Cis-Pt(NH3)2Cl2 and related compounds are among the most promising anti-tumor drugs developed recently. This drug, which has been shown to be active against a wide range of tumors, is currently undergoing Phase II clinical tests at the National Cancer Institute and several hospitals. The action of cis-Pt(NH3)2Cl2 is believed to lie in the drug's apparent ability to suppress DNA replication. The actual mode of molecular interaction is not precisely known, but is believed to involve the formation of interstrand or intrastrand cross-links within a DNA molecule. Many theories of the Pt/DNA interaction have been proposed; most involve the formation of strong covalent bonds between platinum and certain nitrogen atoms of the purines. In order to get a better appreciation for the molecular nature of DNA/Pt interaction, we feel that it is essential to first know these structural details at a more basic level; i.e., at the nucleotide or oligonucleotide level. We therefore propose to prepare and determine the structures of various Pt-nucleotide and Pt-oligonucleotide complexes by X-ray diffraction methods. The Pt-dinucleotide complexes in particular should be extremely useful as models for testing the feasibility of intrastrand cross-link formation across two adjacent bases of a DNA strand.
| Choi, H K; Huang, S K; Bau, R (1988) Octahedral complexes of anti-cancer Pt(IV)(cyclohexyldiamine) agents with 9-methylguanine. Biochem Biophys Res Commun 156:1125-9 |
| Choi, H K; Terzis, A; Stevens, R C et al. (1988) Reaction products of a new anti-cancer agent, Pt(IV)(cyclohexyldiamine)Cl4, with guanosine and 9-methylguanine: first crystal structures of Pt(cyclohexyldiamine) complexes with a nucleobase and a nucleoside. Biochem Biophys Res Commun 156:1120-4 |
