Structure-activity relationships of organofluorine inhibitors of β-amyloid self-assembly.

A broad group of structurally diverse small organofluorine compounds were synthesized and evaluated as inhibitors of beta-amyloid (A beta) self-assembly. The main goal was to generate a diverse library of compounds with the same functional group and to observe general structural features that characterize inhibitors of A beta oligomer and fibril formation, ultimately identifying structures for further focused inhibitor design. The common structural motifs in these compounds are CF3-C-OH and CF3-C-NH groups that were proposed to be binding units in our previous studies. A broad range of potential small-molecule inhibitors were synthesized by combining various carbocyclic and heteroaromatic rings with an array of substituents, generating a total of 106 molecules. The compounds were tested by standard methods such as thioflavin-T fluorescence spectroscopy for monitoring fibril formation, biotinyl A beta 142 single-site streptavidin-based assays for observing oligomer formation, and atomic force microscopy for morphological studies. These assays revealed a number of structures that show significant inhibition against either A beta fibril or oligomer formation. A detailed analysis of the structureactivity relationship of anti-fibril and -oligomer properties is provided. These data present further experimental evidence for the distinct nature of fibril versus oligomer formation and indicate that the interaction of the A beta peptide with chiral small molecules is not stereospecific in nature.