title: Novel polyamine analogues: from substrates towards potential inhibitors of monoamine oxidases.
abstract: New polyamine derivatives 1-8, related to the previously reported N(1),N(12)-dibenzyldodecane-1,12-diamine (Bis-Bza-Diado) and N(1)-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 (K(IE) = 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.
authors.affiliation: Department of Molecular Medicine, University of Padova, Via G. Colombo 3, 35131 Padova, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Bonaiuto
authors.forename: Andrea
authors.initials: A
authors.lastname: Milelli
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cozza
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Tumiatti
authors.forename: Chiara
authors.initials: C
authors.lastname: Marchetti
authors.forename: Enzo
authors.initials: E
authors.lastname: Agostinelli
authors.forename: Carmela
authors.initials: C
authors.lastname: Fimognari
authors.forename: Patrizia
authors.initials: P
authors.lastname: Hrelia
authors.forename: Anna
authors.initials: A
authors.lastname: Minarini
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Di Paolo
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011073:Polyamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity / Q000187:drug effects
chemical_list: D008996:Monoamine Oxidase Inhibitors; D011073:Polyamines; D008995:Monoamine Oxidase
keywords: AITC; BD6; BZA; Bis-Bza-Diado; Docking studies; ITC; Inhibitors; Isothiocyanate; K(IE); K(IES); K(m); MAO; Michaelis–Menten constant; Monoamine oxidase (MAO); N(1),N(12)-dibenzyl-dodecane-1,12-diamine; N(1)-(3-aminopropyl)-N(4)-(3-(benzylamino)propyl)butane-1,4-diamine/N(1)-benzyl-spermine; Polyamine derivatives; V(max); VAP-1; allyl isothiocyanate; benzylamine; enzyme–inhibitor dissociation constant/inhibition constant; enzyme–substrate complex-inhibitor dissociation constant; isothiocyanate; maximum velocity; monoamine oxidase; p-tyramine; semicarbazide-sensitive amine oxidase/vascular-adhesion-protein-1; tyramine