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Séminaire Chimie ED459

Advances in spin trap development for radical detection and therapeutics

Dr. Frederick A. Villamena (Assistant Professor, Department Pharmacology, Center for EPR Spectroscopy & Imaging, Davis Heart and Lung Research Institute, Ohio State University, USA)

publié le

Le Mardi 07 Juillet 2009 à 10h
ENSCM, Salle de conférences du bâtiment Recherche Max Mousseron (4e etg)

Over the past 2 decades, it has become clear that reactive oxygen species (ROS) plays a major role in the initiation of oxidative damage to biomolecular systems and in the pathogenesis of various diseases. Therefore, radical detection in biological systems at the site of their production is important. Electron paramagnetic resonance (EPR) spin trapping using nitrones has been the popular method for the detection of transient radicals in chemical and biological systems. Unlike spin probes such as nitroxides and trityl radicals that work through spin quenching, nitrone spin traps are capable of generating distinctive EPR spectrum upon reaction with free radicals that allows for their identification. In spite of the elegance of this method, nitrone spin traps are faced with certain limitations such as slow reactivity to superoxide radical anion (O2•–), less persistent O2•– adduct, and non-target specificity to intracellular compartments. Overcoming these problems using one molecular design has been a major challenge. For example, 5-ethoxycarbonyl-5-methyl-1-pyrroline-N-oxide (EMPO) and 5-diethoxyphosphoryl-5-methyl-1-pyrroline-N-oxide (DEPMPO), have been an improvement over 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) due to the longer half-lives of their respective O2•– adducts, but the reactivity of DMPO, EMPO and DEPMPO to O2•– remains poor. In our efforts to develop spin traps with improved properties for analytical and therapeutic applications, we have applied a systematic approach to spin trap development that encompasses computational studies, design, synthesis, kinetics and in vitro applications. New advancements in spin trap development will be presented which include the synthesis of newly conceptualized nitrones showing improved efficiency for O2•– trapping, longer O2•– half-life and target specificity.

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