New polyamine derivatives 1-8, related to the previously reported N 1,N12-dibenzyldodecane-1,12-diamine (Bis-Bza-Diado) and N1-benzyl-spermine (BD6), have been synthesized and used as "probes" (potential substrates or inhibitors) of the human monoamine oxidases (MAO A and MAO B) and Vascular-Adhesion-protein -1 (VAP-1). Compound 8, the most effective inhibitor of the series, is characterized by a 12-methylene carbon chain ending with an isothiocyanate (ITC) group. Interestingly, it behaves as competitive inhibitor of MAO B and as irreversible inhibitor of MAO A. Compound 3, an asymmetric spermine analogue bearing a thiophene ring, acts as a reversible mixed inhibitor, selective for MAO B (KIE = 23 μM). Docking studies performed using the available Protein Data Bank (PDB) structures of MAO A and MAO B, suggested that the different mode of inhibition of 8 may be explained by the different binding poses of 8 into the active site cavities of the two MAO isoforms. The ε-amino group of Lys 305 of MAO A is proposed as possible target of the ITC group of the inhibitor. Further studies are in progress to confirm this hypothesis. These results indicate a potential use of the polyamine scaffold for the development of new MAO inhibitors for application in human pathologies involving these enzymes. © 2013 Elsevier Masson SAS. All rights reserved.

Novel polyamine analogues: From substrates towards potential inhibitors of monoamine oxidases / Emanuela, Bonaiuto; Andrea, Milelli; Giorgio, Cozza; Vincenzo, Tumiatti; Chiara, Marchetti; Agostinelli, Enzo; Carmela, Fimognari; Patrizia, Hrelia; Anna, Minarini; Maria Luisa Di, Paolo. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 70:(2013), pp. 88-101. [10.1016/j.ejmech.2013.07.005]

Novel polyamine analogues: From substrates towards potential inhibitors of monoamine oxidases

AGOSTINELLI, Enzo;
2013

Abstract

New polyamine derivatives 1-8, related to the previously reported N 1,N12-dibenzyldodecane-1,12-diamine (Bis-Bza-Diado) and N1-benzyl-spermine (BD6), have been synthesized and used as "probes" (potential substrates or inhibitors) of the human monoamine oxidases (MAO A and MAO B) and Vascular-Adhesion-protein -1 (VAP-1). Compound 8, the most effective inhibitor of the series, is characterized by a 12-methylene carbon chain ending with an isothiocyanate (ITC) group. Interestingly, it behaves as competitive inhibitor of MAO B and as irreversible inhibitor of MAO A. Compound 3, an asymmetric spermine analogue bearing a thiophene ring, acts as a reversible mixed inhibitor, selective for MAO B (KIE = 23 μM). Docking studies performed using the available Protein Data Bank (PDB) structures of MAO A and MAO B, suggested that the different mode of inhibition of 8 may be explained by the different binding poses of 8 into the active site cavities of the two MAO isoforms. The ε-amino group of Lys 305 of MAO A is proposed as possible target of the ITC group of the inhibitor. Further studies are in progress to confirm this hypothesis. These results indicate a potential use of the polyamine scaffold for the development of new MAO inhibitors for application in human pathologies involving these enzymes. © 2013 Elsevier Masson SAS. All rights reserved.
docking studies; inhibitors; isothiocyanate; monoamine oxidase (mao); polyamine derivatives
01 Pubblicazione su rivista::01a Articolo in rivista
Novel polyamine analogues: From substrates towards potential inhibitors of monoamine oxidases / Emanuela, Bonaiuto; Andrea, Milelli; Giorgio, Cozza; Vincenzo, Tumiatti; Chiara, Marchetti; Agostinelli, Enzo; Carmela, Fimognari; Patrizia, Hrelia; Anna, Minarini; Maria Luisa Di, Paolo. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 70:(2013), pp. 88-101. [10.1016/j.ejmech.2013.07.005]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/534102
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