PYRIDOXAL ISONICOTINOYL HYDRAZONE AND ITS ANALOGS - POTENTIAL ORALLY EFFECTIVE IRON-CHELATING AGENTS FOR THE TREATMENT OF IRON OVERLOAD DISEASE

At present, the only iron (Fe) chelator in clinical use for the treatm ent of Fe overload disease is the tris-hydroxamate deferoxamine (DFO). However, DFO suffers from a number of disadvantages, including the ne ed for subcutaneous infusion (12 to 24 hours a day, 5 or 6 times per w eek), its poor intestinal absorption, and high cost. Therefore, there is an urgent need for an efficient, economical, and orally effective F e chelator. Pyridoxal isonicotinoyl hydrazone (PIH) is a tridentate Fe -chelating agent that shows high Fe chelation efficacy both in vitro i n cell culture models and also in vivo in rats and mice. In addition, this chelator is relatively nontoxic, economical to synthesize, and or ally effective, and it shows high selectivity and affinity for Fe. How ever, over the last 10 years the development of PIH and its analogs ha s largely been ignored because of justifiable interest in other ligand s such as 1,2-dimethyl-3-hydroxypyrid-4-one (L1). Unfortunately, recen t clinical trials have shown that significant complications occur with L1 therapy, and it is controversial whether this chelator is effectiv e at reducing hepatic Fe levels in patients. Because of the current la ck of a clinically useful Fe chelator to replace DFO, PIH and its anal ogs appear to be potential candidate compounds that warrant further in vestigation. In this review we will discuss the studies that have been performed to characterize these chelators at the chemical and biologi c levels as effective agents for treating Fe overload. The evidence fr om the literature suggests that these ligands deserve further careful investigation as potential orally effective Fe chelators.