Inhibition
of β-Amyloid Aggregation in
Alzheimer’s Disease: The Key Role of (Pro)electrophilic Warheads |
| |
Authors: | Filippo Basagni Marina Naldi Tiziana Ginex F. Javier Luque Francesca Fagiani Cristina Lanni Matteo Iurlo Massimo Marcaccio Anna Minarini Manuela Bartolini Michela Rosini |
| |
Abstract: | Catechols have been largely investigated as antiaggregating agents toward β-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 β-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. |
| |
Keywords: | β -Amyloid, Alzheimer’ s disease, Natural compounds, Covalent inhibition, Polyphenols |
|
|