Zhang H, Gao Y G, van der Marel G A, van Boom J H, Wang A H
Division of Biophysics, University of Illinois, Urbana-Champaign 61801.
J Biol Chem. 1993 May 15;268(14):10095-101.
Anthracycline antibiotics (notably daunorubicin (DAU) and doxorubicin (DOX)) and nucleoside analog arabinosylcytosine (araC or aC) are important anticancer drugs. They are sometimes used together in the treatment of certain cancers. Both classes of compounds act by blocking DNA replication and transcription. To probe whether both drugs can be incorporated simultaneously into DNA and the possible structural consequences, we carried out x-ray diffraction analyses of the complexes between DAU/DOX and araC-containing DNA hexamers cross-linked with formaldehyde. The crystal structures were determined to high resolution (DAU-CGaCGCG, 1.2 A, space group P4(1)2(1)2, R = 0.182, 3275 reflections; DOX-CAaCGTG, 1.5 A, space group C2, R = 0.175, 3359 reflections), and they are similar to those of the previously studied DAU- and DOX-DNA complexes, despite different crystal packings. Two DAU/DOX molecules intercalate at both ends of the helix with their amino sugars in the minor groove. As in the structure of DAU-CGCGCG (Wang, A.H.-J., Gao, Y.-G., Liaw, Y.-C., and Li, Y.K. (1991) Biochemistry 30, 3812-3815), a covalent methylene bridge (from formaldehyde) between the N3' of daunosamine and the N2 of the guanine is formed in both adducts. In DOX-CAaCGTG, the two halves are slightly different with a root-mean-square deviation of 0.322 A between them. The O14 hydroxyls of the intercalated DOXs are within hydrogen bond distances to the O2P atoms of the A2p(aC3) and A8p(AC9) steps. The O2'-hydroxyl group from araC does not affect the binding of DAU-DOX or the conformation of the drug-DNA complexes. The results suggest that three major drug modifications on DNA, i.e., intercalation, covalent bond formation, and nucleoside analog incorporation, can coexist in the same DNA molecule without difficulty. When they occur in close proximity in DNA, they may provide an additive inhibitory effect for the target enzymes.
蒽环类抗生素（尤其是柔红霉素（DAU）和阿霉素（DOX））以及核苷类似物阿糖胞苷（araC或aC）是重要的抗癌药物。它们有时联合用于某些癌症的治疗。这两类化合物均通过阻断DNA复制和转录发挥作用。为探究这两种药物是否能同时掺入DNA以及可能产生的结构后果，我们对DAU/DOX与经甲醛交联的含araC的DNA六聚体之间的复合物进行了X射线衍射分析。测定了晶体结构的高分辨率数据（DAU-CGaCGCG，1.2 Å，空间群P4(1)2(1)2，R = 0.182，3275个反射；DOX-CAaCGTG，1.5 Å，空间群C2，R = 0.175，3359个反射），尽管晶体堆积不同，但它们与先前研究的DAU-和DOX-DNA复合物的结构相似。两个DAU/DOX分子以其氨基糖位于小沟的方式插入螺旋两端。与DAU-CGCGCG的结构（Wang, A.H.-J., Gao, Y.-G., Liaw, Y.-C., and Li, Y.K. (1991) Biochemistry 30, 3812 - 3815）一样，在两种加合物中均形成了柔红糖胺的N3'与鸟嘌呤的N2之间的共价亚甲基桥（来自甲醛）。在DOX-CAaCGTG中，两半结构略有不同，它们之间的均方根偏差为0.322 Å。插入的DOX的O14羟基与A2p(aC3)和A8p(AC9)步的O2P原子处于氢键距离内。araC的O2'-羟基不影响DAU-DOX的结合或药物-DNA复合物的构象。结果表明，DNA上的三种主要药物修饰，即插入、共价键形成和核苷类似物掺入，可以在同一DNA分子中顺利共存。当它们在DNA中紧密相邻出现时，可能对靶酶产生累加抑制作用。
