Hazlehurst L A, Krapcho A P, Hacker M P
Department of Pharmacology, University of Vermont College of Medicine, Burlington 05405, USA.
Cancer Lett. 1995 May 4;91(1):115-24. doi: 10.1016/0304-3835(95)91035-5.
Doxorubicin and mitoxantrone are carboxyclic anti-cancer drugs that interact with DNA through intercalation. Our laboratory has synthesized a new series of anti-tumor agents, the aza-anthracenediones, which are structurally related to mitoxantrone but contain a heterocyclic, rather than a carbocyclic, chromophore. Both the in vivo and in vitro anti-tumor activities of these compounds were exquisitely sensitive to the positioning of the nitrogen atom within the heterocyclic backbone. Compounds having a 2-aza were 30- to 100-fold more potent than the 1-aza or the di-aza compounds against L1210 cells in vitro. When tested in vivo, the 2-aza-anthracenediones had marked anti-tumor activity, in some cases curative, whereas the 1-aza-anthracenediones had but minimal antitumor activity. To define the importance of the aza positioning on DNA reactivity, spectral shift and gel mobility assays were used. The spectral shift assay suggested that the 2-aza compounds reacted with DNA solely through intercalation whereas the 1-aza-anthracenediones, and mitoxantrone all reacted with DNA through intercalative and non-intercalative processes. The affinity of DNA binding was five to seven times greater for the 2-aza compounds compared to the 1-aza or the di-aza derivatives. The retardation of supercoiled pBR322 DNA mobility in agarose gel electrophoresis further suggested an intercalative type of DNA interaction. Differences in DNA interaction appear related to but can not completely account for differences in cytotoxicity of the aza anthracenediones.
阿霉素和米托蒽醌是通过嵌入作用与DNA相互作用的羧酸类抗癌药物。我们实验室合成了一系列新的抗肿瘤药物，即氮杂蒽二酮，它们在结构上与米托蒽醌相关，但含有一个杂环发色团而非碳环发色团。这些化合物的体内和体外抗肿瘤活性对杂环主链中氮原子的位置极为敏感。在体外，具有2-氮杂结构的化合物对L1210细胞的活性比1-氮杂或二氮杂化合物强30至100倍。在体内试验时，2-氮杂蒽二酮具有显著的抗肿瘤活性，在某些情况下具有治愈效果，而1-氮杂蒽二酮的抗肿瘤活性则极小。为了确定氮杂位置对DNA反应性的重要性，使用了光谱位移和凝胶迁移率测定法。光谱位移测定表明，2-氮杂化合物仅通过嵌入作用与DNA反应，而1-氮杂蒽二酮和米托蒽醌则通过嵌入和非嵌入过程与DNA反应。与1-氮杂或二氮杂衍生物相比，2-氮杂化合物与DNA结合的亲和力大五到七倍。琼脂糖凝胶电泳中超螺旋pBR322 DNA迁移率的阻滞进一步表明了一种嵌入型的DNA相互作用。DNA相互作用的差异似乎与氮杂蒽二酮的细胞毒性差异有关，但不能完全解释这些差异。
