BIOCHEMICAL PHARMACOLOGY OF NEW ANTHRACYCLINES

该研究旨在确定 化学、生物化学和细胞基础， 糖修饰的阿霉素类似物的抗肿瘤活性 (DXR)氰基吗啉基多柔比星（CM-DXR），其为100至 比DXR在体外和动物体内的效力高1000倍 肿瘤和体外人肿瘤细胞中， 动物试验系统中的心脏毒性作用。 它也是不交叉的- 对体外的DXR耐药肿瘤细胞有抵抗力。 关键的化学事件被认为是氰基 的CM-DXR离开分子，导致最小 具有极高效力的烷基化物质。 非- 含氰基吗啉DXR（M-DXR）需要代谢 通过哺乳动物系统激活，产生类似于 CM-DXR支持最小假设。 另外，我们有 最近展示了令人惊讶的简单和快速的交换， 在水溶液中，pH值下，CM-DXR与~（14）CN ~-的氰基反应 7.3. 我们建议研究这些机制，通过一个集成的化学 和生物化学方法。 化学方法将是 直接合成氰基吗啉氧桥 DXR和柔红霉素（DNR）的吗啉基衍生物， 在P388细胞中测试，对DXR敏感（S）和耐药（R）。 生物化学的方法将是检验假设， 吗啉基衍生物被肝脏α-羟基化 微粒体酶 与这些研究相关的将是 通过32 P-评估DNA加合物形成的作用 P388/S和P388/R的敏感性 细胞对DXR、M-DXR、CM-DXR、类似的DNR类似物和其他 化合物在小鼠体内。 最后，我们将测试最活跃，最稳定，最有前途的新 化合物在小鼠中对P388肿瘤细胞的作用。 结合 后面的测试将确定代谢 新化合物的处置。

The proposed research is directed toward determining the chemical, biochemical, and cellular basis for the extremely potent antitumor activity of the sugar-modified analog of doxorubicin (DXR), cyanomorpholinyl doxorubicin (CM-DXR), which is 100 to 1000 times more potent than DXR in vitro and in vivo in animal tumors and in vitro in human tumor cells in the absence of cardiotoxic effects in animal test system. It is also noncross- resistant to DXR-resistant tumor cells in vitro. The pivotal chemical event is proposed to be that the cyano group of CM-DXR leaves the molecule, resulting in an minimum alkylating species of extremely high potency. That the non- cyano-containing morpholinyl DXR (M-DXR) requires metabolic activation by mammalian systems to yield activities similar to CM-DXR supports the minimum postulate. Also, we have recently demonstrated surprisingly facile and rapid exchange of the cyano group of CM-DXR with 14CN- in aqueous systems at pH 7.3. We propose to study these mechanisms by an integrated chemical and biochemical approach. The chemical approach will be to synthesize directly cyanomorpholinyl and oxygen-bridged morpholinyl derivatives of DXR and daunorubicin (DNR) for testing in P388 cells, both sensitive (S) and resistant (R) to DXR. The biochemical approach will be to test the hypothesis that morpholinyl derivatives are alpha-hydroxylated by liver microsomal enzymes. Associated with these studies will be assessments of the role of DNA-adduct formation, via 32P- postlabeling techniques, in the sensitivity of P388/S and P388/R cells to DXR, M-DXR, CM-DXR, similar DNR analogs, and other compounds in the mice. Finally, we will test the most active, stable, promising new compounds in mice against P388 tumor cells. Combined with these later tests will be determinations of the metabolic disposition of the new compounds.