SYSTEMATIC DEVELOPMENT OF NEW ANTITUMOR ANTHRACYCLINES

新型抗肿瘤蒽环类药物的系统开发

• 批准号: 3185571
• 负责人: STEVEN C WELCH
• 金额: $ 15.6万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-06-01 至 1990-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3185571
• 关键词: anthracyclines; antineoplastics; daunorubicin; doxorubicin; drug adverse effect; drug design /synthesis /production; drug metabolism; drug screening /evaluation; human therapy evaluation; laboratory mouse; neoplasm /cancer chemotherapy; tissue /cell culture

We propose a systematic optimization of antitumor anthracycline structures through semisynthetic derivatization of daunorubicin and doxorubicin. Specifically, we plan to pursue the important new leads provided by our recently discovered 3'-(4-morpholinyl) and 3'-(4-methoxy-1-piperidinyl) derivatives of 3'-deaminodaunorubicin. The former compound is the most potent anthracycline analog synthesized so far and the latter is an analog with markedly improved antitumor efficacy. Hence, attachment to the sugar of a new ring that incorporates the amino N and has an ether O at the 4-position appears to provide biologically important additions to the anthracycline structure that were not previously identified. Most of the further analogs will be synthesized by the Borch reductive alkylation, using various dialdehydes and sodium cyanoborohydride. Other structure changes will be based on previous leads indicating that favorably altered biological properties are obtained with the 5-imino (antitumor activity retained, less cardiotoxic) and N,N-dibenzyl derivatives (better antitumor efficacy, less cardiotoxic). A limited effort will be devoted to a totally synthetic morpholinyl analog with the aglycone simplified by deletion of the 4-methoxyl and 9-acetyl substituents. The new products will be systematically screened for antitumor properties in mice. In addition, they will be tested in vitro for DNA interactive properties and for radical-forming properties, which are relevant to the major hypothetical mechanisms of action. A limited number will be tested for cardiotoxicity in rats. Our objective is to develop better anticancer drugs by an integrated process of design, synthesis, and evaluatin, already set in operation under the non-renewable Cancer Research Emphasis grant CA 25711.

我们提出了一个抗肿瘤蒽环类抗生素结构的系统优化 通过柔红霉素和阿霉素的半合成衍生化。 具体而言，我们计划继续利用我们的 最近发现的3 '-（4-吗啉基）和3'-（4-甲氧基-1-哌啶基） 3 ′-脱氨基柔红霉素的衍生物。 前一个化合物是最 迄今为止合成的有效蒽环类类似物，后者是类似物 具有显著提高的抗肿瘤功效。 因此，对糖的依恋 一个新的环，结合了氨基N和醚O在 4-位置似乎提供了生物学上重要的补充， 蒽环结构，以前没有发现。 大部分 其它类似物将通过Borch还原烷基化反应合成， 使用各种二醛和氰基硼氢化钠。 其它结构 变化将基于以前的线索，表明有利的改变 5-亚氨基的生物学性质（抗肿瘤活性 保留，心脏毒性较低）和N，N-二苄基衍生物（抗肿瘤效果更好 功效，心脏毒性较小）。 有限的努力将致力于一个完全 合成的吗啉基类似物，其糖苷配基通过缺失 4-甲氧基和9-乙酰基取代基。 新产品将 在小鼠中系统地筛选抗肿瘤特性。 此外，本发明还提供了一种方法， 它们将在体外测试DNA相互作用特性和 自由基形成的性质，这是相关的主要假设 行动机制。 将对有限数量的患者进行心脏毒性试验 对大鼠 我们的目标是开发更好的抗癌药物， 设计、综合和评估一体化过程已经开始 在不可再生的癌症研究重点补助CA 25711下运作。