Web Release Date: March 25,
Organofluorine Inhibitors of Amyloid Fibrillogenesis
and
Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, Massachusetts 02125-3393, and Michigan Technological University, 1400 Townsend Drive, Houghton, Michigan 49931
Received January 18, 2006
Revised Manuscript Received March 2, 2006
Abstract:
The design and application of an effective, new class of organofluorine inhibitors of amyloid
fibrillogenesis are described. Based on experimental evidence a core structure containing indol-3-yl,
trifluoromethyl, hydroxyl, and carboxylic acid ester functions has been designed. Several substituted
derivatives of this core structure have been synthesized, using various indole derivatives. While all inhibitor
candidates have shown considerable effect (20-70% inhibition) in structure-activity relationship studies
(inhibitor/A
= 10 ratio), several compounds have demonstrated excellent activity (93-96% inhibition).
Using concentration dependence studies, the activity of the most active molecules have been quantified.
These inhibitors practically completely block the fibril formation of A1-40, as shown by maximum
inhibition values (ICmax = 98-100%). The median inhibitor concentration values (IC50 = 0.23-0.53
molinhibitor/molA) demonstrate favorable stoichiometry for the inhibition. The respective elimination of
the functional groups from the core structure has resulted in a partial or complete loss of activity, indicating
the significant role of each group. Experiments with these derivatives suggest the particular importance
of the acidic hydroxyl group during peptide-inhibitor interaction.
Download the full text: PDF | HTML
