NEW DRUGS TO ALLEVIATE ADRIAMYCIN CARDIOTOXICITY

3，5，5-三甲基-2-氧吗啉-3-基(TM-3) 具有潜在应用潜力的稳定有机自由基体系 生物单电子还原剂。自由基稳定下来了 通过氨基和羧基的协同作用以及 在没有A的情况下，存在与介观和dl-二聚体的平衡 可还原的衬底。TM-3与喹诺酮抗肿瘤作用的研究 像蒽环类药物这样的药物会产生许多 由第一个控制的蒽环类氧化还原态的顺序 二聚体均解的有序速率常数。A可溶于水 TM-3的衍生物为3，5-二甲基-5-羟甲基-2- 氧吗啉-3-基(DHM-3)。DHM-3是一种有效的解毒剂 大剂量蒽环类药物在荷瘤小鼠抢救治疗中的应用 L1210、P388或B16肿瘤系统对蒽环类药物和 丝裂霉素C在渗出性坏死中可能通过还原， 在蒽环类化合物的7-脱氧苷元的情况下。这个 抗环素类药物和丝裂霉素C被认为至少在一定程度上 生物还原激活。该计划的长远目标 拟议的研究是为了了解独特的化学和 氨基-羧基稳定自由基的生物学性质 它们的二聚体前体，与这些自由基一起确定为 受控还原剂(和其他还原剂时 必需的)蒽环类化合物和其他化合物的氧化还原化学 醌类抗肿瘤药物，并学会如何操控 体内抗肿瘤药物的治疗优势部分通过 发展氨基-羧基稳定的自由基作为高血压的解药 剂量抢救疗法。具体目标是1)描述 蒽环类化合物的苯醌甲基自由基态，2)研究 甲基苯醌的亲核和亲电反应性 和具有生物底物的苯醌甲基自由基态，3) 一种新的蒽环类化合物的合成、分离和表征 衍生物，无色蒽环类，一种互变异构体，暂时 存储还原并确定与生物的反应性 大分子如DNA，4)进一步研究其反应性 与糖苷类有关的蒽环类对苯二酚状态 裂解、氢化物转移和互变异构化 5)研究丝裂霉素C和丝裂霉素C的反应性。 铁-蒽环类化合物与DHM-3的络合物及其氧化还原性能的比较 并吡唑类化合物与结构相关化合物的化学 5-亚米诺霉素，6)开发新的氨基-羧基 二聚体解毒剂，具有增强的水溶性和减弱的 与分子氧的反应，7)建立新陈代谢 以及解毒剂的细胞膜转运 带放射性标签的材料和8)继续协作 解毒剂在大剂量抢救中的效果实验 治疗，新的蒽类化合物在改良氧化还原中的效果 一些州，如无色杂环类和环二酮类 (与5-亚米诺霉素的还原产物有关)和 氨基-羧基作为辐射增敏剂的活性。

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.