Radiomitigant and anti-apoptotic compounds
Project No. 2035
Principal Investigators/Inventors: Dr. Jeffrey Atkinson, Department of Chemistry and Dr. Jeff Stuart, Department of Biological Sciences
Novel compounds for use in preventing mitochondria-mediated apoptosis due to radiation, freeze-thaw or ischemia and reperfusion events
Irradiation of cells begins a cascade that ends in a mitochondria-mediated commitment to programmed cell death, known as apoptosis. The inventors have developed a library of novel imidazole fatty acid conjugates with triphenylphosphonium cations (TPP) that target mitochondria and prevent apoptosis. These compounds inhibited pro-apoptotic oxidative events, prevented cell death and, in animal studies, were effective radioprotectors (administered before irradiation), and radiomitigators (administered after irradiation) of mice receiving lethal levels of whole body irradiation. Few drugs are currently approved for use as pre-exposure radioprotectants; most have limited utility and are quite toxic and there are no approved radiomitigant treatments to alleviate post-exposure radiation injury. There is data that these compounds may have wider utility in preventing apoptotic cell loss during freeze-thaw events and ischemia/reperfusion incidents, such as stroke.
Atkinson et al., “Mitochondria-targeted inhibitors of cytochrome C perosidase for protection from apoptosis” US provisional application 61/594,678; Canadian application 2757917.
Atkinson et al., (2011). “A mitochondria-targeted inhibitor of cytochrome c peroxidase mitigates radiation-induced death.” Nat. Commun. 2: 497.