NEW DRUGS TO ALLEVIATE ADRIAMYCIN CARDIOTOXICITY

3，5，5-三甲基-2-氧代吗啉-3-基（TM-3） 具有生物单电子电位的有机自由基体系 还原剂自由基与二聚体平衡存在， 缺少可还原的底物。TM-3的水溶性衍生物是 3，5-二甲基-5-羟甲基-2-氧代吗啉-3-基（DHM-3）和5，5- 双（羟甲基）-3-甲基-2-氧代吗啉-3-基（BHM-3）。TM-3的反应， DHM-3或BHM-3与醌类抗肿瘤药物如蒽环类或 丝裂霉素产生许多氧化还原状态，包括醌甲基化物 国家，顺序。DHM-3二聚体是一种有效的解毒剂， 蒽环类抗生素对小鼠的大剂量腹腔内挽救治疗 蒽环类和丝裂霉素C外渗 坏死;腹膜内给药也显著改善了 阿霉素治疗反应。 BHM-3二聚体具有低的静脉内 毒性解毒活性很可能是由细胞外 减少并改善来自细胞内减少的治疗反应。 拟议研究的长期目标是了解 独特的化学和生物性质的氨基-羧基稳定的 自由基，以确定蒽环类和其他 醌类抗肿瘤药物，并发现新的抗肿瘤药物， 协议.具体目标是：1）表征半醌 来自醌甲基化物的空气氧化的甲基化物瞬变; 2）比较 7-脱氧柔红霉素醌甲基化物的空气氧化 在来自11-脱氧蒽环类抗生素还原的醌甲基化物中， menogaril; 3）建立一个中等的配置文件，用于形成氧气 柔红霉素对苯二酚、白柔红霉素稳定互变异构体; 4）探索 醌甲基化物空气氧化的主要产物的氧化还原化学， 7-脱氧-7，13-环氧柔红霉素，在存在和不存在铁的情况下 离子; 5）开发12-脱氧柔红霉素（12- chromodaunomycin），并探讨其氧化还原化学; 6）建立 甲孕酮衍生的醌甲基化物的共价结合要求 7）进一步探讨络合剂的作用 以及在11-和12-位的衍生剂，例如钒酸盐和 金属离子对柔红霉素和阿霉素的氧化还原化学的影响; 8） 探索了无色道诺霉素，表二氧基道诺霉素， 蒽环衍生的醌甲基化物和半醌甲基化物， 色道诺霉素和蒽环类钒酸酯和金属离子 与核酸和寡核苷酸的复合物，9）探索 减少蒽环类和丝裂霉素的可能性和后果 通过共价键的形成，10）合成并研究了氨基羧基 带有胆固醇基和肽基的基团;和11）至 继续组织培养与氨基碳自由基的合作研究 以及作为醌类抗肿瘤药物的调节剂， 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.