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.

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

Iron chelators have potential therapeutic use for the treatment of cancer. Studies with a range of chelators indicate that Fe chelation alone is not enough to generate compounds with pronounced antitumor efficacy. Structure-activity relationships demonstrated that chelators containing hard electron donors such as oxygen typically lead to ligands that bind Fe with high affinity that do not have pronounced antitumor efficacy. Such compounds aremore suitable for the treatment of iron-overload disease, e.g., β-thalassemia major. In contrast, ligands with soft donors such as sulfur and nitrogen lead to compounds that can redox cycle and induce a "double punch", namely, marked chelation and redox activity. Such compounds include the thiosemicarbazone chelators such as 3-AP and the ApT, BpT, and DpT series. Detailed investigations of the thiosemicarbazone group of ligands have demonstrated that they are highly effective chelators that, besides RR, also target a range of other molecules including NDRG1 and top2α, all of which contribute to their anticancer effects.

Thiosemicarbazones from the old to new: iron chelators that are more than just ribonucleotide reductase inhibitors

Triapine (3-aminopyridine-2-carboxaldehyde- thiosemicarbazone): A potent inhibitor of ribonucleotide reductase activity with broad spectrum antitumor activity

Metals and metal compounds have been used in medicine for several thousands of years. In this review we summarized the anti-cancer activities of the ten most active metals: arsenic, antimony, bismuth, gold, vanadium, iron, rhodium, titanium, gallium and platinum. The first reviewed metal, arsenic, presents the anomaly of displaying anti-cancer and oncogenic properties simultaneously. Some antimony derivatives, such as Sb2O3, salt (tartrate) and organic compounds, show interesting results. Bismuth directly affects Helicobacter pylori and gastric lymphoma; the effects of bismuth complexes of 6-mercaptopurine are promising. Gold(I) and (III) compounds show anti-tumour activities, although toxicity remains high. Research into the potential use of gold derivatives is still ongoing. Several derivatives of vanadium show anti-proliferative activity, but their toxicity must be overcome. Several pieces of evidence indicate that iron deprivation could be an excellent therapeutic approach; furthermore, it is synergistic with classic anti-cancer drugs. Rhodium belongs to the same group as platinum and it also presents interesting activity, but with the same nephrotoxicity. Several rhodium compounds have entered phase I clinical trials. In contrast to the platinum complexes, titanium derivatives showed no evidence of nephrotoxicity or myelotoxicity ; titanocene dichloride is undergoing clinical trial. The anti-proliferative effect of gallium could be related to its competition with the iron atom; in addition a derivative appears to reverse the multidrug resistance. The last metal reviewed, platinum, has given some of the very best anti-cancer drugs. Four derivatives are used today in the clinic; their mechanism of action and of resistance are described. The importance of metal compounds in medicine is undisputed, as can be judged by the use of compounds of antimony (anti-protozoal), bismuth (anti-ulcer), gold (anti- arthritic), iron (anti-malarial), silver (anti-microbial) and platinum (anti-cancer) in the treatment of various diseases. In terms of anti-tumour activity, a wide range of compounds of both transition metals and main group elements have been investigated for efficacy (1). The earliest reports on the therapeutic use of metals or metal-containing compounds in cancer and leukemia date from the sixteenth century. Superoxide dismutase inhibition leads to selective killing

Metals and Metal Compounds in Cancer Treatment

A wide variety of studies in vitro, in vivo, and in clinical trials have demonstrated that the chelator currently used to treat iron overload disease, desferrioxamine, has anti-proliferative effects against both leukemia and neuroblastoma. However, the efficacy of desferrioxamine is severely limited due to its poor ability to permeate cell membranes and chelate intracellular iron pools. These studies have led to the development of other iron chelators that are far more effective than desferrioxamine. Some of these chelators such as 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine) have entered phase I clinical trials, while other chelators such as 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone or tachpyridine require evaluation in animal models. The high anti-tumor activity observed with these ligands certainly suggests further development of chelators as anti-cancer agents is warranted.

Iron chelators as therapeutic agents for the treatment of cancer.

Summary 5-Hydroxy-2-formylpyridine thiosemicarbazone (5-HP) is the first of a relatively new class of antineoplastic agents, the α-( N )-heterocyclic carboxaldehyde thiosemicarbazones, to be studied in man. This study characterizes the toxicity and pharmacological disposition of the drug in 13 patients. Plasma levels of 5-HP decayed in biphasic mode with an initial half-life of 2.5 to 10.5 min. Of the administered dose, 47 to 75% was excreted within 24 hr, and the major metabolites (50 to 74% or urinary radioactivity) were glucuronide conjugates. A characteristically dark green urine resulted from the excretion of significant amounts of iron (2 to 11 mg/24 hr) in chelate form with 5-HP. The incorporation of thymidine- 3 H into DNA was inhibited in isolated normal and leukemic leukocyte suspensions after exposure in vitro and in vivo to 5-HP. Transient decreases in blast counts were observed in three of five patients with acute leukemia, although no remissions were obtained. No antitumor effects were noted in eight patients with solid tumors. Administration of larger doses of drug was limited by gastrointestinal toxicity. Mild myelosuppressant effects and hemolysis were noted in five patients treated with 5-day courses of drug. While toxicity appears to limit the usefulness of this compound as an antineoplastic agent, antileukemic activity was shown, and studies of other members of this class of agents are warranted.

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Kirshna C. Agrawal

Papers

Clinical and pharmacological studies with 5-hydroxy-2-formylpyridine thiosemicarbazone.