NEW DRUGS TO ALLEVIATE ADRIAMYCIN CARDIOTOXICITY

3，5，5-三甲基-2-氧代吗啉-3-基（TM-3） 稳定的有机自由基体系， 生物单电子还原剂。 自由基稳定 通过氨基和羧基取代基的协同效应， 在不存在A的情况下，存在与内消旋和DL-二聚体的平衡 可还原底物 TM-3与醌类抗肿瘤药物的反应 药物如蒽环类产生许多 蒽环类药物的氧化还原状态顺序控制的第一个 二聚体均裂的顺序速率常数。 水溶性 TM-3的衍生物是3，5-二甲基-5-羟甲基-2-甲基-N-（2-（2-（三氟甲基）苯基）-2-甲基-N-（三氟甲基）苯基）-N-（三氟甲基）苯基）-N-（三氟甲基）苯基）-N-（三氟甲基）苯基。 氧代吗啉-3-基（DHM-3）。 DHM-3是一种有效的解毒剂 大剂量蒽环类抗生素对荷瘤小鼠的挽救治疗 L1210、P388或B16肿瘤系统， 丝裂霉素C在外渗性坏死中可能通过还原作用， 在蒽环类药物的情况下，转化为它们的7-脱氧糖苷配基。 的 认为，至少部分地， 生物还原活化。 的长期目标 拟议的研究是了解独特的化学和 氨基-羧基稳定的自由基的生物学性质， 它们的二聚体前体，以确定与这些自由基， 受控还原剂（以及当 蒽环类和其他的氧化还原化学 醌类抗肿瘤药物，并学会操纵醌 抗肿瘤药物在体内的治疗优势部分是通过 开发氨基-羧基稳定的自由基作为高 剂量补救治疗。 具体目标是：1）表征 醌甲基自由基状态的蒽环类，2）研究 醌甲基化物亲核亲电反应性 和醌甲基化物自由基状态与生物底物，3） 合成、分离和表征一种新的蒽环类抗生素 衍生物，无色蒽环类，一种互变异构体， 储存物减少并确定与生物反应性 大分子如DNA，4）进一步研究的反应性 蒽环类对苯二酚糖苷状态 裂解、氢化物转移和互变异构， 无色衍生物，5）研究丝裂霉素C和 蒽环铁配合物与DHM-3和比较氧化还原 蒽吡唑类化合物化学 5-亚氨基道诺霉素; 6）产生新的氨基羧基 具有增强的水溶性和降低的 与分子氧的反应性，7）建立代谢 以及解毒剂的细胞膜转运， 放射性标记材料和8）继续合作 大剂量解毒剂抢救效果试验 治疗，新的蒽环类药物在修饰的氧化还原 例如无色蒽环类和并四苯二酮类 （与5-亚氨基道诺霉素的还原产物有关）和 氨基-羧基自由基作为放射增敏剂的活性。

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.