New Biocompatible β‐Phosphorylated Linear Nitrones Targeting Mitochondria: Protective Effect in Apoptotic Cells

Marcel Culcasi (1) , Caroline Delehedde (1) , Mathieu Esgulian (1) , Mathieu Cassien (1, 2) , Mathieu Chocry (1) , Antal Rockenbauer (3) , Sylvia Pietri (1) , Sophie Thétiot-Laurent (1)

1 ICR - Institut de Chimie Radicalaire
2 YELEN
3 Institute of Materials and Environmental Chemistry [Budapest]

Mitochondria, an essential organelle involved in cellular respiration, energy production, and cell death, is the main cellular source of reactive oxygen species (ROS), including superoxide. Mitochondrial diseases resulting from uncontrolled/excess ROS generation are an emerging public health concern and there is current interest for specific mitochondriotropic probes to get information on in situ ROS production. As such, nitrones vectorized by the triphenylphosphonium (TPP) cation have recently drawn attention despite reported cytotoxicity. Herein, we describe the synthesis of 13 low-toxic derivatives of N-benzylidene-1-diethoxyphosphoryl-1-methylethylamine N-oxide (PPN) alkyl chain-grafted to a pyridinium, triethylammonium or berberinium lipophilic cation. These nitrones showed in vitro superoxide quenching activity and EPR/spin-trapping efficiency towards biologically relevant free radicals, including superoxide and hydroxyl radicals. Their mitochondrial penetration was confirmed by 31P NMR and anti-apoptotic properties assessed in hydrogen peroxide treated Schwann cells. Two pyridinium substituted PPNs were identified as potentially better alternatives to TPP nitrones conjugates for studies of mitochondrial oxidative damage.

Keywords: cellular viability; EPR spin-trapping; mitochondria-targeted nitrones; 31P NMR; superoxide quenching

Domains: Chemical Sciences; Organic chemistry

Marcel Culcasi, Caroline Delehedde, Mathieu Esgulian, Mathieu Cassien, Mathieu Chocry, et al.. New Biocompatible β‐Phosphorylated Linear Nitrones Targeting Mitochondria: Protective Effect in Apoptotic Cells. ChemBioChem, In press, ⟨10.1002/cbic.202200749⟩. ⟨hal-03986344⟩