Chelators in Iron and Copper Toxicity

Abstract

Purpose of ReviewChelation therapy is used for diseases causing an imbalance of iron levels (for example haemochromatosis and thalassaemia) or copper levels (for example Menkes' and Wilson's diseases). Currently, most pharmaceutical chelators are relatively simple but often have side effects. Some have been taken off the market.This review attempts to find theory and knowledge required to design or find better chelators. Recent FindingsRecent research attempting to understand the biological mechanisms of protection against iron and copper toxicity is reviewed. Understanding of molecular mechanisms behind normal iron/copper regulation may lead to the design of more sophisticated chelators. The theory of metal ion toxicity explains why some chelators, such as EDTA, which chelate metal ions in a way which exposes the ion to the surrounding environment are shown to be unsuitable except as a means of killing cancer cells.The Lewis theory of acids and bases suggests which amino acids favour the attachment of the hard/intermediate ions Fe . Non-polar amino acids will chelate the ion in a position not in contact with the surrounding cellular environment. The conclusion is that only the soft ion binding cysteine and methionine appear as suitable chelators. Clearly, nature has developed proteins which are less restricted.Recent research on naturally produced chelators such as siderophores and phytochemicals show some promise as pharmaceuticals. SummaryAlthough an understanding of natural mechanisms of Fe/Cu regulation continues to increase, the pharmaceutical chelators for metal overload diseases remain simple non-protein molecules. Natural and synthetic alternatives have been studied but require further research before being accepted.

Copper: An Intracellular Achilles’ Heel Allowing the Targeting of Epigenetics, Kinase Pathways, and Cell Metabolism in Cancer Therapeutics

“…When considering copper chelators, it is important to consider their chemical structures and ability to form a successful ligand‐copper interaction. The chemistry behind chelates consists of the formation of a complex where a ligand forms a ring around the metal ion through dative bonds involving several electron pairs of the ligand molecule [46] . Since metal ions and ligands act as Lewis acids and bases, respectively, the Lewis acids and bases theory can help predict which metal ions interact with which atoms of the ligand.…”

“…Since metal ions and ligands act as Lewis acids and bases, respectively, the Lewis acids and bases theory can help predict which metal ions interact with which atoms of the ligand. As a rule, hard bases interact with hard acids, while soft bases interact with soft acids [46] . This “hard and soft” classification is related to the ability in retaining (metal ions) or donating (ligand) the valence electrons during chelate formation, with the dative bond becoming electrostatic and covalent in character for hard and soft complexes, respectively.…”

“…In all cases, the biological effect depends on two key parameters: the binding constant and the metal concentration. In a physiological environment, competition phenomena are often recorded due to the possibility that either endogenous substances can compete with the therapeutic metal binding compound, or different metals within the body can compete for interaction with the bioactive molecule [46] . Furthermore, it should be considered that most of the metal‐binding compounds possess a Brønsted base character, making them highly sensitive to pH variation, with great implications for the treatment of several pathological conditions [53] .…”

Flow-injection Determination of Glutathione, Penicillamine and Tiopronin Based on the Reduction of Copper(II)-neocuproine Reagent

“…PEN was the first chelator used for Wilson's disease and it can be also used for lead, mercury and arsenic poisoning. [3,4] Tiopronin (mercaptopropionyl glycine, MPG) is a synthetic aminothiol compound with reducing and complexation properties. It is used primarily for the treatment of cystinuria, as it increases cystine solubility by a thiol-disulfide exchange with cystine to form a complex with the cysteine monomer, forming a highly soluble disulfide compound.…”

Determination of penicillamine, tiopronin and glutathione in pharmaceutical formulations by kinetic spectrophotometry

“…Penicillamine (PEN) is a synthetic amino acid that contains an additional SH group and is capable of forming non-toxic, water-soluble chelates with heavy metals, which are then excreted in the urine. PEN was the first chelator used for Wilson's disease and it can be also used for lead, mercury and arsenic poisoning (1,2). Tiopronin (mercaptopropionyl glycine, MPG) is a synthetic aminothiol with reducing and complexation properties used primarily for the treatment of cystinuria, as it increases cystine solubility (3,4).…”