Ishiguro K, Takahashi K, Yazawa K, Sakiyama S, Arai T
J Biol Chem. 1981 Mar 10;256(5):2162-7.
Saframycin A is antitumor antibiotic structurally characterized by twin heterocyclic quinone skeletons and alpha-cyanoamine moiety. The binding of saframycin A to DNA was investigated using the antibiotic labeled at different positions. Heterocyclic quinone skeletons were biosynthetically labeled with [14C]tyrosine. The cyano residue of saframycin A was specifically labeled as a result of the reaction of [14C]cyanide with a derivative of saframycins, decyanosaframycin A, in the culture filtrate. When calf thymus DNA was incubated with [14C]tyrosine-labeled saframycin A in the presence of dithiothreitol, radioactivities were progressively recovered from DNA fraction. In contrast, saframycin A in the absence of dithiothreitol was completely devoid of reactivity toward DNA. When [14C]cyanide-labeled saframycin A was reacted with DNA, however, none of the radioactivity was associated with DNA. The release of cyano residue from the antibiotic was triggered by the reduction. Thus, conversion of quinone to hydroquinone skeletons as well as conversion of alpha-cyanoamine to immonium or alpha-carbinolamine is the consequence of the reduction. The fact that dithiothreitol-inducible binding of saframycin A to DNA was blocked by the addition of excess cyanide indicates that immonium or alpha-carbinolamine is the actual species involved in the interaction with DNA. The striking similarities between saframycin A and anthramycin in regard to the mode of binding to DNA are discussed.
沙弗霉素A是一种抗肿瘤抗生素，其结构特征为双杂环醌骨架和α-氰基胺部分。使用在不同位置标记的抗生素研究了沙弗霉素A与DNA的结合。杂环醌骨架用[14C]酪氨酸进行生物合成标记。沙弗霉素A的氰基残基通过[14C]氰化物与沙弗霉素衍生物脱氰沙弗霉素A在培养滤液中的反应而被特异性标记。当在二硫苏糖醇存在下将小牛胸腺DNA与[14C]酪氨酸标记的沙弗霉素A一起孵育时，放射性物质逐渐从DNA部分中回收。相反，在没有二硫苏糖醇的情况下，沙弗霉素A对DNA完全没有反应性。然而，当[14C]氰化物标记的沙弗霉素A与DNA反应时，没有任何放射性与DNA相关。抗生素中氰基残基的释放是由还原引发的。因此，醌向氢醌骨架的转化以及α-氰基胺向亚胺离子或α-氨基醇胺的转化是还原的结果。添加过量氰化物可阻断二硫苏糖醇诱导的沙弗霉素A与DNA的结合，这一事实表明亚胺离子或α-氨基醇胺是参与与DNA相互作用的实际物种。文中讨论了沙弗霉素A与安曲霉素在与DNA结合模式方面的显著相似性。
