Synthesis and evaluation of iron chelators with masked hydrophilic moieties.
Synthetic iron chelators based on the natural siderophore ferrichrome have previously been shown to bind Fe(III) with high affinity (pKf > 27) and have shown no toxicity to mammalian cell cultures in vitro. A new class of lipophilic ferrichrome analogues carrying acetoxymethyl ester moieties has been synthesized. We have shown that these molecules penetrate rapidly through cell membranes and turn highly hydrophilic while inside the cells, upon esterase mediated hydrolysis of the lipophilic termini. The intracellular retention was visualized by labeling these analogues with a fluorescent naphthalic diimide probe. The prohydrophilic iron chelators have been shown to inhibit the metal-catalyzed intracellular formation of reactive oxygen species with high effectivity, and preliminary results suggest these molecules to be potent antimalarial agents.
Meijler
Michael M
MM
Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, Israel 76100.
Arad-Yellin
Rina
R
Cabantchik
Z Ioav
ZI
Shanzer
Abraham
A
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D004952:Esters / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D005291:Ferrichrome / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000962:Antimalarials; D004952:Esters; D007502:Iron Chelating Agents; D005291:Ferrichrome