Inhibition of β-Amyloid Aggregation in Alzheimer's Disease: The Key Role of (Pro)electrophilic Warheads

Catechols have been largely investigated as anti-aggregating agents toward beta-amyloid peptide. Herein, as a follow up of a previous series of hydroxycinnamic derivatives, we synthesized a small set of dihydroxy isomers for exploring the role of the reciprocal position of the two hydroxyl functions at a molecular level. Para- and ortho-derivatives effectively reduced amyloid fibrillization, while the meta-analogue was devoid of any activity in this respect. Electrochemical analyses showed that the antiaggregating potency correlates with the oxidation potential, hence indicating the proelectrophilic character as a prerequisite for activity. Interestingly, mass spectrometry studies and quantum mechanical calculations revealed different modes of action for active para- and ortho-derivatives, involving covalent or noncovalent interactions with beta-amyloid. The distinctive mode of action is also translated into a different cytotoxicity profile. This work clearly shows how apparently minimal structural modifications can completely change the compound behavior and generate alternative mechanisms of action of proelectrophilic chemical probes.

Automated summary

This study investigates the role of the reciprocal position of two hydroxyl functions in inhibiting the aggregation of beta-amyloid peptide. The results show that para- and ortho-derivatives effectively reduce amyloid fibrillization, while the meta-analogue has no activity. Electrochemical analyses indicate that the antiaggregating potency correlates with the oxidation potential. Mass spectrometry studies and quantum mechanical calculations reveal different modes of action for active para- and ortho-derivatives.