Novel polyamine analogues: from substrates towards potential inhibitors of monoamine oxidases.

Polyamine analogues are extensively researched investigated for their potential pharmacological applications as anticancer (Casero et al. 2009) and antimalarial agents (Verlinden et al., 2011), as well as in the development of multitarget-directed ligands (MTDLs) for novel therapies in neurodegenerative and other multi-factorial diseases (Melchiorre et al. 2010). In the MTLDs field, the polyamine backbone behaves as a “universal template”, able to bind different biological targets with an affinity and selectivity that may be fine-tuned by inserting appropriate substituents on nitrogen atoms and by varying the polymethylene chain lengths (Minarini et al. 2010). In the search of new MTDLs to combat neurodegenerative diseases, we designed new polyamines with the aim to inhibit additional target involved in these pathologies. Among these, human monoamine oxidases (MAOs) are emerging potential targets (Bortolato et al., 2008, Boomsma et al., 2003), since may contribute to the oxidative damage involved not only in neurodegenerative diseases but also in other ones and other pathologies, such as diabetes, cardiovascular and inflammatory disorders (Cohen and Tong 2010). Monoamine oxidases (MAO A and MAO B) and Semicarbazide-Sensitive Amine Oxidase/Vascular Adhesion Protein-1 (SSAO/VAP-1) catalyze the oxidative deamination of biogenic amines to produce aldehyde, hydrogen peroxide and ammonia. The starting points of our study were the negligible enzyme activities of MAOs and SSAO/VAP-1 on spermine and our previous results on Bis-BZA-DIADO, which we found able to inhibit both MAO B and SSAO/VAP-1 (Bonaiuto et al., 2012). Eight novel synthetic polyamines were tested as substrates and inhibitors on SSAO/VAP-1 and MAOs. From the kinetic studies carried out so far, we found novel substrates of SSAO/VAP-1 and two novel types of specific MAOs inhibitors: BD28, more selective for MAO B (Ki= 32 M) and NT27 (Ki = 15 M). Interestingly, NT 27 acts as an irreversible inhibitor of MAO A while, on MAO B, it behaves as a mixed and reversible inhibitor. Further studies are in progress to understand elucidate the binding mode of these compounds to MAOs, in such a way, to modify their structure in order to improve their affinity and selectivity for future application as MTLDs in neurodegenerative diseases.