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.

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

Basagni, Filippo;Naldi, Marina;Iurlo, Matteo;Marcaccio, Massimo;Minarini, Anna;Bartolini, Manuela;Rosini, Michela
2022

Abstract

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.
Basagni, Filippo; Naldi, Marina; Ginex, Tiziana; Luque, F Javier; Fagiani, Francesca; Lanni, Cristina; Iurlo, Matteo; Marcaccio, Massimo; Minarini, Anna; Bartolini, Manuela; Rosini, Michela
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/906294
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