title: The mechanism of antimalarial action of [Au(CQ)(PPh(3))]PF(6): structural effects and increased drug lipophilicity enhance heme aggregation inhibition at lipid/water interfaces.
abstract: The mechanism of antimalarial action of [Au(CQ)(PPh(3))]PF(6) (1), which is active in vitro against CQ-resistant P. falciparum and in vivo against P. berghei, has been investigated in relation to hemozoin formation and DNA as possible important targets. Complex 1 interacts with heme and inhibits β-hematin formation both in aqueous medium and near water/n-octanol interfaces at pH ~5 to a greater extent than chloroquine diphosphate (CQDP) or other known metal-based antimalarial agents; the higher inhibition activity is probably related to the higher lipophilicity observed for 1 through partition coefficient measurements at low pH, with respect to CQDP. The interactions of complex 1 with DNA were explored using spectrophotometric and fluorimetric titrations, circular dichroism spectroscopy, viscosity and melting point studies, as well as electrophoresis and covalent binding assays. The experimental data indicate that complex 1 interacts with DNA predominantly by intercalation and electrostatic association of the CQ moiety, similarly to free CQDP, while no covalent metal-DNA binding seems to take place. The most likely antimalarial mechanism for complex 1 is thus heme aggregation inhibition; the high activities observed against resistant parasites are probably due to the structural modification of CQ introduced by the presence of the gold-triphenylphosphine fragment, together with the enhanced lipophilic character.
authors.affiliation: Laboratorio de Química Bioinorgánica, Centro de Química, Instituto Venezolano de Investigaciones Científicas, Carretera Panamericana Km.11, Altos de Pipe. Caracas 1020-A, Venezuela. mnavarro@ivic.ve
authors.forename: Maribel
authors.initials: M
authors.lastname: Navarro
authors.forename: William
authors.initials: W
authors.lastname: Castro
authors.forename: Alberto
authors.initials: A
authors.lastname: Martínez
authors.forename: Roberto A
authors.initials: RA
authors.lastname: Sánchez Delgado
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D002738:Chloroquine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D006420:Hemeproteins / Q000737:chemistry; D006427:Hemin / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology; D050607:Organogold Compounds / Q000737:chemistry / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects
chemical_list: D000962:Antimalarials; D006420:Hemeproteins; D007364:Intercalating Agents; D050607:Organogold Compounds; C106604:chloroquine(triphenylphosphine)gold(I); C020753:hemozoin; D006427:Hemin; D002738:Chloroquine; D004247:DNA; C427203:calf thymus DNA