NEW DRUGS TO ALLEVIATE ADRIAMYCIN CARDIOTOXICITY

3，5，5-三甲基-2-氧吗啉-3-基(TM-3)是一种稳定的 具有生物单电子势能的有机自由基体系 还原剂。自由基与二聚体处于平衡状态。 缺少可还原的底物。TM-3的水溶性衍生物是 3，5-dimethyl-5-hydroxymethyl-2-oxomorpholin-3-yl(DHM-3)和5，5- Bis(hydroxymethyl)-3-methyl-2-oxomorpholin-3-yl(BHM-3)。TM-3的反应， DHM-3或BHM-3与喹酮类抗肿瘤药物，如蒽环类或 丝裂霉素会产生许多氧化还原状态，包括甲基苯醌。 状态，按顺序。DHM-3二聚体是一种有效的解毒剂 大剂量蒽环类药物在小鼠腹腔抢救治疗中的应用 荷瘤及对蒽环类药物和丝裂霉素C渗出的影响 坏死性；伴有I.P.它还显著改善了管理 阿霉素治疗反应。BHM-3二聚体静脉输注低 毒性。解毒活性很可能来自细胞外 减少和改善细胞内复位的治疗反应。 拟议研究的长期目标是了解 氨基-羧基稳定化合物独特的化学和生物学性质 自由基，以确定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，并发现新的抗肿瘤药物和 协议。具体目的是L)来刻画半喹酮 空气氧化产生的暂态甲烷；2)比较 7-脱氧柔红霉素对苯二酚甲醚的空气氧化 从11-脱氧蒽环素还原而来的对苯二酚甲醚， 月桂醇；3)建立形成氧的介质轮廓 柔红霉素对苯二酚、白霉素的稳定互变异构体；4)探索 空气氧化主要产物甲基苯二酚的氧化还原化学 7-脱氧-7，13-表氧柔红霉素在铁存在和不存在的情况下 5)合成12-脱氧柔红霉素(12-DU)。 并对其氧化还原化学进行了研究；6)建立了 月桂酚衍生的苯醌甲醚的共价结合要求 对寡核苷酸；7)进一步探讨络合剂的作用 以及11位和12位的衍生化试剂，如钒酸盐和 金属离子对柔红霉素和阿霉素氧化还原化学的影响 探索白霉素、环二氧基柔红霉素、环磷酰胺的共价反应性 苯环素衍生的甲基对苯二酚和甲基半喹酮， 色丹菌素、蒽环素钒酸酯和金属离子 与核酸和寡核苷酸的络合物，9)探索 蒽环类和丝裂霉素类药物减少的可能性和后果 通过共价键的形成，10)合成和研究氨基-羧基 含有胆固醇基团和多肽基团的自由基；以及11)至 继续与氨基-碳盒自由基的组织培养合作研究 作为醌类抗肿瘤药物的调节剂，具有潜在的 对心脏毒性较小的蒽环类衍生物。

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.