Synthesis of 2,5-Diaryl-Substituted Thiophenes as Helical Mimetics: Towards the Modulation of Islet Amyloid Polypeptide (IAPP) Amyloid Fibril Formation and Cytotoxicity

A range of 2,5‐diarylated thiophenes were synthesised as small molecule mimetics of the α‐helix to modulate the amyloidogenesis and cytotoxic effect of islet amyloid polypeptide (IAPP). 3‐Substituted thiophene‐2‐carboxylic acids were used as key intermediates and functionalised by palladium decarboxylative cross‐coupling and direct CH activation successively with overall yields ranging from 23 to 95 %. The effect of the ligands on IAPP amyloid fibril formation was evaluated with the thioflavin T (ThT) fluorescence‐based assay. Furthermore, the capacity of these compounds to inhibit the cytotoxic effect of IAPP was assessed using β‐pancreatic cells. A twist manipulated: A range of 2,5‐diarylated thiophenes was synthesised as small molecule mimetics of the α‐helix to modulate the amyloidogenesis and cytotoxic effect of islet amyloid polypeptide (IAPP; see scheme). The effect of the ligands on IAPP amyloid fibril formation was evaluated. Furthermore, the capacity of these compounds to inhibit the cytotoxic effect of IAPP was assessed using β‐pancreatic cells.