Silverman Adam P, Bu Weiming, Cohen Seth M, Lippard Stephen J
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
J Biol Chem. 2002 Dec 20;277(51):49743-9. doi: 10.1074/jbc.M206979200. Epub 2002 Oct 10.
cis-trans-cis-Ammine(cyclohexylamine)diacetatodichloroplatinum(IV) is an oral analog of the platinum anti-cancer drug cisplatin that is currently in phase III clinical trials. Its active form, [Pt(ammine)(cyclohexylamine)]2+, binds to DNA similarly to cisplatin, forming intra- and interstrand cross-links between adjacent purine bases. Since [Pt(ammine)(cyclohexylamine)]2+ contains two different ligands, it can form two isomeric 1,2-d(GpG) intrastrand cross-links. Here we report the 2.4-A resolution x-ray crystal structure of the major adduct between [Pt(ammine)(cyclohexylamine)]2+ and a DNA dodecamer, using the same sequence as previously reported for crystal structures of cisplatin-DNA (Takahara, P. M., Rosenzweig, A. C., Frederick, C. A., and Lippard, S. J. (1995) Nature 377, 649-652) and oxaliplatin-DNA (Spingler, B., Whittington, D. A., and Lippard, S. J. (2001) Inorg. Chem. 40, 5596-5602). Both duplexes in the asymmetric unit contain 1,2-intrastrand cross-links in which the cyclohexylamine ligand is directed toward the 3'-end of the platinated strand. The chair conformation of the cyclohexyl group is clearly resolved. Platination distorts the duplex, resulting in a global bend angle of about 38(o) and a dihedral angle between platinated guanine bases of approximately 31(o). Both end-to-end and end-to-groove packing interactions occur in the crystal lattice, the latter positioned in the minor groove across from the site of the platinum cross-link. A high degree of homology observed between this structure and the previously reported platinum-DNA structures suggests that these platinum complexes distort the DNA duplex in a very similar manner. These results suggest that differences in activity between these drugs are unlikely to result from gross conformational distortions in DNA structure following platinum intrastrand cross-link formation.
顺-反-顺-氨（环己胺）二乙酸二氯铂（IV）是铂类抗癌药物顺铂的口服类似物，目前正处于III期临床试验阶段。其活性形式[Pt（氨）（环己胺）]2+与顺铂类似地与DNA结合，在相邻嘌呤碱基之间形成链内和链间交联。由于[Pt（氨）（环己胺）]2+包含两种不同的配体，它可以形成两种异构的1,2-d（GpG）链内交联。在此，我们报道了[Pt（氨）（环己胺）]2+与DNA十二聚体之间主要加合物的2.4埃分辨率X射线晶体结构，使用的序列与先前报道的顺铂-DNA（Takahara，P.M.，Rosenzweig，A.C.，Frederick，C.A.，和Lippard，S.J.（1995）Nature 377，649-652）和奥沙利铂-DNA（Spingler，B.，Whittington，D.A.，和Lippard，S.J.（2001）Inorg.Chem.40，5596-5602）晶体结构相同。不对称单元中的两条双链都包含1,2-链内交联，其中环己胺配体指向铂化链的3'-末端。环己基的椅式构象清晰可辨。铂化使双链扭曲，导致全局弯曲角度约为38°，铂化鸟嘌呤碱基之间的二面角约为31°。在晶格中发生了端到端和端到沟的堆积相互作用，后者位于铂交联位点对面的小沟中。该结构与先前报道的铂-DNA结构之间观察到的高度同源性表明，这些铂配合物以非常相似的方式扭曲DNA双链。这些结果表明，这些药物之间活性的差异不太可能是由于铂链内交联形成后DNA结构中的总体构象扭曲所致。
