Novel and old polyamine analogues to target human monoamine oxidases and vascular adhesion protein-1

Polyamine analogues are extensively investigated for their potential pharmacological applications as anticancer, antiparasitic, antibacterial, and antineurodegenerative agents. Indeed, polyamine structures can bind to various targets and their affinity and selectivity may be fine-tuned by inserting appropriate substituents and varying the methylene chain lengths on the polyamine backbone (Minarini et al., 2010 Amino Acids, 42, 913-28). The aim of our studies was to develop polyamine-based scaffolds to hit novel targets: human Semicarbazide-sensitive amine oxidase/Vascular Adhesion Protein-1 (VAP-1) and monoamine oxidases (MAO A and MAO B). MAOs are “old” and well-known targets of antineurodegenerative drugs and antidepressant therapies and VAP-1 is a potential drug target of inflammatory diseases because of its involvement in leukocyte trafficking (Jalkanen and Salmi 2001 EMBO J 20:3893-3901). To investigate the polyamine structural features required to interact with MAO A, MAO B or VAP-1 active site, “old” and novel polyamine analogues were evaluated both as potential substrates and inhibitors. Kinetic studies integrated with docking experiments were performed to understand the mechanism of inhibition and the binding mode of the best inhibitors. From the results obtained so far, ELP 12, an “old” methoctramine derivative (a muscarinic M2 receptor antagonist), might be a good lead to develop reversible VAP-1 inhibitors: it behaves as non-competitive inhibitors of VAP-1 and its binding induces a rearrangement of the secondary structure of the enzyme. In our studies we found that the novel compound 8, characterized by a 12-methylene carbon chain ending with an isothiocyanate (ITC) group, behaves as competitive inhibitor of MAO B and as irreversible inhibitor of MAO A. Docking studies proposed the ε-amino group of Lys 305 of MAO A as possible target of the ITC group of 8. In addition, compound 3, an asymmetric spermine analogue bearing a thiophene ring, was found to act as a reversible inhibitor with good selectivity for MAO B. These results confirm that polyamine analogues might represent suitable scaffolds for the development of MAO and VAP-1 inhibitors potentially useful in human pathologies involving these enzymes.