Add time:07/22/2019         Source:sciencedirect.com

Iron overload secondary to β-thalassemia and other iron-loading anemias is the most serious obstacle to be overcome in the treatment of these diseases, since there is no physiological mechanism for excretion of the excess iron acquired by chronic blood transfusion. Due to the inconvenience and cost of the current iron chelation therapy, the search for an orally available iron chelator is ongoing. Pyridoxal isonicotinoyl hydrazone (PIH) and many of its analogs are effective at mobilizing iron in vivo and in vitro at doses that are not toxic. PIH analogs were approximately equally effective at binding 59Fe within K562 cells; their efficacy depended upon the kinetics of release of the iron–chelator complex from the cell, which was correlated inversely with the lipophilicity of the chelators. Addition of BSA, which has a well-characterized affinity for lipophilic species, to the extracellular medium enhanced iron–chelator efflux, such that all analogs caused 59Fe release from the cells as quickly as it was chelated; this suggests that BSA acts as an extracellular sink for the iron–chelator complexes, many of which are highly lipophilic. The toxicity of the free chelators varied over two orders of magnitude, and was correlated with the amount of intracellular 59Fe–chelator complexes, implicating the complexes in the mechanism of toxicity of the chelators. Understanding the structural features that determine the efficacy and toxicity of iron chelators in biological systems is of value in the selection of PIH analogs for in vivo examination.

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