Chelating copper ions by aminohydroxamic acids as a potential way to remove them from the body

Abstract

The excess of copper in the human body can lead to serious metabolic disturbances, such as liver, kidney, brain and blood vessel damage. The reason for the abnormally high copper concentration in tissues is either copper poisoning or the genetically determined Wilson’s disease. In both cases it is crucial to selectively bind and remove the ions from the bogy. In this work, the presence of pentameric complexes of 12- metallocrown- 4 type of copper and hydroxamic derivatives of α-phenylalanine [Cu5Pheha4H-4] and α-glycine [Cu5Glyha4H-4], as well as mixed complexes [Cu5Pheha3GlyhaH-4] has been proved by mass spectrometry. The stability constants of these compounds have been calculated using potentiometric measurements. The stability of the complexes has been additionally proved by tandem mass spectrometry.
Autor: Magdalena ŻYREK

1. The consequences of improper copper metabolism

1.1. Copper poisoning

Copper ions are a crucial element of copper enzymes [7], such as superoxide dismutase, cytochrome c oxidase, lisol oxidase, dopamine β-hydroxylase, peptydyl monooxidase or tyrosinase. In the center of such enzymes, electron transfer occurs [1]. In the human body there is, on average, about 80 mg of copper; the highest concentration is to be found in the liver (about 30 ppm, copper is bound to sulphur containing aminoacids of metalothioneine), in the brain (about 20 ppm) and in the blood (up to 130 µg/100ml) [6]. For humans, the daily requirement for this compound is minimum 1,5 mg; the nutritive absorption varies from 5 to 20%. Copper poisoning (above 4 mg) is most commonly caused by the excessive digestion of copper sulphate, present in wine and fruit; it results in metabolic disturbances in liver, kidney and brain. Another reason for copper poisoning are copper oxides, formed in technological processes, which are inhaled and absorbed; such poisoning results in gastritis, hyperemia of the nose mucous membrane, or even chronic lung failure [8].

1.2. WILSON’S DISEASE

Wilson’s disease in an autosomal and recessive mutation of the ATP7B gene, which encodes the protein responsible for the transport of copper (Wilson’s ATPase). The reason of the disorder is the decrease of ceruloplasmine and the excess of copper in the liver, kidneys and the central nervous system; it may be visible as rusty circles around the cornea of the eye (Kayser-Fleischer’s rings). The disease becomes obvious in late childhood as a neurological dysfunction with the disturbance of motion; the symptoms are psychological disorders, dementia and lack of orientation. In the case of lack of treatment death occurs as a result of brain decay [2]. The treatment is based on a low copper diet, on oral administration of zinc sulphate (which decreases the absorption of copper from nutrition) and on the administration of different copper chelating agents, such as triethylentetraamine, BAL (2,3-dimerkaptopropanol) and D-penicylamine [5]. New copper chelating compounds are still being looked for. This work focuses on metalomacrocycles, which copper forms with α- and β-aminohydroxamic acids.