SYSTEMATIC DEVELOPMENT OF NEW ANTITUMOR ANTHRACYCLINES

我们提出了一种抗肿瘤的蒽环类化合物的系统优化方法。 通过柔红霉素和阿霉素的半合成衍生化。 具体地说，我们计划追查我们的 新近发现的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。前者的化合物最多 到目前为止合成的强效蒽环类类似物，后者是一种类似物 具有显著提高的抗肿瘤效果。因此，对糖的依附 一种新的环，它结合了氨基N，并在 4-位似乎提供了生物上重要的补充 以前未鉴定的蒽环类化合物的结构。大多数 进一步的类似物将通过Borch还原烷基化反应合成， 使用各种二醛和氰基硼氢化钠。其他结构 更改将基于之前的线索，表明有利的更改 利用5-亚氨基(抗肿瘤活性)获得生物学特性 残留，心脏毒性较小)和N，N-二苯基衍生物(更好的抗肿瘤 功效，心脏毒性较小)。有限的努力将致力于一个完全 通过删除简化的苷元合成吗啉基类似物 4-甲氧基和9-乙酰基。新产品将是 在小鼠中系统地筛选抗肿瘤特性。此外, 它们将在体外进行DNA相互作用特性和 自由基形成性质，这与主要假设有关 行动机制。有限数量的人将接受心脏毒性测试 在老鼠身上。我们的目标是通过开发更好的抗癌药物 设计、综合和评估的集成流程，已在 根据不可再生的癌症研究重点拨款CA 25711进行手术。

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.