title: Pro-oxidant properties of indolone-N-oxides in relation to their antimalarial properties.
abstract: Indolone-N-oxides (INODs) are bioreducible and possess remarkable anti-malarial activities in the low nanomolar range in vitro against different Plasmodium falciparum (P. falciparum) strains and in vivo. INODs have an original mechanism of action: they damage the host cell membrane without affecting non-parasitized erythrocytes. These molecules produce a redox signal which activates SYK tyrosine kinases and induces a hyperphosphorylation of AE1 (band 3, erythrocyte membrane protein). The present work aimed to understand the early stages of the biochemical interactions of these compounds with some erythrocyte components from which the redox signal could originate. The interactions were studied in a biomimetic model and compared with those of chloroquine and artemisinin. The results showed that INODs i) do not enter the coordination sphere of the metal in the heme iron complex as does chloroquine; ii) do not generate iron-dependent radicals as does artemisinin; iii) generate stable free radical adducts after reduction at one electron; iv) cannot trap free radicals after reduction. These results confirm that the bioactivity of INODs does not lie in their spin-trapping properties but rather in their pro-oxidant character. This property may be the initiator of the redox signal which activates SYK tyrosine kinases.
authors.affiliation: Université de Toulouse, UPS, UMR 152 PHARMA-DEV, 118 route de Narbonne, F-31062 Toulouse cedex 9, France.
authors.forename: Nguyen Thi Hoang
authors.initials: NT
authors.lastname: Yen
authors.forename: Hany
authors.initials: H
authors.lastname: Ibrahim
authors.forename: Karine
authors.initials: K
authors.lastname: Reybier
authors.forename: Pierre
authors.initials: P
authors.lastname: Perio
authors.forename: Florence
authors.initials: F
authors.lastname: Souard
authors.forename: Ennaji
authors.initials: E
authors.lastname: Najahi
authors.forename: Paul-Louis
authors.initials: PL
authors.lastname: Fabre
authors.forename: Francoise
authors.initials: F
authors.lastname: Nepveu
mesh_terms: D000962:Antimalarials / Q000737:chemistry*; D037621:Artemisinins / Q000737:chemistry; D002738:Chloroquine / Q000737:chemistry; D003497:Cyclic N-Oxides / Q000737:chemistry*; D003545:Cysteine / Q000737:chemistry*; D004578:Electron Spin Resonance Spectroscopy; D004789:Enzyme Activation; D004910:Erythrocyte Membrane / Q000737:chemistry; D006418:Heme / Q000737:chemistry*; D006427:Hemin / Q000737:chemistry*; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry; D007501:Iron / Q000737:chemistry; D008954:Models, Biological; D008956:Models, Chemical; D010084:Oxidation-Reduction; D011505:Protein-Tyrosine Kinases / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000737:chemistry*; D012996:Solutions; D000072377:Syk Kinase
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D003497:Cyclic N-Oxides; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D012996:Solutions; D006418:Heme; D006427:Hemin; D002738:Chloroquine; C031327:artemisinin; D007501:Iron; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D003545:Cysteine
keywords: Antimalarial drugs; Cyclic voltammetry; Electron paramagnetic resonance (EPR); Indolone-N-oxides; Pro-oxidant drugs