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

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• 作者：Emanuela Bonaiuto ; Andrea Milelli ; Giorgio Cozza ; Vincenzo Tumiatti ; Chiara Marchetti ; Enzo Agostinelli ; Carmela Fimognari ; Patrizia Hrelia ; Anna Minarini ; Maria Luisa Di Paolo
• 关键词：Monoamine oxidase (MAO) ; Inhibitors ; Isothiocyanate ; Polyamine derivatives ; Docking studies
• 刊名：European Journal of Medicinal Chemistry
• 出版年：December, 2013
• 年：2013
• 卷：70
• 期：Complete
• 页码：88-101
• 全文大小：1700 K

文摘

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 鈥減robes鈥?(potential substrates or inhibitors) of the human monoamine oxidases (MAO A and MAO B) and Vascular-Adhesion-protein聽鈭? (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聽=聽23聽渭M). 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 蔚-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.