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Department of Biological Chemistry, Institute of Life Sciences,
Hebrew University of Jerusalem, Jerusalem, Israel 91904 (G.Z., H.G.,
W.B., P.M., Z.I.C.),
Liver Research Unit, Institut National de la
Santé et de la Recherche Medicale U-49, Pontchaillou University
Hospital, 35033 Rennes, France (G.Z., P.B.),
Department of Pharmacy,
King's College, W8 7AH London, UK (R.C.H.),
Department of Public
Health, Hadassah Medical School, Jerusalem, 91120 Israel (A.M.K.), and
Department of Organic Chemistry, Weizmann Institute of Science, Rehovot
76100, Israel (J.L., A.S.)
Iron chelators belonging to three distinct chemical families were
assessed in terms of their physicochemical properties and the kinetics
of iron chelation in solution and in two biological systems. Several
hydroxypyridinones, reversed siderophores, and desferrioxamine
derivatives were selected to cover agents with different iron-binding
stoichiometry and geometry and a wide range of lipophilicity, as
determined by the octanol-water partition coefficients. The selection
also included highly lipophilic chelators with potentially
cell-cleavable ester groups that can serve as precursors of hydrophilic
and membrane-impermeant chelators. Iron binding was determined by the
chelator capacity for restoring the fluorescence of iron-quenched
calcein (CA), a dynamic fluorescent metallosensor. The iron-scavenging
properties of the chelators were assessed under three different
conditions: (a) in solution, by mixing iron salts with free CA; (b) in
resealed red cell ghosts, by encapsulation of CA followed by loading
with iron; and (c) in human erythroleukemia K562 cells, by loading with
the permeant CA-acetomethoxy ester, in situ formation of
free CA, and binding of cytosolic labile iron. The time-dependent
recovery of fluorescence in the presence of a given chelator provided a
continuous measure for the capacity of the chelator to access the
iron/CA-containing compartment. The resulting rate constants of
fluorescence recovery indicated that chelation in solution was
comparable for the members of each family of chelators, whereas
chelation in either biological system was largely dictated by the
lipophilicity of the free chelator. For example, desferrioxamine was
among the fastest and most efficient iron scavengers in solution but
was essentially ineffective in either biological system when used at
200 µM over a 2-hr period at 37°. On the other hand,
the highly lipophilic and potentially cell-cleavable hydroxypyridinones
and reversed siderophores were highly efficient in all biological
systems tested. It is implied that in K562 cells, hydrolysis of these
chelators is relatively slower than their ingress and binding of
intracellular iron. The chelator-mediated translocation of iron from
cells to medium was assessed in 55Fe-transferrin-loaded
K562 cells. The speed of iron mobilization by members of the three
families of chelators correlated with the lipophilicity of the free
ligand or the iron-complexed chelator. The acquired information is of
relevance for the design of chelators with improved biological
performance.
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