SYNTHESIS AND PHARMACOLOGY OF AMINOANTHRACYCLINES

蒽环类抗生素阿霉素是公认的 所有抗癌药物中最有价值的。它的临床范围 有效性包括急性白血病、淋巴瘤和癌症。 乳房、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。一些调查人员已经将这种疾病的发展 对存在于喹环体系分子中的心脏毒性 其能够支持自由基的形成(E.F.， 产生细胞脂质过氧化的超氧化物和羟基)。 心脏似乎特别容易受到这种影响，因为它 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)。我们的目标是 加深对自由基间关系的了解 苯二酮类药物的产生和生物效应。 具体地说，提出了一种多步合成阿霉素衍生物的方法 它们在发色团中含有氨基。电子捐献 这一功能的性质有望降低自由基 队形。这应该会产生一种具有抗肿瘤活性的分子 同时大大降低了导致心脏损伤的倾向。几个 目标苷元的合成中的几个步骤已经完成 规模很小，尽管一些低收益的步骤需要改进。 计划中其余的每一步都有足够的先例 蒽环类药物合成文献。目标糖苷元将是 转化为一系列糖苷，将用三种 不同的药理标准(超氧化物生成、脂质 过氧化和心脏对组胺的反应)，以评估其 心脏毒性潜在性。在这项研究中制备的所有化合物都将是 接受细胞毒性筛选。

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.