clinical trials. TTR amyloidogenesis has been implicated to cause amyloid diseases (TTR amyloidosis, ATTR) [5,6]
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