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 exists in equilibrium with dimers in the absence of a reducible substrate. Water soluble derivatives of TM-3 are 3,5-dimethyl-5-hydroxymethyl-2-oxomorpholin-3-yl (DHM-3) and 5,5- bis(hydroxymethyl)-3-methyl-2-oxomorpholin-3-yl (BHM-3). Reaction of TM-3, DHM-3 or BHM-3 with quinone anti-tumor drugs such as the anthracyclines or mitomycins generates the many redox states, including the quinone methide state, sequentially. DHM-3 dimer is an effective antidote for the anthracyclines in high intraperitoneal-dose rescue therapy for mice bearing tumor and for the anthracyclines and mitomycin C in extravasation necrosis; with i.p. administration it also dramatically improves adriamycin therapeutic response. BHM-3 dimer has low intravenous toxicity. Antidotal activity most likely results from extracellular reduction and improved therapeutic response from intracellular reduction. The long-term objectives of the proposed research are to understand the unique chemical and biological properties of amino-carboxy stabilized radicals, to determine the redox chemistry of the anthracyclines and other quinone anti-tumor drugs, and to discover new antitumor drugs and protocols. The specific aims are l) to characterize the semiquinone methide transient from air oxidation of the quinone methide; 2) to compare air oxidation of 7-deoxydaunomycinone quinone methide with air oxidation of the quinone methide from reduction of the 11-deoxy anthracycline, menogaril; 3) to establish a medium profile, for formation of the oxygen stable tautomer of daunomycin hydroquinone, leucodaunomycin; 4) to explore the redox chemistry of the major product of quinone methide air oxidation, 7-deoxy-7,13-epidioxydaunomycinol, in the presence and absence of iron ions; 5) to develop a synthesis for 12-deoxydaunomycin (12- chromodaunomycin) and explore its redox chemistry; 6) to establish the requirements for covalent binding of the menogaril-derived quinone methide to oligonucleotides; 7) to explore further the effect of complexing agents and derivatizing agents at the 11- and 12-positions such as vanadate and metal ions on the redox chemistry of daunomycin and adriamycin; 8) to explore covalent reactivity of leucodaunomycin, eipidioxy-daunomycinol, anthracycline-derived quinone methides and semiquinone methides, chromodaunomycins, and anthracycline vanadate esters and metal ion complexes with nucleic acids and oligonucleotides, 9) to explore the possibility and consequences of reduction of anthracyclines and mitomycins through covalent bond formation, 10) to synthesize and study amino-carboxy radicals bearing cholesteryl groups and peptide groups; and 11) to continue tissue culture collaborative research with amino-carbox radicals and as modulating agents for quinone anti-tumor drugs and with potentially less cardiotoxic anthracycline derivatives.