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.