title: [Interaction of chloroquine with ferriprotophorphyrin IX. Nuclear magnetic resonance study].
abstract: Chloroquine is still the antimalarial drug which is the most utilized. Nevertheless the molecular mode of action of this drug is not very well understood. When mouse erythrocytes injected with Plasmodium berghei are exposed to chloroquine, the first biochemical event is rapid accumulation of the drug. This process is energy dependent, saturable and competitively inhibited by drugs of the same therapeutic class (Quinine, Amodiaquine, Mefloquine). Receptors for chloroquine have been proposed for the process of accumulation. The nature of the chloroquine receptor is presently the subject of debates. The latest hypothesis proposed by Chou and coll. [12], is that ferriprotoporphyrin IX, formed by the degradation of hemoglobin by the parasite, binds to chloroquine with a dissociation constant of 3.5.10(-9) M. We studied here the molecular interactions between these two species by Proton Nuclear Magnetic Resonance in order to elucidate the nature and the geometry of were undertaken. The perturbations of the NMR spectra of chloroquine (10(-2) M) induced by addition of hematin or hemin were measured. Two types of measures were undertaken. The first study carried out in organic solvent (DMSO) has shown that the interaction occurred between the acidic functions of hemin and the side-chain nitrogen of chloroquine. The iron atom was not implicated in this process. The second study carried out in aqueous medium (phosphate buffer; 0.1 M; pH = 7) allowed us to demonstrate that chloroquine is able to intercalate into a polymer of hematin. The quinoleic nucleus of chloroquine was intercalated between two dimers of hematin as shown by the broadening of the signal of the quinoleic protons due to very large increase in the correlation time. Finally it was shown that chloroquine is associated as a dimer in aqueous medium by hydrophobic interactions. The association constant is 5.5 M-1.
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D002738:Chloroquine / Q000378:metabolism*; D004121:Dimethyl Sulfoxide; D006427:Hemin / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008433:Mathematics; D051379:Mice; D011166:Porphyrins / Q000378:metabolism*; D011524:Protoporphyrins / Q000378:metabolism*
chemical_list: D011166:Porphyrins; D011524:Protoporphyrins; D006427:Hemin; D002738:Chloroquine; C028025:protoporphyrin IX; D004121:Dimethyl Sulfoxide
vernacular_title: Interactions de la chloroquine avcc la ferriprotoporphyrine IX. Etude par résonance magnétique nucléaire.