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New Amine Oxidase Inhibitors and Enzymes in Oxidative Stress-Related Pathologies
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New Amine Oxidase Inhibitors and Enzymes in Oxidative Stress-Related Pathologies

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 10277

Special Issue Editors

Dr. Maria Luisa di Paolo

E-Mail Website
Guest Editor
Department of Molecular Medicine, University of Padova, Italy
Interests: amineoxidases; polyamines analogues; metalloenzymes; structure–function relationship studies; redox balance and antioxidants
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Lisa Dalla Via

E-Mail Website
Guest Editor
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, I-35131 Padova, Italy
Interests: drug discovery; MAO inhibitors; anticancer drugs; natural compounds
Prof. Dr. Antonella Roveri

E-Mail Website
Guest Editor
Department of Molecular Medicine, University of Padova, Padova, Italy
Interests: enzymes kinetics; post-translational modifications in proteins; antioxidants and redox
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleague,

Amine oxidases (AOs) are a heterogeneous group of enzymes that catalyze the oxidative deamination of biogenic and exogenous amines to generate biologically active reaction products, such as aldehydes, ammonia and hydrogen peroxide, which may in turn influence cells and tissues. In particular, an overproduction of aldehydes and hydrogen peroxide has been related to a condition of oxidative stress, which is known to play an essential role in the pathogenesis and progression of many diseases, from neurodegenerative to cardiovascular diseases and diabetes mellitus, in addition to being associated with an increased risk of tumorigenesis. Consequently, AOs are considered important pharmacological targets in various pathologies, and various types of AO inhibitors have been developed, some of which are currently used in clinical settings.

Among the FAD-containing AOs, monoamine oxidase (MAO) A and B are some of the earliest and most well-known pharmacological targets in neurological and neurodegenerative diseases (such as depression, Parkinson’s and Alzheimer’s diseases). In recent years, to face these emerging multifactorial diseases, novel pharmacological strategies are being studied along with the design of novel types of inhibitors able to simultaneously attack different targets involved in the same pathology (for example, dual inhibitors for MAO and acetylcholine–butyrylcholinesterase). Additionally, recent studies have highlighted how increased MAO activity (mainly of the MAO A isoform) is also involved in some age-related diseases, such cardiac aging, heart failure and cancer, renewing the interest in the physiopathological role of these enzymes and opening new pharmacological perspectives.

Other examples of FAD-containing enzymes are the polyamine oxidases, involved in the catabolism of polyamines, whose levels increase in proliferating cells and are involved in cancer development. For this reason, the recently discovered spermine oxidase, an inducible enzyme, represents a potential target in cancer for which the development of potent and selective inhibitors is necessary.

Among the various topaquinone/semicarbazide-sensitive amine oxidases (SSAOs), it is worth underline the intriguing role of human vascular adhesion protein-1 (VAP-1), a multifunctional enzyme with two domains: an amine oxidase activity and an adhesive domain. Its amine oxidase activity is able to regulate the adhesion and migration of some leukocytes to the inflammation site and to modulate the inflammation signaling pathways. VAP-1 expression is abundant in the vascular system, and because of its important role in vascular inflammation, it is a potential target for different systemic and cerebral diseases, including stroke and Alzheimer’s disease. Additionally, VAP-1 is highly expressed in adipocyte cell membranes, liver endothelial cells and smooth muscle, and a soluble form of VAP-1 is released in plasma in some oxidative-related diseases. The physiopathological role of VAP-1 in these tissues is not well clarified and understood.

Therefore, it seems extremely important to study, in depth, the cellular pathways linked to the different AOs both to understand their role in the various pathologies and, consequently, to develop more focused therapies. Additionally, the development of novel inhibitors and novel pharmacological strategies seem necessary, particularly for the multifactorial and oxidative stress-related pathologies involving AOs.

The aim of this Special Issue is to collate original research, clinical studies and review articles describing the current findings on the development of novel inhibitors of the different AOs in targeting various pathologies, and on novel correlations between amine oxidase activity and the various oxidative stress-related diseases.

We are particularly interested in articles that might significantly contribute to better understanding of the biochemical and molecular mechanisms underlying the pathological role of AOs; articles focusing on pharmacological strategies involving AOs are also welcome.

Specific topics of interest include but are not limited to the following:

  • Novel inhibitors of AOs in relation to oxidative stress-related pathologies;
  • New pharmacological approaches involving AOs as molecular targets;
  • Novel physiological and pathological roles of spermine oxidase, MAOs, VAP-1 and other AOs (lysyl oxidase, LSD-1, diamine oxidase, ...)
  • Relationships between oxidative stress and amine oxidase activity under healthy and disease conditions.

Dr. Maria Luisa di Paolo
Prof. Dr. Lisa Dalla Via
Prof. Dr. Antonella Roveri
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • amine oxidases
  • oxidative stress
  • drug discover
  • spermine oxidase
  • oxidative stress-related diseases
  • multifactorial pathologies
  • polyamine derivatives

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Published Papers (5 papers)

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Research

18 pages, 5962 KiB  
Article
From Monoamine Oxidase Inhibition to Antiproliferative Activity: New Biological Perspectives for Polyamine Analogs
by Giulia Nordio, Francesco Piazzola, Giorgio Cozza, Monica Rossetto, Manuela Cervelli, Anna Minarini, Filippo Basagni, Elisa Tassinari, Lisa Dalla Via, Andrea Milelli and Maria Luisa Di Paolo
Molecules 2023, 28(17), 6329; https://doi.org/10.3390/molecules28176329 - 29 Aug 2023
Viewed by 1587
Abstract
Monoamine oxidases (MAOs) are well-known pharmacological targets in neurological and neurodegenerative diseases. However, recent studies have revealed a new role for MAOs in certain types of cancer such as glioblastoma and prostate cancer, in which they have been found overexpressed. This finding is [...] Read more.
Monoamine oxidases (MAOs) are well-known pharmacological targets in neurological and neurodegenerative diseases. However, recent studies have revealed a new role for MAOs in certain types of cancer such as glioblastoma and prostate cancer, in which they have been found overexpressed. This finding is opening new frontiers for MAO inhibitors as potential antiproliferative agents. In light of our previous studies demonstrating how a polyamine scaffold can act as MAO inhibitor, our aim was to search for novel analogs with greater inhibitory potency for human MAOs and possibly with antiproliferative activity. A small in-house library of polyamine analogs (2–7) was selected to investigate the effect of constrained linkers between the inner amine functions of a polyamine backbone on the inhibitory potency. Compounds 4 and 5, characterized by a dianiline (4) or dianilide (5) moiety, emerged as the most potent, reversible, and mainly competitive MAO inhibitors (Ki < 1 μM). Additionally, they exhibited a high antiproliferative activity in the LN-229 human glioblastoma cell line (GI50 < 1 μM). The scaffold of compound 5 could represent a potential starting point for future development of anticancer agents endowed with MAO inhibitory activity. Full article
(This article belongs to the Special Issue New Amine Oxidase Inhibitors and Enzymes in Oxidative Stress-Related Pathologies)
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16 pages, 2154 KiB  
Article
Antibodies-Abzymes with Antioxidant Activities in Two Th and 2D2 Experimental Autoimmune Encephalomyelitis Mice during the Development of EAE Pathology
by Anna S. Tolmacheva, Kseniya S. Aulova, Andrey E. Urusov, Vasiliy B. Doronin and Georgy A. Nevinsky
Molecules 2022, 27(21), 7527; https://doi.org/10.3390/molecules27217527 - 3 Nov 2022
Cited by 3 | Viewed by 1740
Abstract
The exact mechanisms of multiple sclerosis development are still unknown. However, the development of EAE (experimental autoimmune encephalomyelitis) in Th and 2D2 mice is associated with the infringement of the differentiation profiles of bone marrow hematopoietic stem cells which are bound with the [...] Read more.
The exact mechanisms of multiple sclerosis development are still unknown. However, the development of EAE (experimental autoimmune encephalomyelitis) in Th and 2D2 mice is associated with the infringement of the differentiation profiles of bone marrow hematopoietic stem cells which are bound with the production of compounds that are harmful for human autoantibodies-abzymes that hydrolyze myelin oligodendrocyte glycoprotein, myelin basic protein, and DNA. It showed that autoimmune patients’ antioxidant IgG antibodies oxidise some compounds due to their peroxidase (H2O2-dependent) and oxidoreductase (H2O2-independent) activities more effectively than those in healthy humans can. It was interesting to identify whether the redox activities of the antibodies change during the development of autoimmune diseases. Here, we analyzed the change in these redox activities of the IgGs from the blood of Th and 2D2 mice, which corresponded to different stages of the EAE development. The peroxidase activity in the oxidation of ABTS (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) in the Th (4-fold) and 2D2 (2-fold) mice IgGs, on average, is higher than the oxidoreductase activity is. The peroxidase activity of the Th (1.9-fold) and 2D2 (3.5-fold) mice IgGs remarkably increased during the 40 days of the spontaneous development of EAE. Forty days after the immunization of the MOG peroxidase activity, the IgGs of the Th and 2D2 mice increased 5.6–6.0 times when they were compared with those that presented no increase (3 months of age). The mice IgGs were oxidized with 3,3′-diaminobenzidine (2.4–4.3-fold) and o-phenylenediamine (139–143-fold) less efficiently than they were with ABTS. However, the temper of the change in the IgG activity in the oxidation of these substrates during the spontaneous and MOG-induced development of EAE was close to that which occurred for ABTS. All of the data show that the IgG peroxidase and oxidoreductase activities of EAE mice can play an important role in their protection from toxic compounds and oxidative stress. Full article
(This article belongs to the Special Issue New Amine Oxidase Inhibitors and Enzymes in Oxidative Stress-Related Pathologies)
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20 pages, 6111 KiB  
Article
Computational Insights into β-Carboline Inhibition of Monoamine Oxidase A
by Alja Prah, Tanja Gavranić, Andrej Perdih, Marija Sollner Dolenc and Janez Mavri
Molecules 2022, 27(19), 6711; https://doi.org/10.3390/molecules27196711 - 9 Oct 2022
Cited by 4 | Viewed by 1999
Abstract
Monoamine oxidases (MAOs) are an important group of enzymes involved in the degradation of neurotransmitters and their imbalanced mode of action may lead to the development of various neuropsychiatric or neurodegenerative disorders. In this work, we report the results of an in-depth computational [...] Read more.
Monoamine oxidases (MAOs) are an important group of enzymes involved in the degradation of neurotransmitters and their imbalanced mode of action may lead to the development of various neuropsychiatric or neurodegenerative disorders. In this work, we report the results of an in-depth computational study in which we performed a static and a dynamic analysis of a series of substituted β-carboline natural products, found mainly in roasted coffee and tobacco smoke, that bind to the active site of the MAO-A isoform. By applying molecular docking in conjunction with structure-based pharmacophores and molecular dynamics simulations coupled with dynamic pharmacophores, we extensively investigated the geometric aspects of MAO-A binding. To gain insight into the energetics of binding, we used the linear interaction energy (LIE) method and determined the key anchors that allow productive β-carboline binding to MAO-A. The results presented herein could be applied in the rational structure-based design and optimization of β-carbolines towards preclinical candidates that would target the MAO-A enzyme and would be applicable especially in the treatment of mental disorders such as depression. Full article
(This article belongs to the Special Issue New Amine Oxidase Inhibitors and Enzymes in Oxidative Stress-Related Pathologies)
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22 pages, 2963 KiB  
Article
Effects of Chemical Structures Interacting with Amine Oxidases on Glucose, Lipid and Hydrogen Peroxide Handling by Human Adipocytes
by Christian Carpéné, Pénélope Viana, Zsuzsa Iffiú-Soltesz, Pál Tapolcsányi, Anna Ágota Földi, Péter Mátyus and Petra Dunkel
Molecules 2022, 27(19), 6224; https://doi.org/10.3390/molecules27196224 - 22 Sep 2022
Cited by 1 | Viewed by 1680
Abstract
Benzylamine is a natural molecule present in food and edible plants, capable of activating hexose uptake and inhibiting lipolysis in human fat cells. These effects are dependent on its oxidation by amine oxidases present in adipocytes, and on the subsequent hydrogen peroxide production, [...] Read more.
Benzylamine is a natural molecule present in food and edible plants, capable of activating hexose uptake and inhibiting lipolysis in human fat cells. These effects are dependent on its oxidation by amine oxidases present in adipocytes, and on the subsequent hydrogen peroxide production, known to exhibit insulin-like actions. Virtually, other substrates interacting with such hydrogen peroxide-releasing enzymes potentially can modulate lipid accumulation in adipose tissue. Inhibition of such enzymes has also been reported to influence lipid deposition. We have therefore studied in human adipocytes the lipolytic and lipogenic activities of pharmacological entities designed to interact with amine oxidases highly expressed in this cell type: the semicarbazide-sensitive amine oxidase (SSAO also known as PrAO or VAP-1) and the monoamine oxidases (MAO). The results showed that SZV-2016 and SZV-2017 behaved as better substrates than benzylamine, releasing hydrogen peroxide once oxidized, and reproduced or even exceeded its insulin-like metabolic effects in fat cells. Additionally, several novel SSAO inhibitors, such as SZV-2007 and SZV-1398, have been evidenced and shown to inhibit benzylamine metabolic actions. Taken as a whole, our findings reinforce the list of molecules that influence the regulation of triacylglycerol assembly/breakdown, at least in vitro in human adipocytes. The novel compounds deserve deeper investigation of their mechanisms of interaction with SSAO or MAO, and constitute potential candidates for therapeutic use in obesity and diabetes. Full article
(This article belongs to the Special Issue New Amine Oxidase Inhibitors and Enzymes in Oxidative Stress-Related Pathologies)
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13 pages, 4218 KiB  
Article
Development of a Novel Class of Pyridazinone Derivatives as Selective MAO-B Inhibitors
by Mehmet Abdullah Alagöz, Jong Min Oh, Yaren Nur Zenni, Zeynep Özdemir, Mohamed A. Abdelgawad, Ibrahim A. Naguib, Mohammed M. Ghoneim, Nicola Gambacorta, Orazio Nicolotti, Hoon Kim and Bijo Mathew
Molecules 2022, 27(12), 3801; https://doi.org/10.3390/molecules27123801 - 13 Jun 2022
Cited by 14 | Viewed by 2153
Abstract
Sixteen compounds (TR1–TR16) were synthesized and evaluated for their inhibitory activities against monoamine oxidase A and B (MAOs). Most of the derivatives showed potent and highly selective MAO-B inhibition. Compound TR16 was the most potent inhibitor against MAO-B with an IC [...] Read more.
Sixteen compounds (TR1–TR16) were synthesized and evaluated for their inhibitory activities against monoamine oxidase A and B (MAOs). Most of the derivatives showed potent and highly selective MAO-B inhibition. Compound TR16 was the most potent inhibitor against MAO-B with an IC50 value of 0.17 μM, followed by TR2 (IC50 = 0.27 μM). TR2 and TR16 selectivity index (SI) values for MAO-B versus MAO-A were 84.96 and higher than 235.29, respectively. Compared to the basic structures, the para-chloro substituent in TR2 and TR16 increased the inhibitory activity of MAO-B. TR2 and TR16 were reversible MAO-B inhibitors that were competitive, with Ki values of 0.230 ± 0.004 and 0.149 ± 0.016 µM, respectively. The PAMPA method indicated that compounds TR2 and TR16 had the tendency to traverse the blood–brain barrier. Docking investigations revealed that lead compounds were beneficial for MAO-B inhibition via association with key as well as selective E84 or Y326 residues, but not for MAO-A inhibition via interaction primarily driven by hydrophobic contacts. In conclusion, TR2 and TR16 are therapeutic prospects for the management of multiple neurodegenerative diseases. Full article
(This article belongs to the Special Issue New Amine Oxidase Inhibitors and Enzymes in Oxidative Stress-Related Pathologies)
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