title: Discovery of ethyl urea derivatives as inhibitors of islet amyloid polypeptide fibrillization and cytotoxicity.
abstract: Islet amyloid polypeptide (IAPP) has been shown to form amyloid deposits in pancreatic islets, thereby furthering type 2 diabetes disease progression. Further discovery of new molecules is needed to create a diverse set of molecules that impede pancreatic amyloidosis. We have recently designed and synthesized N-phenyl-N'-(2-ethyl)ureas (EU) that are non-cytotoxic small molecules, to evaluate the role of the aryl-substituted moiety on the inhibition of hIAPP fibrillization. Several EUs were tested in vitro for their anti-amyloidogenic activity using the fluorometric ThT assay, the photo-induced cross-linking (PIUCP) assay, and cell survival assay in pancreatic MIN-6 cells. EU-362 and EU-418 were able to significantly inhibit the formation of hIAPP fibrils and protected cells from amyloid cytotoxic effects. Our results suggest that increasing the nucleophilic potency of the aryl moiety significantly enhances the anti-amyloidogenic activity of the molecules.
authors.affiliation: a Département de Pathologie et de Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, QC J2S 2M2, Canada.
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Fortin
authors.affiliation: a Département de Pathologie et de Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, QC J2S 2M2, Canada.
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Benoit-Biancamano
authors.affiliation: b CR CHU de Québec, Axe oncologie, Hôpital Saint-François d'Assise, 10 rue de l'Espinay, Québec, QC G1L 3L5, Canada.
authors.forename: René
authors.initials: R
authors.lastname: C-Gaudreault
mesh_terms: D000682:Amyloid / Q000378:metabolism; D000686:Amyloidosis / Q000188:drug therapy / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D054852:Small Molecule Libraries; C007685:ethylurea; D014508:Urea
keywords: IAPP; N-phenyl-N′-(2-ethyl)urea (EU); amyloid; amyloïde; diabetes; diabète; inhibiteurs de la fibrillisation; inhibitors of fibrillization