title: Mitochondria-targeted spin traps: synthesis, superoxide spin trapping, and mitochondrial uptake.
abstract: Development of reliable methods and site-specific detection of free radicals is an active area of research. Here, we describe the synthesis and radical-trapping properties of new derivatives of DEPMPO and DIPPMPO, bearing a mitochondria-targeting triphenylphosphonium cationic moiety or guanidinium cationic group. All of the spin traps prepared have been observed to efficiently trap superoxide radical anions in a cell-free system. The superoxide spin adducts exhibited similar spectral properties, indicating no significant differences in the geometry of the cyclic nitroxide moieties of the spin adducts. The superoxide adduct stability was measured and observed to be highest (t1/2 = 73 min) for DIPPMPO nitrone linked to triphenylphosphonium moiety via a short carbon chain (Mito-DIPPMPO). The experimental results and DFT quantum chemical calculations indicate that the cationic property of the triphenylphosphonium group may be responsible for increased superoxide trapping efficiency and adduct stability of Mito-DIPPMPO, as compared to the DIPPMPO spin trap. The studies of uptake of the synthesized traps into isolated mitochondria indicated the importance of both cationic and lipophilic properties, with the DEPMPO nitrone linked to the triphenylphosphonium moiety via a long carbon chain (Mito10-DEPMPO) exhibiting the highest mitochondrial uptake. We conclude that, of the synthesized traps, Mito-DIPPMPO and Mito10-DEPMPO are the best candidates for potential mitochondria-specific spin traps for use in biologically relevant systems.
authors.affiliation: Aix Marseille Université , CNRS, ICR UMR 7273, 13397 Marseille, France.
authors.forename: Micael
authors.initials: M
authors.lastname: Hardy
authors.forename: Florent
authors.initials: F
authors.lastname: Poulhés
authors.forename: Egon
authors.initials: E
authors.lastname: Rizzato
authors.forename: Antal
authors.initials: A
authors.lastname: Rockenbauer
authors.forename: Karol
authors.initials: K
authors.lastname: Banaszak
authors.forename: Hakim
authors.initials: H
authors.lastname: Karoui
authors.forename: Marcos
authors.initials: M
authors.lastname: Lopez
authors.forename: Jacek
authors.initials: J
authors.lastname: Zielonka
authors.forename: Jeannette
authors.initials: J
authors.lastname: Vasquez-Vivar
authors.forename: Savitha
authors.initials: S
authors.lastname: Sethumadhavan
authors.forename: Balaraman
authors.initials: B
authors.lastname: Kalyanaraman
authors.forename: Paul
authors.initials: P
authors.lastname: Tordo
authors.forename: Olivier
authors.initials: O
authors.lastname: Ouari
mesh_terms: D000818:Animals; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000378:metabolism*; D063065:Organophosphonates / Q000737:chemistry / Q000378:metabolism*; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D019097:Spin Trapping; D013481:Superoxides / Q000737:chemistry / Q000378:metabolism*
chemical_list: C510912:(diethoxyphosphoryl)-5-methylpyrroline N-oxide; C512236:5-diisopropoxyphosphoryl-5-methyl-1-pyrroline-N-oxide; D003497:Cyclic N-Oxides; D063065:Organophosphonates; D011758:Pyrroles; D013481:Superoxides