Fine Tuning of Cholinesterase and Glutathione-S-Transferase Activities by Organoruthenium(II) Complexes.

Tomaž Trobec,Jerneja Kladnik,Iztok Turel,Catarina Cardoso Páscoa,Monika Cecilija Žužek,Robert Frangež,Kristina Sepčić,Nina Podjed

doi:10.3390/biomedicines9091243

Tomaž Trobec, Jerneja Kladnik + Show 6 more

Open Access

https://doi.org/10.3390/biomedicines9091243

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Abstract

Cholinesterases (ChEs) show increased activities in patients with Alzheimer’s disease, and remain one of the main therapeutic targets for treatment of this neurodegenerative disorder. A library of organoruthenium(II) complexes was prepared to investigate the influence of their structural elements on inhibition of ChEs, and on another pharmacologically important group of enzymes, glutathione S-transferases (GSTs). Two groups of organoruthenium(II) compounds were considered: (i) organoruthenium(II) complexes with p-cymene as an arene ligand, and (ii) organoruthenium(II) carbonyl complexes as CO-releasing molecules. Eight organoruthenium complexes were screened for inhibitory activities against ChEs and GSTs of human and animal origins. Some compounds inhibited all of these enzymes at low micromolar concentrations, while others selectively inhibited either ChEs or GSTs. This study demonstrates the importance of the different structural elements of organoruthenium complexes for their inhibitory activities against ChEs and GSTs, and also proposes some interesting compounds for further preclinical testing as ChE or GST inhibitory drugs.

Highlights

For at least 3500 years, precious metals have been used for different medicinal purposes, and it is known that the medicinal properties of metals are linked to their specific biological effects
We have focused on the study of the inhibitory activities of different organoruthenium(II) compounds against various enzymes, including ChEs (i.e., acetylcholinesterases (AChEs) and butyrylcholinesterases
We focused on anti-ChE and anti-glutathione S-transferases (GSTs) activities of two groups of ruthenium(II) compounds: organoruthenium(II) complexes with p-cymene as an arene ligand (Figure 1A), and organoruthenium(II) carbonyl complexes as CO-releasing molecules (CORMs) (Figure 1B)

Summary

Introduction

For at least 3500 years, precious metals have been used for different medicinal purposes, and it is known that the medicinal properties of metals are linked to their specific biological effects. Ruthenium compounds show a broad spectrum of biological activities, which range from immunosuppressant, antibacterial, antiviral and antitumour, to antiparasitic effects. These activities are due to selective inhibition of many medicinally essential enzymes that are involved in different pathological conditions. These enzymes comprise in particular the cholinesterases (ChEs), glutathione S-transferases (GSTs), protein kinases, aldo-keto reductase, thioredoxin reductase, cathepsin B, topoisomerase II and HIV−1 reverse transcriptase, along with many others [5,6,7,8,9,10,11]. We have focused on the study of the inhibitory activities of different organoruthenium(II) compounds against various enzymes, including ChEs (i.e., acetylcholinesterases (AChEs) and butyrylcholinesterases

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