Wang A H, Gao Y G, Liaw Y C, Li Y K
Department of Physiology and Biophysics, University of Illinois, Urbana-Champaign 61801.
Biochemistry. 1991 Apr 23;30(16):3812-5. doi: 10.1021/bi00230a002.
Formaldehyde (HCHO) cross-links the anticancer drug daunorubicin (DAU) to DNA efficiently. When DAU is mixed with DNA hexamers, d(CGCGCG) and d(CGTDCG), in the presence of HCHO, stable covalent adducts of DNA are formed, as shown by the HPLC analyses. The major adducts are identical with the materials in the respective crystals which can be readily obtained from the 1:1 mixture of DAU-d(CGCGCG) and DAU-d(CGTDCG) plus HCHO, but not from the solution without HCHO. The high-resolution (1.5 A) X-ray crystal structure of those adducts shows unambiguously that they contain a covalent methylene bridge between the N3' of daunosamine and the N2 of the guanine or 2-aminoadenine. The perfect juxtaposition of the two amino groups in the minor groove of the complex provides a template for an efficient addition of HCHO. The methylene bridge does not perturb the conformation of the drug-DNA complex, when compared to the structure of DAU-d(CGTACG). The results suggest new approaches for synthesizing a new type of potential anticancer drug by attaching a reactive (e.g., alkylating) functional group at the N3' amino position of daunorubicin/doxorubicin. The stable drug-DNA adduct may be useful as probes for other biological studies.
甲醛（HCHO）能有效地将抗癌药物柔红霉素（DAU）与DNA交联。当在HCHO存在的情况下，将DAU与DNA六聚体d（CGCGCG）和d（CGTDCG）混合时，通过高效液相色谱分析表明，会形成稳定的DNA共价加合物。主要加合物与各自晶体中的物质相同，这些晶体可以很容易地从DAU - d（CGCGCG）和DAU - d（CGTDCG）加HCHO的1:1混合物中获得，但不能从没有HCHO的溶液中获得。这些加合物的高分辨率（1.5埃）X射线晶体结构明确显示，它们在柔红糖胺的N3'与鸟嘌呤或2 - 氨基腺嘌呤的N2之间含有一个共价亚甲基桥。复合物小沟中两个氨基的完美并列提供了一个高效添加HCHO的模板。与DAU - d（CGTACG）的结构相比，亚甲基桥不会干扰药物 - DNA复合物的构象。结果表明了通过在柔红霉素/阿霉素的N3'氨基位置连接一个反应性（如烷基化）官能团来合成新型潜在抗癌药物的新方法。这种稳定的药物 - DNA加合物可能作为其他生物学研究的探针有用。
