IRON CHELATORS OF THE PYRIDOXAL ISONICOTINOYL HYDRAZONE CLASS - RELATIONSHIP OF THE LIPOPHILICITY OF THE APOCHELATOR TO ITS ABILITY TO MOBILIZE IRON FROM RETICULOCYTES IN-VITRO

Analogues of the iron (m) chelator, pyridoxal isonicotinoyl hydrazone (PM) show high potential as orally active agents for the treatment of iron-overload diseases, such as thalassemia. In the present study, the n-octanol-water partition coefficients of 30 analogues of PIH were me asured by thin-layer chromatography and also calculated using the addi tive schemes of Rekker. The purpose was to examine the relationship be tween lipophilicity of the apochelator and its ability to promote the release of Fe-59 from reticulocytes loaded with nonheme Fe-59. Interes tingly, maximum activity occurred when the partition coefficient of th e apochelator was approximately 1 (log P = 0). Considering the results in the context of the design and synthesis of more active analogues o f PM, it can be suggested that before initiating synthesis, a useful i ndication of biological activity can be determined by examining the li pophilicity of the molecule, using the schemes of Rekker to calculate the partition coefficient. By using this strategy, analogues of PM wit h inappropriate lipophilicity can be excluded before initiating the ex pensive process of screening in biological models.