DIDOX (3,4-dihydroxybenzohydroxamic acid) is one member of a series of hydroxy-substituted benzohydroxamic acids which are potent ribonucleotide reductase inhibitors, have anti-tumor activity, and are powerful free radical scavengers. Since DIDOX administration as a chemotherapeutic agent has shown promise during Stage I clinical trials in England it is appropriate to ask what chemical properties of DIDOX make it superior to others in the series and, further whether its biological activity is related to its (largely unstudied) free radical scavenging properties. No systematic studies have been conducted of the reduction/oxidation (redox) properties of these compounds and their rich associated chemistry. This MBRS project will permit a high-quality, intensive research investigation of a biologically important system for undergraduate students about to make choices between professional, teaching and research careers in biomedical fields. The following will be studied: (a) the redox properties of DIDOX and its oxidation products in aqueous solution near physiological pH, (b) the effect of structural isomerization on redox properties of related compounds, (c) the effect of metal ion complexation on the redox properties of DIDOX and related compounds, and (d) the mechanism for electrochemical oxidation of these compounds. Finally, (e) we intend to compare mechanisms for the biological oxidation with the electrochemical one and (f) we will test for correlations between the chemical properties and biological activity. Experimental Design: (1) The electrochemical properties of this series of molecules will be measured with modern electroanalytical techniques in a microprocessor controlled instrument. Techniques will include cyclic voltammetry, chronoamperometry, controlled potential electrolysis, and spectroelectrochemistry. (2) Separation of chemical and electrochemical oxidation products and the determination of specific compounds in biological fluids will be performed with HPLC and UV or electrochemical detection. (3) UV/visible spectroscopy will be used to characterize each molecule in the series, measure pK's near physiological pH, and follow appropriate reaction rates.
