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

• 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
• ISSN: 1520-4804
• DOI: 10.1021/jm301866e

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.