DNA binding of the anti-cancer platinum complex trans-[{Pt(NH3)2Cl}2μ-dpzm]2+

The DNA binding of the dinuclear platinum complex trans-[{Pt(NH3)2Cl}2μ-dpzm]2+ (di-Pt), linked with the 4,4′-dipyrazolylmethane (dpzm) linker, was examined by 1H and 195Pt NMR and transcription assays. At 60 °C, di-Pt reacts with guanosine two-fold slower (t1/2: 1 h) than cisplatin (t1/2: 0.5 h). With adenosine, the di-Pt complex reacts much slower (t1/2: 7 h) forming a range of different adducts through the N7 and either the N1 or N3 positions of the nucleoside. From 1H NMR analysis of the major product of the reaction of di-Pt with the oligonucleotide d(ATGCAT)2, purified by HPLC, it was determined that the dinuclear platinum complex can readily form a 1,2-GG interstrand DNA cross-link. Transcription assays using di-Pt and the lac UV5 promoter indicated that the metal complex forms an array of adducts vastly different from cisplatin. The two greatest blockages occurred at adenine residues, with possible interstrand and intrastrand AA and AG adducts being formed. These results indicate that unlike other platinum based anti-cancer agents, di-Pt binds to DNA with a preference for adenine bases.

[1]  J. Collins,et al.  Multi-nuclear platinum complexes as anti-cancer drugs , 2003 .

[2]  N. Farrell,et al.  Cooperative effects in long-range 1,4 DNA-DNA interstrand cross-links formed by polynuclear platinum complexes: an unexpected syn orientation of adenine bases outside the binding sites , 2002, JBIC Journal of Biological Inorganic Chemistry.

[3]  J. Collins,et al.  Thermal Rearrangement of N-Substituted Pyrazoles to 4,4'-Dipyrazolylmethane and 1,1,2-(4,4',4''-Tripyrazolyl)ethane , 2001 .

[4]  J. Collins,et al.  Synthesis, cytotoxicity, cell uptake and DNA interstrand cross-linking of 4,4'-dipyrazolylmethane-linked multinuclear platinum anti-cancer complexes. , 2001, Anti-cancer drug design.

[5]  J. Collins,et al.  The binding of [(en)Pt(mu-dpzm)2Pt(en)]4+ to G/C-rich regions of DNA. , 2001, Journal of inorganic biochemistry.

[6]  N. Farrell,et al.  Kinetic analysis of the stepwise formation of a long-range DNA interstrand cross-link by a dinuclear platinum antitumor complex: evidence for aquated intermediates and formation of both kinetically and thermodynamically controlled conformers. , 2001, Journal of the American Chemical Society.

[7]  J. Collins,et al.  Synthesis, DNA binding and cytotoxicity of isohelical DNA groove binding platinum complexes. , 2000, Anti-cancer drug design.

[8]  W. Denny,et al.  Transcriptional blockages in a cell-free system by sequence-selective DNA alkylating agents. , 2000, Chemico-biological interactions.

[9]  J. Collins,et al.  A 1H NMR study of the oligonucleotide binding of [(en)Pt(mu-dpzm)2Pt(en)]Cl4. , 2000, Journal of inorganic biochemistry.

[10]  C. Giandomenico,et al.  Current status of platinum-based antitumor drugs. , 1999, Chemical reviews.

[11]  S. Lippard,et al.  Structure, Recognition, and Processing of Cisplatin-DNA Adducts. , 1999, Chemical reviews.

[12]  C. Cullinane,et al.  Sequence specificity and reactivity of the binding of phenazine-tethered platinum complexes to DNA. , 1999, Anti-cancer drug design.

[13]  V. Brabec,et al.  DNA modifications by a novel bifunctional trinuclear platinum phase I anticancer agent. , 1999, Biochemistry.

[14]  W. Mcfadyen,et al.  Reactions of cisplatin and the cis-diamminediaqua platinum(II) cation with tris and hepes , 1997 .

[15]  Huifang Huang,et al.  Solution Structure of a Cisplatin-Induced DNA Interstrand Cross-Link , 1995, Science.

[16]  J. H. Boom,et al.  A novel DNA structure induced by the anticancer bisplatinum compound crosslinked to a GpC site in DNA , 1995, Nature Structural Biology.

[17]  W. Denny,et al.  The use of bidirectional transcription footprinting to detect platinum-DNA crosslinks by acridine-tethered platinum diamine complexes and cisplatin. , 1993, Nucleic acids research.

[18]  V. Saudek,et al.  Gradient-tailored excitation for single-quantum NMR spectroscopy of aqueous solutions , 1992, Journal of biomolecular NMR.

[19]  P. Fantucci,et al.  Electronic and geometrical structure of the pyrazole ligand co-ordinated to metal centres , 1992 .

[20]  N. Farrell,et al.  Interaction of bis(platinum) complexes with the mononucleotide 5'-guanosine monophosphate. Effect of diamine linker and the nature of the bis(platinum) complex on product formation , 1991 .

[21]  D. Patel,et al.  Sequence-dependent conformation of DNA duplexes. The AATT segment of the d(G-G-A-A-T-T-C-C) duplex in aqueous solution. , 1986, The Journal of biological chemistry.

[22]  L. Marzilli,et al.  Interaction of platinum antitumor agents with guanine nucleosides and nucleotides. Platinum-195 and proton NMR spectroscopic characterization of compound III , 1985 .

[23]  R. Kaptein,et al.  Sequential resonance assignments in 1H NMR spectra of oligonucleotides by two-dimensional NMR spectroscopy. , 1984, Biochemistry.

[24]  J. Feigon,et al.  Two-dimensional proton nuclear magnetic resonance investigation of the synthetic deoxyribonucleic acid decamer d(ATATCGATAT)2. , 1983, Biochemistry.

[25]  A. Gronenborn,et al.  Kinetic and structural studies on the intermediates formed in the reactions of 5'-adenosine monophosphate and 5'-guanosine monophosphate with cis-dichlorodiammineplatinum(II) using proton and platinum-195 magnetic resonance spectroscopy , 1982 .

[26]  S. Trofimenko.  The coordination chemistry of pyrazole-derived ligands , 1972 .