Reversed siderophores as antimalarial agents. II. Selective scavenging of Fe(III) from parasitized erythrocytes by a fluorescent derivative of desferal.
We introduce here a fluorescent derivative of desferrioxamine B (DFO) that retains the high affinity of the parent compound and displays a powerful inhibition of intraerythrocytic Plasmodium falciparum growth. NBD-DFO was synthesized by coupling 7-Nitrobenz-2-oxa-1,3-diazole (NBD) to the terminal amino group of DFO. The NBD group at this position renders the DFO molecule more lipophilic and imparts to it fluorescent properties. The novel NBD-DFO probe displays a unique combination of chemical and biological properties, such as 1) improved and selective permeation properties across membranes of P. falciparum-infected erythrocytes, 2) improved efficacy as an inhibitor of intraerythrocytic P. falciparum growth (including multidrug-resistant strains), 3) demonstrable Fe3+ scavenging within parasitized red cells, and 4) usefulness as a sensitive and versatile analytical tool for quantitative assessment of Fe3+ and for following iron-scavenging processes, because the fluorescence of NBD-DFO is demonstrably quenched upon complexation with Fe3+.
Department of Biological Chemistry, Institute of Life Sciences, Hebrew University, Jerusalem, Israel.
S D
SD
Lytton
Z I
ZI
Cabantchik
J
J
Libman
A
A
Shanzer
D009327:4-Chloro-7-nitrobenzofurazan / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002463:Cell Membrane Permeability; D002614:Chelating Agents / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003676:Deferoxamine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000378:metabolism* / Q000382:microbiology; D005456:Fluorescent Dyes / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007501:Iron / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics; D008288:Malaria / Q000097:blood / Q000188:drug therapy; D008670:Metals / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects; D013050:Spectrometry, Fluorescence
D000962:Antimalarials; D002614:Chelating Agents; D005456:Fluorescent Dyes; D008670:Metals; C071323:7-nitrobenz-2-oxa-1,3-diazole desferrioxamine B; D007501:Iron; D009327:4-Chloro-7-nitrobenzofurazan; D003676:Deferoxamine