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. 2023 Aug 29;28(17):6329.
doi: 10.3390/molecules28176329.

From Monoamine Oxidase Inhibition to Antiproliferative Activity: New Biological Perspectives for Polyamine Analogs

Giulia Nordio  1   2 , Francesco Piazzola  1 , Giorgio Cozza  3 , Monica Rossetto  3 , Manuela Cervelli  4 , Anna Minarini  5 , Filippo Basagni  5 , Elisa Tassinari  6 , Lisa Dalla Via  1   2 , Andrea Milelli  6 , Maria Luisa Di Paolo  3
Affiliations

From Monoamine Oxidase Inhibition to Antiproliferative Activity: New Biological Perspectives for Polyamine Analogs

Giulia Nordio et al. Molecules. .

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 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.

Keywords: LN-229 cells; antiproliferative activity; docking studies; inhibitors; monoamine oxidases; polyamine analogs.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Methoctramine (1) and its constrained analogs 2–7. Octamethylene linker replaced with constrained cycles is highlighted in pink. Inner basic nitrogens are highlighted in green.
Figure 2
Figure 2
Effects of polyamine analogs 3–7 on MAO A and MAO B activity. (A) Effect of different concentrations (1.25–40 μM) of tested compounds on human recombinant MAO A (◯, circle) or MAO B (□, square) activity. The ratio between the velocity in the absence (Vo) and in the presence (VI) of the tested compound (Vo/VI) increased linearly with the concentration (r > 0.99) (B) Effect of incubation time with compounds 4 and 5 on MAO A and B activity. The (Vo/VI) ratio was determined after different pre-incubation times (0–30 min) of the enzyme with the inhibitor (at 2.5 μM concentration) before the addition of the substrate (kynuramine, 10 μM).
Figure 3
Figure 3
Mainly competitive inhibition of MAO A and MAO B by compounds 4 and 5. Double reciprocal plots of MAO A (panels A,C) and of MAO B (panels B,D) activity in the absence (●, control) and in the presence of 4 or 5 (0.25–2 μM). Continuous lines are the results of the linear regression analysis of the plotted data (r > 0.99).
Figure 4
Figure 4
Docking simulation of compound 5 inside the catalytic site of MAO A. The catalytic pocket of MAO A is configured as a predominantly hydrophobic tunnel (green regions), while the polar portions (purple) mainly face the solvent. The molecule (yellow) is almost totally immersed inside the catalytic pocket of MAO A.
Figure 5
Figure 5
Cell viability percentage curves as a function of compound concentration (μM). LN-229 cells were incubated for 48 h in the presence of compounds 4, 5, and 7 (A) or 2, 3, and 6 (B) at different concentrations (0.1–10 μM). Data are the means ± SD of five independent experiments in duplicate. The GI50 values were determined by fitting the standard four-parameter logistic curve to the percentage of cell viability–compound concentration data using Sigma Plot 9.0 software. The reports of best fits were: r2 > 0.99 for compounds 2–6 and r2 = 0.97 for compound 4; p < 0.005 was obtained in the analysis of variance corrected for the mean of the observations for all the tested compounds.
Figure 6
Figure 6
MAO activity and effects of compounds 4 and 5 in LN-229 lysates. (A) MAO activity at various substrate concentrations. The continuous line is the result of the best fit of the Michaelis–Menten equation to the experimental data. (B) Effects of compounds 4 and 5 on MAO activity in LN-229 lysates. The ratio between the velocity in the absence (Vo) and in the presence (VI) of test compound is plotted vs. the compound concentration. Straight lines are the results of the linear regression analysis (for fit of compound 5 data, r > 0.99).
Scheme 1
Scheme 1
(a) A 2 M borane N-ethyl-N-isopropylaniline complex in THF, dry diglyme, reflux, 5 h, N2, 32% yield.
See this image and copyright information in PMC

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