Aluminum chelation: Chemistry, clinical, and experimental studies and the search for alternatives to desferrioxamine

Abstract

This review focuses on aluminum (Al) chelation, its chemistry and biology. The toxicology and biology of Al in mammalian organisms are briefly reviewed to introduce the problems associated with excessive Al exposure and accumulation and the challenges facing an effective Al chelator. The basics of Al chelation chemistry are considered to help the reader understand the Al chelation chemical literature. The chemical properties of Al enable prediction of effective functional groups for Al chelation. A compilation of distribution coefficients between octanol and aqueous phases (D_o/a) for chelators and their complexes with Al shows the effect of complexation on lipophilicity. A compilation of stability constants for Al·chelator complexes illustrates the role of oxygen in ligands that form stable complexes. The history of clinical Al chelation therapy is reviewed, with emphasis on desferrioxamine (DFO), which has been extensively used since 1980. The beneficial and adverse effects and limitations of DFO use in end‐stage renal‐diseased patients, in patients with neurodegenerative disorders, including Alzheimer's disease, and in animal models of Al intoxication are presented. The methods to evaluate potential Al chelators in vitro, in vivo, and using computer modeling are discussed. The Al chelation literature is reviewed by the chemical class of chelators, including fluoride, carboxylic acids, amino acids, catechols, polyamino carboxylic acids, phenyl carboxylic acids, the hydroxypyridinones, and hydroxamic acids.