Conformational analysis of the adductcis[Pt(NH₃)₂{d(GpG)}]⁺in aqueous solution. A high field (500–300 MHz) nuclear magnetic resonance investigation

Abstract

A 500, 400 and 300 MHz proton NMR study of the reaction product of cis-Pt(NH3)2Cl2 or cis-[Pt(NH3)2 (H2O)2] (NO3)2 with the deoxydinucleotide d(GpG): cis-[Pt(NH3)2 d(GpG)] was carried out. Complete assignment of the proton resonances by decoupling experiments and computer simulation of the high field part of the spectrum yield proton-proton and proton-phosphorus coupling constants of high precision. Analysis of these coupling constants reveal a 100% N (C3'-endo) conformation for the deoxyribose ring at the 5'-terminal part of the chelated d(GpG) moiety. In contrast, the 3'-terminal -pG part of the molecule displays the normal behaviour for deoxyriboses: the sugar ring prefers to adopt an S (C2'-endo) conformation (about 70%). Extrapolating from this model compound, it is suggested that Pt chelation by a -dGpdG- sequence of DNA would require a S to N conformational change of one deoxyribose moiety as the main conformational alteration and lead to a kink in one strand of the double-helical structure of DNA.

Formation and structure of reaction products of cis‐PtCl2(NH3)2 with d(ApG) and/or d(GpA) in di‐, tri‐ and penta‐nucleotides

“…However, a similar extra downfield shift of H8 of the 3' guanine was also observed in going from N7,N7-anti,anti-platinated d(GpG) [15] to the larger fragments d(pGpG) [34], d(CpGpG) [41] and…”

Synthetic Metallomolecules as Agents for the Control of DNA Structure

“…One application of NOESY was to show that the X-ray detected DNA conformational changes induced by cisplatin 15 were consistent with the behaviour observed when 560 in solution. Assignment of the proton resonances were used to inform molecular dynamics simulations, from which was elucidated proton-proton and proton-phosphorus coupling constants.…”

“…2.3.1) whilst seeking to understand the binding modes of the genre of platinum-based anti-tumour agents that were beginning to emerge. 15 Another class of potential metallo intercalators is cationic porphyrins which combine readily with metal centres in their central cavity 425 and exhibit a strong binding affinity for DNA. There have been three binding methods described in the literature for such molecules( references within 35 ): self-induced external autoaggregation along the DNA helix axis, binding in either the major or minor groove of DNA and intercalation between 430 base pairs.…”

“…In 1868 Miescher 1 first isolated cell nuclei from pus cells and observed the presence of a phosphorus-containing 15 compound. The resulting nucleic acids were found on hydrolysis to yield the purine bases: adenine and guanine and the pyrimidine bases: thymine and cytosine ( Fig.…”

“…2.2.1.2). 15 The first indication that cis-platin causes such a distortion was the crystal structure for the major cis-platin-DNA adduct, cis-[Pt(NH 3 ) 2 {d(pGpG)}], obtained in 1988 16 which showed the platinum metal centre co-ordinated in a square planar mode 180 to two cis ammine ligands and two guanine N7 atoms, in a manner that caused unstacking of the guanines. 16 The concomitant bending and local unwinding of the DNA double helix caused by platinum binding are important structural motifs; in recognition and differential processing 185 of damaged DNA by repair enzymes or alternatively the binding of proteins which protect the lesion from repair  as in the case of cis-platin.…”