Aggregation of the pancreatic protein Islet Amyloid Polypeptide (IAPP, amylin) into soluble toxic oligomers and insoluble amyloid appears to play a direct role in the progression of type 2 diabetes. While it remains unclear whether the formation of toxic oligomers and amyloid is a direct cause of this disease or merely a side-effect, evidence is mounting that suggests that inhibiting this aggregation may be a key step toward slowing, if not preventing altogether, the progression of this disease. A series of small polyphenol analogs were synthesized based on the structures of known amyloid inhibitors. Treatment of the phenolic acids with benzyl bromide followed by hydrolysis of the benzyl ester afforded the aryl benzyl ethers in good yields. Steglich esterification of the polyols with protected phenolic acids and DCC, followed by deprotection of the benzyl ethers, completed the synthesis of the polyphenol analogs. These compounds were assayed for their ability to inhibit IAPP amyloid formation using standard methods for detecting and quantitating amyloid.  Specifically, thioflavin T binding fluorescence, atomic force microscopy, circular dichroism, and immunodetection assays were used to assess the inhibitory potential of select substances.

Synthesis and screening of novel polyphenol compounds targeted to inhibit IAPP amyloid aggregation

251st National Meeting (2016)

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