Iron Chelators and Therapeutic Uses

Abstract

Iron is an essential cofactor in a variety of biological redox reactions; life without this metal is virtually unknown. Because of its exceptionally poor solubility in the biosphere, bacteria produce relatively low molecular weight, virtually iron(III)‐specific, ligands, siderophores, for the purpose of acquiring this transition metal. On the other hand, higher eukaryotes generate proteins to acquire and store iron. In humans, the process of iron absorption and processing is very tightly controlled. However, the lack of an efficient means of elimination can, under certain conditions, result in iron overload, which can elicit oxidative tissue damage through the Fenton reaction. Accordingly, chelating agents have been tested over the last several decades for the purpose of rendering excess iron excretable. The currently accepted therapy for global iron overload, as occurs after repeated blood transfusions, is a siderophore, desferrioxamine B (DFO), which is administered subcutaneously as its mesylate salt (Desferal). Two synthetic agents, diethylenetriamine pentaacetic acid (DTPA) and 1,2‐dimethyl‐3‐hydroxypyridin‐4‐one (Ferriprox, deferiprone, L1), have been used for the treatment of iron overload as well. Unfortunately, all three of these ligands have drawbacks. The kinetics and lack of oral bioavailability of DFO require that this compound be administered subcutaneously 12 h/day, up to 6 days/week, a regimen with which many patients find it difficult to comply. The lack of chelating specificity of DTPA restricts its use to those who cannot tolerate therapy with DFO; questions remain unanswered regarding the efficacy and toxicity profile of L1. The ongoing efforts to find a worthy successor to DFO include the use of a synthetic agent, N,N ′‐bis(2‐hydroxybenzyl)ethylenediamine‐ N,N ′‐diacetic acid (HBED), which, although it would require subcutaneous administration, is significantly more efficient than DFO. Another avenue is using siderophores (e.g., desferrithiocin, parabactin) as platforms from which to design either orally or parenterally active iron chelators. Because of the necessity of striking a balance between efficacy (i.e., sufficient iron chelation) and toxicity (i.e., excessive iron removal), drug development in the arena of iron chelation therapy presents unique challenges. However, the application of sensible drug design principles predicated on our understanding of iron metabolism, modern synthetic techniques, and the use of appropriate animal models should bring about improved therapeutic agents for the treatment of both global and focal iron overload in the years to come.

Design, Synthesis, and Testing of Non-Nephrotoxic Desazadesferrithiocin Polyether Analogues

“…25,[28][29][30] The solution to the problem is to remove excess unmanaged iron. 31 In the majority of patients with transfusion-dependent refractory anemias, treatment with a chelating agent capable of sequestering iron and permitting its excretion from the body is the only therapeutic approach available.The iron-chelating agents that are now in use or that have been clinically evaluated 32 include desferrioxamine B mesylate (DFO a ), l,2-dimethyl-3-hydroxypyridin-4-one (deferiprone, L1), [33][34][35][36] 4-[3,5-bis(2-hydroxyphenyl)-l,2,4-triazol-l-yl]benzoic acid (deferasirox, ICL670A), [37][38][39][40] and the desferrithiocin (DFT) analogue, (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid [deferitrin (1), A previous investigation focused on the design of desferrithiocin analogues that balance the lipophilicity/toxicity relationship while iron-clearing efficiency (ICE) is maintained in hopes of eliminating nephrotoxicity. 45 This study led to the less lipophilic, more water-soluble ligand, the polyether (S)-4,5-dihydro-2-[2-hydroxy-4-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid (2).…”

“…25,[28][29][30] The solution to the problem is to remove excess unmanaged iron. 31 In the majority of patients with transfusion-dependent refractory anemias, treatment with a chelating agent capable of sequestering iron and permitting its excretion from the body is the only therapeutic approach available.…”

Substituent Effects on Desferrithiocin and Desferrithiocin Analogue Iron-Clearing and Toxicity Profiles

“…38,51 Clearly, hydroxylation had a significant effect on toxicity reduction. One of these ligands, 3 , was taken into human clinical trials by Genzyme and was moving forward until the once daily dosing was changed to twice daily.…”

“…This led to the discovery that the lipophilicity (partition between octanol and water, expressed as the log of the fraction in the octanol layer, log P app ) 50 of the DADFT analogues could have a profound effect on the ligand's iron-clearing efficiency (ICE), organ distribution, and toxicity profile. 38,51,52 …”

“…38,51 Further reduction in 3 -induced nephrotoxicity, observed when the chelator was given po at 237 µmol/kg twice daily, was accomplished by the addition of polyether fragments, e.g., 4 , 5 , and 7 (Chart 1, Table 1). 42,53–55 The purpose of the current study was to determine how these same structural modifications to DFT itself would impact the new ligands’ ICE and nephrotoxicity.…”