NEW DRUGS TO ALLEVIATE ADRIAMYCIN CARDIOTOXICITY

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3,5,5-Trimethyl-2-oxomorpholin-3-yl (TM-3) exemplifies a stabilized organic free radical system with potential as a biological one electron reducing agent. The radical is stabilized by the synergistic effect of amino and carboxy substituents and exists of equilibrium with meso and dl-dimers in the absence of a reducible substrate. Reaction of TM-3 with quinone anti-tumor drugs such as the anthracyclines generates the many anthracycline redox states sequencially as controlled by the first order rate constant for homolysis of the dimers. A water soluble derivative of TM-3 is 3,5-dimethyl-5-hydroxymethyl-2- oxomorpholin-3-yl (DHM-3). DHM-3 is an effective antidote for the anthracyclines in high dose rescue therapy with mice bearing L1210, P388, or B16 tumor systems for the anthracyclines and mitomycin C in extravasation necrosis presumably via reduction, in the case of the anthracyclines to their 7-deoxyaglycones. The antracyclines and mitomycin C are thought to be, at least in part, bioreductively activated. The long-term objectives of the proposed research are to understand the unique chemical and biological properties of amino-carboxy stabilized radicals and their dimer precursors, to determine with these radicals as controlled reducing agents (and other reducing agents when necessary) the redox chemistry of the anthracyclines and other quinone anti-tumor drugs, and to learn to manipulate quinone anti-tumor drugs in vivo to therapeutic advantage in part by developing amino-carboxy stabilized radicals as antidotes for high dose rescue therapy. The specific aims are 1) to characterize the quinone methide radical state of the anthracyclines, 2) to study the nucleophilic and electrophilic reactivity of quinone methide and quinone methide radical states with biological substrates, 3) to synthesize, isolate, and characterize a new anthracycline derivative, leuco-anthracycline, a tautomer which temporarily stores reduction and determine reactivity with biological macromolecules such as DNA, 4) to study further the reactivity of the anthracycline hydroquinone state with regard to glycosidic cleavage, hydride transfer, and tautomerization to leucoderivatives, 5) to study the reactivity of mitomycin C and iron anthracycline complexes with DHM-3 and compare the redox chemistry of anthrapyrazoles with that of the structurally related 5-iminodaunomycin, 6) to develop new amino-carboxy radical dimer antidotes with enhanced water solubility and diminished reactivity with molecular oxygen, 7) to establish the metabolism and cell membrane transport of the antidotes with specifically radio-labeled materials and 8) to continue collaborative experiments on the efficacy of antidotes in high dose rescue therapy, the efficacy of new anthracylines in modified redox states such as the leuco-anthracyclines and naphthacenediones (related to product of reduction of 5-iminodaunomycin) and the activity of amino-carboxy radicals as radio sensitizers.