Fixing the conformations of diamineplatinum(II)-GpG chelates: NMR and CD signatures of individual rotamers

Abstract

The bulky, asymmetric analog of the antitumor drug cisplatin, [PtCl(2)(tmen)] (tmen = N,N,N'-trimethylethylenediamine), was used to produce crosslinks with the dinucleotide d(GpG), modeling the most frequent lesions that cisplatin and its analogs cause to DNA. The ligand tmen was chosen because it is expected to constrain the guanine cis to the NMe(2) group in the adduct [Pt(tmen){d(GpG)}](+) to an orientation perpendicular to the coordination plane and to stabilize the other guanine in an oblique orientation, thus maintaining a head-to-head geometry typical of cisplatin-d(GpG) crosslinks within single- and double-stranded DNA. Of the four possible combinations of tmen chirality (R or S symmetry of the coordinated NHMe group) and crosslink direction (5'-G bound cis to the secondary or the tertiary amino group of tmen), two isomers were preponderantly formed, [Pt(R-tmen){d(GpG)}](+) with 5'-G bound cis to NMe(2) and [Pt(S-tmen){d(GpG)}](+) with 5'-G bound cis to NHMe. The former was shown to have a right-handed R2 orientation of guanines similar to that found in duplex DNA, whereas the latter had a left-handed L1 orientation that modeled cisplatin-d(GpG) adducts within single-stranded DNA. The R2 rotamer was found to be in an equilibrium (as observed using EXSY spectroscopy) with a minor fraction (< or =4%) of a Delta-HT rotamer related to R2 by rotation of the 3'-G about the Pt-N7 bond. The major rotamers R2 and L1 were isolated using reverse-phase HPLC, and their NMR and CD signatures were compared to those of the corresponding rotamers of the less hindered adduct [Pt(dmen)(GpG)](+) (dmen = N,N-dimethylethylenediamine). From this and other comparisons with previously reported platinum dinucleotide complexes, and from molecular modeling, it could be concluded that both steric repulsion between guanine and substituents of the cis amino group and N-H...O6 hydrogen bonding are significant effects favoring the oblique orientation of one guanine base typical of the HH rotamers of [Pt(diamine){d(GpG)}](+) and [Pt(diamine)(GpG)](+) complexes.

Cisplatin Adducts on a GGG Sequence within a DNA Duplex Studied by NMR Spectroscopy and Molecular Dynamics Simulations

“…The influence of such hydrogen bonding on the structure of the adduct and its eventual role in anticancer activity has been a recurrent issue of debate (refs. [4,29,44,45], and references therein). In the crystal structure of a cisplatin-bound DNA dodecamer, for instance, the 5'-oriented NH 3 ligand is hydrogen-bonded to the phosphodiester group at the 5'-side.…”

“…A similar 31 P downfield shift for was found for dsCG*G*A [8] and is a common feature of pyG*G*-platinated duplexes. [1] We have discussed the origin of this downfield shift previously [29] and pointed out that the a and g torsion angles of the 3'-guanosine are likely to populate significantly the trans conformation as a consequence of the platinum cross-link. A switch of the a torsion angle from the canonical g À conformation to trans could explain the downfield shift of the G* 4 pG* 5 phosphorus NMR spectroscopic signal.…”

“…[29] During our MD simulation, this step remained in the canonical a À b t g + conformation throughout. This does not, however, rule out low-lying alternative conformations such as a t b t g t , since the energy barrier for such a/g transitions is known to be relatively high, [32] and would not necessarily appear in a 20 ns simulation.…”

Complexes of dichloro(ethylenediamine)palladium(II) observed from aqueous solutions by electrospray mass spectrometry

“…The hydrolytic products are also strongly linked to issues of renal toxicity [10]. The mechanisms of action for these coordination complexes are closely tied to their hydrolysis products, and these products and mechanisms are poorly understood, partly due to the possibility of multiple equilibria with similar energetics [11,12]. It is for these reasons that coordination complexes of Ni(II), Pd(II), and Pt(II) in aqueous solutions have been the focus of a number of investigations [13][14][15][16][17].…”

DNA fragment conformations in adducts with Kiteplatin

“…A similar explanation for changes in shift has been proposed by Kozelka et al for the (N,N,N′-trimethylethylenediamine)Pt(d(GpG)) adduct. 93 Thus, the spectral changes observed for the (cis-1,4-DACH)Pt-(d(GpG)) adduct can be rationalized by the presence of two dominant conformers, HH1 and ΔHT1, in rapid interconver- sion at high temperature and by a decrease in the rate of interconversion and a change in the equilibrium composition greatly favouring the HH1 conformer upon lowering the temperature. However, a small abundance of the ΔHT1 conformer in moderately fast exchange with the HH1 conformer cannot be ruled out because this situation will not significantly broaden the HH1 H8 signals, and broad, weak ΔHT1 signals would escape detection.…”