New polyamine derivatives 1-8, related to the previously reported N1,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 MAOB) 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 mM). 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 e-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.
Bonaiuto E, Milelli A, G. Cozza, Tumiatti V, Marchetti C, Agostinelli E, et al. (2013). Novel polyamine analogues: from substrates towards potential inhibitors of monoamine oxidases. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 70, 88-101 [10.1016/j.ejmech.2013.07.005].
Novel polyamine analogues: from substrates towards potential inhibitors of monoamine oxidases
MILELLI, ANDREA;TUMIATTI, VINCENZO;MARCHETTI, CHIARA;FIMOGNARI, CARMELA;HRELIA, PATRIZIA;MINARINI, ANNA;
2013
Abstract
New polyamine derivatives 1-8, related to the previously reported N1,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 MAOB) 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 mM). 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 e-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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.