Synthesis and biological characterization of new aminophosphonates for mitochondrial pH determination by (31)P NMR spectroscopy

A series of mitochondria targeted α-aminophosphonates combining a diethoxyphosphoryl group and an alkyl chain-connected triphenylphosphonium bromide tail were designed and synthesized, and their pH-sensitive (31)P NMR properties and biological activities in vitro and in vivo were evaluated. The resu...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2013-03, Vol.56 (6), p.2487-2499
Main Authors: Culcasi, Marcel, Casano, Gilles, Lucchesi, Céline, Mercier, Anne, Clément, Jean-Louis, Pique, Valérie, Michelet, Laure, Krieger-Liszkay, Anja, Robin, Maxime, Pietri, Sylvia
Format: Article
Language:English
Subjects:
3T3 Cells
Animals
Chemistry Techniques, Synthetic
Chlamydomonas reinhardtii - drug effects
Cytosol - metabolism
Humans
Hydrogen-Ion Concentration
Hydrophobic and Hydrophilic Interactions
Liver - cytology
Magnetic Resonance Spectroscopy
Mice
Mitochondria - chemistry
Mitochondria - metabolism
Organophosphonates - chemical synthesis
Organophosphonates - chemistry
Organophosphonates - metabolism
Organophosphonates - toxicity
Perfusion
Permeability
Rats
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Summary:A series of mitochondria targeted α-aminophosphonates combining a diethoxyphosphoryl group and an alkyl chain-connected triphenylphosphonium bromide tail were designed and synthesized, and their pH-sensitive (31)P NMR properties and biological activities in vitro and in vivo were evaluated. The results showed a number of these mito-aminophosphonates exhibiting pKa values fitting the mitochondrial pH range, short relaxation, and chemical shift parameters compatible with sensitive (31)P NMR detection, and low cytotoxicity on green algae and murine fibroblasts cell cultures. Of these, two selected compounds demonstrated to distribute at NMR detectable levels within the cytosolic and mitochondrial sites following their perfusion to isolated rat livers, with no detrimental effects on cell energetics and aerobic respiration. This study provided a new molecular scaffold for further development of in situ spectroscopic real-time monitoring of mitochondrion/cytosol pH gradients.
ISSN:1520-4804
DOI:10.1021/jm301866e