SYNTHESIS AND PHARMACOLOGY OF AMINOANTHRACYCLINES

蒽环类抗生素阿霉素被认为是 最有价值的抗癌药物。 其临床范围 有效性包括急性白血病，淋巴瘤，和癌症的 乳腺、肺和甲状腺。 然而，这种药物的临床效用是 由于其倾向于产生严重的，有时是致命的 心脏毒性 几位研究人员将 醌式环系统分子中存在的心脏毒性 其能够支持自由基的形成（例如， 超氧化物和羟基），其产生细胞脂质的过氧化。 心脏似乎特别容易受到这种影响， 含有较低水平的保护酶（超氧化物歧化酶， 谷胱甘肽过氧化物酶和过氧化氢酶）。 目标是 为了更好地理解自由基与 醌类药物产生的生物学效应。 具体来说，提出了阿霉素衍生物的多步合成方法 其在发色团中含有氨基。 给电子 该功能性的性质预期降低自由基 阵 这将导致具有抗肿瘤活性的分子 同时具有大大降低的导致心脏损伤的倾向。 几 目标糖苷配基的合成步骤已经完成 小规模生产，尽管一些低产率步骤需要改进。 该计划的其余每一步都有足够的先例， 蒽环类抗生素合成文献。 目标糖苷配基将是 转化为一系列糖苷，将使用三种 不同的药理学标准（超氧化物生成、脂质 过氧化和心脏对组胺的反应），以评估其 潜在心脏毒性 在本研究中制备的所有化合物将被 进行细胞毒性筛选。

The anthracycline antibiotic adriamycin is recognized as being among the most valuable of all anticancer agents. Its range of clinical effectiveness includes acute leukemias, lymphomas, and carcinomas of the breast, lung, and thyroid. However, the clinical utility of this drug is hampered by its tendency to produce severe and sometimes fatal cardiotoxicity. Several investigators have linked the development of cardiotoxicity to the presence in the molecule of a quinoid ring system which is capable of supporting the formation of free radicals (e.f., superoxide and hydroxyl) which produce peroxidation of cellular lipids. The heart appears to be particularly vulnerable to this effect since it contains lower levels of protective enzymes (superoxide dismutase, glutathione peroxidase, and catalase) than other tissues. The objective is to develop a better understanding of the relationship between free radical generation and the biological effects produced by quinone-type drugs. Specifically, propose a multi-step synthesis of derivatives of adriamycin which contain an amino group in the chromophore. The electron-donating property of this functionality is expected to lower free radical formation. This should result in a molecule possessing antitumor activity while having a greatly reduced tendency to cause cardiac damage. Several of the steps in the synthesis of the target aglycone have been accomplished on a small scale although some of the low yield steps require improvement. Each of the remaining steps in the scheme has adequate precedent in the literature of anthracycline syntheses. The target aglycone will be converted to a series of glycosides which will be studied using three different pharmacological criteria (superoxide generation, lipid peroxidation, and cardiac response to histamine) in order to assess their cardiotoxic potential. All of the compounds prepared in this study will be subjected to cytotoxicity screening.