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; Ginex, Tiziana; Luque, F Javier; Fagiani, Francesca; Lanni, Cristina; Iurlo, Matteo; Marcaccio, Massimo; Minarini, Anna; Bartolini, Manuela; Rosini, Michela. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - ELETTRONICO. - 13:11(2022), pp. 1812-1818. [10.1021/acsmedchemlett.2c00410]

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.
2022
Inhibition of β-Amyloid Aggregation in Alzheimer's Disease: The Key Role of (Pro)electrophilic Warheads / Basagni, Filippo; Naldi, Marina; Ginex, Tiziana; Luque, F Javier; Fagiani, Francesca; Lanni, Cristina; Iurlo, Matteo; Marcaccio, Massimo; Minarini, Anna; Bartolini, Manuela; Rosini, Michela. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - ELETTRONICO. - 13:11(2022), pp. 1812-1818. [10.1021/acsmedchemlett.2c00410]
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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