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Review Article

The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer

Iron Metabolism and Chelation Program, Children's Cancer Institute Australia for Medical Research, Sydney, New South Wales, Australia

Abstract

I. Introduction

II. Redox Activity of Iron

III. Iron Metabolism in Normal Cells

A. Iron Absorption from the Gut

B. Iron Uptake

C. The Labile Iron Pool and Iron Storage

D. Iron Homeostasis

1. Iron-Regulatory Proteins 1 and 2.

2. Iron-Regulatory Protein Binding: Control of Iron Homeostasis.

IV. Iron Overload Disease

A. {beta}-Thalassemia

B. Friedreich's Ataxia

V. Targeting Iron in Cancer Therapy: Iron Metabolism in Neoplastic Cells

A. Antiproliferative Activity and Lipophilicity

B. Antiproliferative Activity and Redox Activity

VI. The Evolution of Iron Chelators

A. Siderophores

1. Desferrioxamine.

2. Desferrithiocin.

a. A structure-activity relationship examination of the desferrithiocin scaffold.

b. A structure-activity relationship examination of chemical parameters.

c. Hexadentate desferrithiocin analog.

d. Desferrithiocin as a selective antiproliferative agent.

3. Desferri-exochelin.

B. Synthetic Iron Chelators

1. ICL670A.

2. Deferiprone and Hydroxypyridinone Analogs.

a. Combination therapy: deferiprone and desferrioxamine.

b. Deferiprone metabolism.

c. CP94.

d. Hydroxypyridinone ester prodrugs.

e. Increasing pFe(III) values of hydroxypyridinones.

f. Hexadentate hydroxypyridinone analogs.

3. Tachpyridine.

a. Novel tachpyridine analogs.

4. Aroylhydrazones: Pyridoxal Isonicotinoyl Hydrazone and Analogs.

a. 100 series analogs.

b. 200 series analogs.

c. 300 series analogs.

d. 2-Pyridylcarboxaldehyde isonicotinoyl hydrazone analogs.

e. Di-2-pyridylketone isonicotinoyl hydrazone analogs.

5. Thiosemicarbazones.

a. Triapine.

b. Development of hybrid chelators derived from thiosemicarbazones and aroylhydrazones: the 2-hydroxy-1-naphthylaldehyde-3-thiosemicarbazone series.

c. Development of hybrid chelators derived from thiosemicarbazones and aroylhydrazones: the di-2-pyridylketone thiosemicarbazone analogs.

VII. Conclusions

The evolution of iron chelators from a range of primordial siderophores and aromatic heterocyclic ligands has lead to the formation of a new generation of potent and efficient iron chelators. For example, various siderophore analogs and synthetic ligands, including ICL670A [4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid], 4'-hydroxydesazadesferrithiocin, and Triapine, have been developed from predecessors and illustrate potent iron-mobilizing or antineoplastic activities. This review focuses on the evolution of iron chelators from initial lead compounds through to the development of novel chelating agents, many of which show great potential to be clinically applied in the treatment of iron overload disease and cancer.

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