Synthesis and Biological Characterization of New Aminophosphonates for Mitochondrial pH Determination by 31P NMR Spectroscopy

Marcel Culcasi (1) , Gilles Casano (1) , Céline Lucchesi (1) , Anne Mercier (1) , Jean-Louis Clément (1) , Valerie Pique (1) , Laure Michelet (2) , Anja Krieger-Liszkay (2) , Maxime Robin (1) , Sylvia Pietri (1)

1 ICR - Institut de Chimie Radicalaire
2 IBITECS - Institut de Biologie et de Technologies de Saclay

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 31P NMR properties and biological activities in vitro and in vivo were evaluated. The results showed a number of these mitoaminophosphonates exhibiting pKa values fitting the mitochondrial pH range, short relaxation, and chemical shift parameters compatible with sensitive 31P 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.

Domains: Chemical Sciences

Marcel Culcasi, Gilles Casano, Céline Lucchesi, Anne Mercier, Jean-Louis Clément, et al.. Synthesis and Biological Characterization of New Aminophosphonates for Mitochondrial pH Determination by 31P NMR Spectroscopy. Journal of Medicinal Chemistry, 2013, 56, pp.2487−2499. ⟨10.1021/jm301866e⟩. ⟨hal-01142293⟩