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-octanol 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: 4294-4306. 1994), 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 59Fe from reticulocytes when they have log P = 2.8 (P = 630), and not log P = 0 (P = 1), as reported by Ponka et al. (P. Ponka, D.R Richardson, J.T. Edward, and F.L Chubb. Can. J. Physiol. Pharmacol. 72: 659-666 1994).
Edward
J T
JT
Department of Chemistry, McGill University, Montréal, QC, Canada. edward@omc.lan.mcgill.ca
Chubb
F L
FL
Sangster
J
J
D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000737:chemistry* / Q000494:pharmacology; D007538:Isoniazid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008956:Models, Chemical; D011730:Pyridoxal / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D012156:Reticulocytes / Q000187:drug effects / Q000378:metabolism*
D007502:Iron Chelating Agents; D011730:Pyridoxal; C021079:pyridoxal isonicotinoyl hydrazone; D007501:Iron; D007538:Isoniazid