Copper complexation by 3-hydroxypyridin-4-one iron chelators: structural and iron competition studies.
Clinical trials of 1,2-dimethyl-3-hydroxypyridine-4-one (1) as an orally available iron chelator are presently underway in several centers. Discrepant reports of toxicity in human and animal studies have stimulated debate on the role of iron status and the availability of iron for chelation relative to other essential elements like copper in determining the clinical effects of 1. Therefore, we investigated the ability of 1, its 1,2-diethyl analog 2, and their iron chelates to complex copper. Both compounds formed tetracoordinate 2:1 Cu(II) complexes which X-ray structure analysis showed to be planar and coordinated through the oxygen atoms of the hydroxy ketone functionality. Potentiometric analysis revealed that these complexes dominated at physiological pH, although between pH 6 and 7 approximately equal amounts of the mono and bis complexes of Cu with 1 were present at equilibrium. Comparing the stepwise formation constants deduced from the stability constants of these complexes (log beta 2 = 21.7 +/- 0.8 (1) and 20.2 +/- 2.0 (2)) with those of their Fe(III) complexes (Motekaitis,R.J.;Martell,A.E.Inorg.Chim.Acta 1991, 183,71-80) leads to a prediction of insignificant copper complexation when equimolar iron is present and dissociation products are thermodynamically unimportant. However, displacement of Fe3+ occurred from both complexes with stoichiometric amounts of Cu2+, implicating the participation of metal hydrolysis products in the equilibria. We conclude that Cu(II) complexes of the 3-hydroxypyridin-4-one chelators are stable under physiological conditions and that copper can effect displacement of iron by these agents under circumstances where hydrolysis of the metals is important.
el-Jammal
A
A
Department of Clinical Biochemistry, University of Toronto, Canada.
Howell
P L
PL
Turner
M A
MA
Li
N
N
Templeton
D M
DM
D013956:Antithyroid Agents / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D000077543:Deferiprone; D007502:Iron Chelating Agents / Q000737:chemistry*; D008024:Ligands; D011199:Potentiometry; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry*; D013053:Spectrophotometry
D013956:Antithyroid Agents; D007502:Iron Chelating Agents; D008024:Ligands; D011728:Pyridones; C020366:3-hydroxy-4-pyridone; C068543:1,2-diethyl-3-hydroxypyridin-4-one; D000077543:Deferiprone; D003300:Copper