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.
Concordia University, Department of Chemistry and Biochemistry, Pharmaqam, 7141 rue Sherbrooke O., Montréal, QC H4B 1R6 (Canada).
Avid
A
Hassanpour
Carole Anne
CA
De Carufel
Steve
S
Bourgault
Pat
P
Forgione
D000682:Amyloid / Q000737:chemistry* / Q000633:toxicity; D052160:Benzothiazoles; D050417:Insulin-Secreting Cells / Q000737:chemistry*; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000633:toxicity; D015394:Molecular Structure; D013844:Thiazoles / Q000737:chemistry*; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry
D000682:Amyloid; D052160:Benzothiazoles; D058228:Islet Amyloid Polypeptide; D013844:Thiazoles; D013876:Thiophenes; C009462:thioflavin T
CH arylation; amyloids; decarboxylative arylation; peptidomimetics; thiophenes