Beyond Topoisomerase Inhibition: Antitumor 1,4‐Naphthoquinones as Potential Inhibitors of Human Monoamine Oxidase

Abstract

Monoamine oxidase (MAO) action has been involved in the regulation of neurotransmitters levels, cell signaling, cellular growth, and differentiation as well as in the balance of the intracellular polyamine levels. Although so far obscure, MAO inhibitors are believed to have some effect on tumors progression. 1,4-naphthoquinone (1,4-NQ) has been pointed out as a potential pharmacophore for inhibition of both MAO and DNA topoisomerase activities, this latter associated with antitumor activity. Herein, we demonstrated that certain antitumor 1,4-NQs, including spermidine-1,4-NQ, lapachol, and nor-lapachol display inhibitory activity on human MAO-A and MAO-B. Kinetic studies indicated that these compounds are reversible and competitive MAO inhibitors, being the enzyme selectivity greatly affected by substitutions on 1,4-NQ ring. Molecular docking studies suggested that the most potent MAO inhibitors are capable to bind to the MAO active site in close proximity of flavin moiety. Furthermore, ability to inhibit both MAO-A and MAO-B can be potentialized by the formation of hydrogen bonds between these compounds and FAD and/or the residues in the active site. Although spermidine-1,4-NQs exhibit antitumor action primarily by inhibiting topoisomerase via DNA intercalation, our findings suggest that their effect on MAO activity should be taken into account when their application in cancer therapy is considered.

The evaluation of 1,4-benzoquinones as inhibitors of human monoamine oxidase

“…For [30]. Another study reported that other 1,4-naphthoquinones such as menadione (2) and the parent 1,4-naphthoquinone (3), also inhibits the MAO isoforms [31]. An older study reports that 1,4-benzoquinone …”

Evaluation of Natural and Synthetic 1,4‐naphthoquinones as Inhibitors of Monoamine Oxidase

“…Each experiment was conducted in triplicate, and IC 50 values are expressed as mean ± standard deviation (SD). It should be noted that in the current and a previous study, the recombinant human MAOs were used as MAO sources, while the MAO inhibition of TMN was investigated using the human gastrointestinal tract (MAO‐A) and liver (MAO‐B) enzymes . Although inhibition data recorded with MAO of one species cannot always be extrapolated to another, it is expected that potencies recorded with the human enzymes, although from different tissues and production techniques (e.g.…”

“…A subsequent study has shown that the structurally related menadione ( 2 ), also a 1,4‐naphthoquinone compound, is a MAO inhibitor with selectivity for the MAO‐B isoform ( K i = 0.4 μ m ) over MAO‐A ( K i = 26 μ m ) . Lapachol ( 3 ), a 1,4‐naphthoquinone from natural origin, and norlapachol ( 4 ), semi‐synthetic derivative of lapachol, also proved to inhibit the MAOs, albeit with lower potencies compared to TMN . By acting as topoisomerase inhibitors via DNA intercalation, the 1,4‐naphthoquinone class of compounds is also of interest as potential antitumor agents .…”

Dihydrithieno[2,3-b]naphto-4,9-dione analogues as anticancer agents: Synthesis and in cell pharmacological studies

“…Nevertheless, scientific interest in this class of compounds has not abated thanks to their positive risk-benefit ratio, especially when combined with anti-tumour therapies, and to their recently demonstrated synergy with biotechnological drugs [12,13]. Indeed, interest in the quinone-based scaffold and its derivatives, either as modulators or as pharmacological tools, has even increased consequent to their involvement in such metabolic pathways as purinergic signalling [14], inhibition of human monoamine oxidase [15], telomerase [16] and vasorelaxation [17].…”