THERMODYNAMIC STABILITY OF SEMIQUINONES AS A FUNCTION OF THEIR ENVIRONMENT

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Semiquinones are important intermediates in the cytotoxic action of quinone-containing drugs utilized in the treatment of several human illnesses. Our major aim is to understand the interrelated roles of environment and structure of semiquinones in determining the thermodynamic stability (or kinetic reactivity) of semiquinones since, by knowing these, an understanding of the cytotoxic action of quinones may be obtained and more efficient quinone-based drugs could be designed. This major aim can be subdivided in two types of specific aims, i.e., those where physical properties which measure semiquinone physical properties and association constants with their biologically relevant environment (metal cations and membranes) are determined, and those aimed at measuring the effectiveness of potential cytotoxic reactions as a function of changes in these physical properties. According to their nature, semiquinones can undergo ion-pairing with metal cations, disproportionation, electron transfer reactions, partition into phospholipid membranes and others. In addition, quinone- containing anti-tumor drugs are known to enhance their anti-tumor activity in the presence of ultrasound irradiation. Two potential cytotoxic reactions in which semiquinones play their role as mediators are electron donating reactions and lipid peroxidation. In particular, electron transfer to oxygen and nitric oxide to produce cytotoxic intermediates are biomedically relevant processes. This subproject will measure the rates of semiquinone/hydroquinone-mediated reduction of oxygen and nitric oxide, rates of quinone-induced lipid peroxidation and rates of ultrasound-induced oxygen reduction in the presence of quinones. Correlations will be sought between quinone-semiquinones physical properties and these rates. Undergraduate students will participate in this subproject. They will be trained in different laboratory, spectroscopic and computational techniques as applied to free radicals biomedical research. It is expected that the involvement of students in this subproject will serve as a means to obtain one of the desired goals, i.e. students entering and graduation from graduate, medical or odontology schools and pursuing biomedical research careers.