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Mode of action of iron (III) chelators as antimalarials: I. Membrane
permeation properties and cytotoxic activity
SD Lytton, B Mester, I Dayan, H Glickstein, J Libman, A Shanzer and ZI Cabantchik
Department of Biological Chemistry, Hebrew University, Jerusalem, Israel.
We have designed two subfamilies of lipophilic iron (III) chelators
previously termed reversed siderophores (RSFs). The agents display
physicochemical properties that favor extraction of iron beyond membrane
barriers of Plasmodium falciparum-infected red blood cells. We studied the
in vitro antimalarial potency of RSFs and their relationship to the
membrane permeation properties of these agents. The mode of RSF action
involves: (1) fast access to intracellular compartments of parasitized
cells; (2) selective and high-affinity chelation of iron (III) from
parasitized cells; (3) fast exit from cells after iron (III) complexation;
and (4) exertion of cell damage on parasites exposed for 3 to 5 hours to
drugs, irrespective of the stage of parasite development. These results
suggest that on reaching a critical intraerythrocyte target, RSFs induce an
iron deficit that parasites in general, and rings in particular, have
limited capacity to restore.
Volume 81,
Issue 1,
pp. 214-221,
01/01/1993
Copyright © 1993 by The American Society of Hematology
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