Interaction of cis-diaquodiammineplatinum dinitrate with ribose dinucleoside monophosphates

Skilandat

Metal Ions in Life Sciences

et al. 2012

Cadmium(II), commonly classified as a relatively soft metal ion, prefers indeed aromaticnitrogen sites (e.g., N7 of purines) over oxygen sites (like sugar-hydroxyl groups). However, matters are not that simple, though it is true that the affinity of Cd(2+) towards ribose-hydroxyl groups is very small; yet, a correct orientation brought about by a suitable primary binding site and a reduced solvent polarity, as it is expected to occur in a folded nucleic acid, may facilitate metal ion-hydroxyl group binding very effectively. Cd(2+) prefers the guanine(N7) over the adenine(N7), mainly because of the steric hindrance of the (C6)NH(2) group in the adenine residue. This Cd(2+)-(N7) interaction in a guanine moiety leads to a significant acidification of the (N1)H meaning that the deprotonation reaction occurs now in the physiological pH range. N3 of the cytosine residue, together with the neighboring (C2)O, is also a remarkable Cd(2+) binding site, though replacement of (C2)O by (C2)S enhances the affinity towards Cd(2+) dramatically, giving in addition rise to the deprotonation of the (C4)NH(2) group. The phosphodiester bridge is only a weak binding site but the affinity increases further from the mono-to the di-and the triphosphate. The same also holds for the corresponding nucleotides. Complex stability of the pyrimidine-nucleotides is solely determined by the coordination tendency of the phosphate group(s), whereas in the case of purine-nucleotides macrochelate formation takes place by the interaction of the phosphate-coordinated Cd(2+) with N7. The extents of the formation degrees of these chelates are summarized and the effect of a non-bridging sulfur atom in a thiophosphate group (versus a normal phosphate group) is considered. Mixed ligand complexes containing a nucleotide and a further mono-or bidentate ligand are covered and it is concluded that in these species N7 is released from the coordination sphere of Cd(2+). In the case that the other ligand contains an aromatic residue (e.g., 2,2'-bipyridine or the indole ring of tryptophanate) intramolecular stack formation takes place. With buffers like Tris or Bistris mixed ligand complexes are formed. Cd(2+) coordination to dinucleotides and to dinucleoside monophosphates provides some insights regarding the interaction between Cd(2+) and nucleic acids. Cd(2+) binding to oligonucleotides follows the principles of coordination to its units. The available crystal studies reveal that N7 of purines is the prominent binding site followed by phosphate oxygens and other heteroatoms in nucleic acids. Due to its high thiophilicity, Cd(2+) is regularly used in so-called thiorescue experiments, which lead to the identification of a direct involvement of divalent metal ions in ribozyme catalysis.

Section: Dinucleoside Monophosphatesmentioning

confidence: 99%

Complex Formation of Cadmium with Sugar Residues, Nucleobases, Phosphates, Nucleotides, and Nucleic Acids

Skilandat

Metal Ions in Life Sciences

et al. 2012

“…In RNA and DNA fragments, the cisPt-(NH& moiety can bind to two bases of the same strand [I91 (and references therein). The feasibility of such cross-links between two adjacent guanines has been established for r(G-G) [3,5], d(G-G) [8], d(C-C-G-G) [7] and recently for d(A-G-G-C-C-T) [12] and d(T-G-G-C-C-A) [13]. It has also been supported by the results of several studies with various DNAs, using enzymatic restriction techniques [20 -231.…”

mentioning

confidence: 99%

DNA fragment conformations. A 1H-NMR conformational analysis of the d(G-G)-chelated platinum-oligonucleotide d(A-T-G-G)cisPt

Neumann¹,

Tran-Dinh²,

Girault

et al. 1984

Eur J Biochem

The conformation of d(A‐T‐G‐G) and d(A‐T‐G‐G)cisPt has been investigated by 1H‐NMR at 500 MHz and 90 MHz under various experimental conditions of temperature and concentration. Analysis of the coupling constants between the deoxyribose protons shows that all the sugar rings of d(A‐T‐G‐G) adopt the S(C2′‐endo) conformation most of the time. By contrast, in the platinated tetramer, d(A‐T‐G‐C)cisPt, the N(C3′‐endo) conformation is highly predominant for the internal dG residue while the S(C2′‐endo) conformation is largely favoured for the other residues as in the case of the unplatinated compound. The relaxation time and nuclear Overhauser effect measurements indicate that the orientation of the two guanines of d(A‐T‐G‐G)cisPt is anti in agreement with the previous results obtained for the dimers: r(G‐G)cisPt, d(G‐G)cisPt. On lowering the temperature from 80° to 20 °C, several proton resonances of d(A‐T‐G‐G)cisPt exhibit large chemical shift and linewidth variations. The most spectacular temperature effect was observed for the internal dG(H1′) and dT(H4′) protons. All the Δ=f(t) curves display a sigimoid form with the same mid‐point temperature of 44 ± 2 °C. This mid‐point temperature together with the observed chemical shift and linewidth variations were found to be independent of the d(A‐T‐G‐G)cisPt concentration. These results suggest that d(A‐T‐G‐G)cisPt can adopt two different conformations depending on the temperature. The enthalpy for the transition between the high and low temperature conformations is about 84 kJ/mol.

Arch. Pharm. Pharm. Med. Chem.

“…In vitro studies of DNA platinated by cDDP show that a strong preference exists for binding to sequences containing two or more adjacent guanosine nucleosides, and that among the detected crosslinks those of d(GpG) and d(ApG) (in the ratio of about 3:1) prevail. The structure of the predominant d(GpG) platinum adduct and its impact on the DNA conformation were studied by proton NMR spectroscopy and X-ray analysis on the example of the cDDP derivative [20][21][22][23][24] . The conformational changes result in an inhibition of DNA replication [17][18][19] and of transcription of essential genes [25,26] , which seems to be the major cause of the antitumor activity of platinum(II) complexes which contain simple neutral ligands like those in cDDP.…”

Section: -----------------------------mentioning

confidence: 99%

[meso-1,2-Bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]sulfato-platinum(II) — Pharmacokinetic Studies

Bernhardt¹,

Koch²,

Spruß³

et al. 1999

The maximally attainable level of the non‐plasma protein bound fraction of a single 10.0 μmol/kg i.p. dose of [meso‐1,2‐bis(2,6‐di‐chloro‐4‐hydroxyphenyl)ethylenediamine]sulfatoplatinum(II), a drug active on the murine, hormone‐sensitive MXT‐M‐3.2 breast cancer, lies markedly below the concentration causing a significant cytotoxic effect on a cell line derived from this tumor. This result confirms our opinion that the strong in vivo activity of this drug on hormone‐sensitive breast cancers is mediated by its estrogenic potency by analogy with high dosed steroidal and non‐steroidal estrogens. A specific cytotoxic effect utilizing the estrogen receptor as carrier, as formerly postulated, is unlikely.