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: reappraisal of reported partition coefficients

The partition coefficients P between n-actanol and water of pyridoxal isonicotinoyl hydrazone and 34 analogues have been determined experimentally; the values indicate that the partition coefficients calculated for these compounds, and previously reported (P, Ponka, D.R. Richardson, J.T. Edward, and F.L. Chubb. Can. J. Physiol. Pharmacol. 72: 659-666. 1994; D.R. Richardson, E.H. Tran, and P. Ponka, Blood, 86: 4295-4306. 1995), are too low by 2-3 orders of magnitude. The calculations, using Rekker's additive method, failed because the molecules have two or more hydrophilic sites close together. More recent additive schemes (CLOGP, KOWWIN, ACD/LogP) also failed, The only reliable method was the semi-empirical method of Hansch, This requires the experimental determination of the partition coefficient of at least one representative in each series of compounds of related structure. In the present paper, determination of log P of three representatives enabled us to calculate the partition coefficients of the other 32 compounds with acceptable accuracy. The new results show that apochelators have maximum activity in releasing Fe-59 from reticulocytes when they have log P approximate to 2.8 (P approximate to 630), and not log P approximate to 0 (P approximate to I), as reported by Ponka et al. (P. Ponka, D.R Richardson, J.T. Edward, aad F.L. Chubb. Can. J. Physiol, Pharmacol. 72: 659-666, 1994).