This research program is based on the thesis that oxygen free radicals contribute in a significant way to the deleterious aspect of reperfusion after a tissue or organ is deprived of oxygen and flow is reinitiated. The objective of this proposal is to determine the potential of a new series of compounds to protect against ischemia reperfusion injury. These compounds were originally developed for cancer chemotherapy and have free radical scavenging and antiinflammatory activity. One is presently in clinical trial. Representative functional groups will be inserted and in vitro experiments will be performed to evaluate the ability of each subclass to scavenge free radicals including the superoxide and hydroxyl radicals. Additionally, the Fe chelating capacity of the different congeners will be measured to evaluate which part of the structure contributes to biological activity for new drug design. Fe chelating activity is an attribute of these compounds. Finally, the efficacy of the compounds to prevent reperfusion ischemia injury will be performed in the perfused heart model in which hearts will be subjected to ischemia and then reperfused in the presence or absence of the drugs. The drugs effect on the formation of oxygen free radicals on reperfusion as determined by EPR techniques will be measured. Simultaneously with the EPR free radical measurements in the perfused hearts, the functional capacity of the heart will also be measured. Also chemical methods measuring lipid and glutathione oxidation will be performed to monitor oxidant stress. Positive results from the phase I proposal would be followed by more extensive experiments in phase II with emphasis of the toxicity of the compounds and whether the candidate compound would work in the reperfusion ischemia injury model in whole animals.
