Recent Developments in Metal-Based Drugs and Chelating Agents for Neurodegenerative Diseases Treatments

Abstract

The brain has a unique biological complexity and is responsible for important functions in the human body, such as the command of cognitive and motor functions. Disruptive disorders that affect this organ, e.g. neurodegenerative diseases (NDDs), can lead to permanent damage, impairing the patients’ quality of life and even causing death. In spite of their clinical diversity, these NDDs share common characteristics, such as the accumulation of specific proteins in the cells, the compromise of the metal ion homeostasis in the brain, among others. Despite considerable advances in understanding the mechanisms of these diseases and advances in the development of treatments, these disorders remain uncured. Considering the diversity of mechanisms that act in NDDs, a wide range of compounds have been developed to act by different means. Thus, promising compounds with contrasting properties, such as chelating agents and metal-based drugs have been proposed to act on different molecular targets as well as to contribute to the same goal, which is the treatment of NDDs. This review seeks to discuss the different roles and recent developments of metal-based drugs, such as metal complexes and metal chelating agents as a proposal for the treatment of NDDs.

Transition metals and metal complexes in autophagy and diseases

“…Maintaining the balance of metal metabolism in nerve cells may be a vital component of any comprehensive therapy. To date, metal chelating agents have been shown to have a positive effect in some neurodegenerative diseases (Belaidi & Bush, 2016; Sales et al, 2019; Yu et al, 2019a). However, because of the complex roles played by different metals in these different diseases, the scope of application of metal chelating agents appears to be limited.…”

Pyrazolyl-pyrimidones inhibit the function of human solute carrier protein SLC11A2 (hDMT1) by metal chelation

“…Our combined experiments suggest that this non-selective inhibition reflects chelation of Fe 2+ in the assay medium by these molecules to form an insoluble precipitate. Although metal chelation is often exploited as a mechanism of drug action, [10][11][12] metal chelation is in principle an assay interference. This effect might occur across thousands of bioactive molecules reported in ChEMBL that share the same potentially chelating substructure and explain some of their reported bioactivities.…”

“…hDMT1 is also linked to pathologies such as hereditary hemochromatosis, β-thalassemia, Parkinson's disease and Alzheimer's disease, highlighting that its pharmacological inhibition may be beneficial to treat human diseases. [4][5][6][7][8][9] While metal chelators have been classically used to treat metal intoxication 10 and neurodegenerative diseases, 11,12 a recently reported highly potent and specific inhibitor of ferroportin (SLC40), a different iron transporter acting on the same pathway as hDMT1, has been shown to have clinical efficacy against β-thalassemia. 13 Two families of small molecule hDMT1 inhibitors have been reported in the literature as the results of high-throughput screening campaigns, namely bis-cationic isothioureas such as dibenzofurans 1 and mesitylene 2, 14 as well as pyrazolyl-pyridine 3 (Fig.…”

Redox‐Responsive Nanobiomaterials‐Based Therapeutics for Neurodegenerative Diseases

“…[214,215] Sequestering metal ions involved in neuronal plaque formation by sacrificial non-catalytic molecules could, therefore, help prevent oxidative stress in NDs. Further analysis of this type of ND treatment is out of the scope of this review (please refer to the following articles for further information [216,217] ). An alternative strategy for adequate delivery to the intended site of action is coupling the antioxidant with small molecules including naked oligonucleotides, viral and non-viral vectors or other macromolecules, such as polyethylene glycol (PEG), to form nano-complexes.…”