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Structure–Activity Relationships of Organofluorine Inhibitors of β‐Amyloid Self‐Assembly
Author(s) -
Török Béla,
Sood Abha,
Bag Seema,
Kulkarni Aditya,
Borkin Dmitry,
Lawler Elizabeth,
Dasgupta Sujaya,
Landge Shainaz,
Abid Mohammed,
Zhou Weihong,
Foster Michelle,
LeVine Harry,
Török Marianna
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100569
Subject(s) - oligomer , fibril , chemistry , molecule , thioflavin , small molecule , stereochemistry , amyloid (mycology) , combinatorial chemistry , biophysics , crystallography , biochemistry , organic chemistry , biology , medicine , inorganic chemistry , disease , pathology , alzheimer's disease
A broad group of structurally diverse small organofluorine compounds were synthesized and evaluated as inhibitors of β‐amyloid (Aβ) 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 Aβ oligomer and fibril formation, ultimately identifying structures for further focused inhibitor design. The common structural motifs in these compounds are CF 3 ‐C‐OH and CF 3 ‐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 Aβ 1–42 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 Aβ fibril or oligomer formation. A detailed analysis of the structure–activity 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 Aβ peptide with chiral small molecules is not stereospecific in nature.