cis-Pt(NH₃)₂(GpG) Properties Interpreted through Comparison with Retro-Model GpG Adducts Having Carrier Ligands Designed to Slow Dynamic Motion and Control Cross-Link Handedness

Abstract

Cisplatin forms the cis-Pt(NH3)2(d(GpG)) intrastrand cross-link with DNA. Recently our experiments showed that the phosphodiester backbone can have a normal (1) or opposite (2) backbone propagation direction, leading to four conformer classes, HH1, HH2, ΔHT1, and ΛHT2, with the bases in either a head-to-head or head-to-tail orientation. In addition, since each G residue can be syn or anti and the base canting can be left (L) or right (R) handed, 32 variants of this cross-link are conceivable. Reported evidence supported the existence of only the two anti,anti HH1 variants, L in single strands and in cis-Pt(NH3)2(d(GpG)) and R in duplexes and in the ribo analogue, cis-Pt(NH3)2(GpG); in this regard, the latter is an excellent simple model of the DNA lesion. To test such interpretations, we used retro-model adducts (complexes with carrier ligands designed to slow dynamic motion in the d(GpG) cross-link). In retro-model d(GpG) adducts, anti,syn ΔHT1 L (5‘-G anti and 3‘-G syn) and anti,anti HH2 R variants have energy comparable to the previously known anti,anti HH1 variants; our work has led to the hypothesis that cis-Pt(NH3)2 adducts may actually be mixtures of conformers exchanging rapidly on the NMR time scale (Marzilli et al. J. Am. Chem. Soc. 1999, 121, 9133−9142). To test this hypothesis, we have now conducted NMR and CD spectroscopic studies of GpG adducts. Retro models containing the Bip (2, 2‘-bipiperidine) carrier ligand in two enantiomeric forms, (R,S,S,R)-Bip and (S,R,R,S)-Bip (N, C, C, and N chelate ring atoms having the respective R or S configurations), control, respectively, the R and L base canting direction. For low pH (both G N1H's still protonated), (R,S,S,R)-BipPt(GpG) is almost entirely anti,anti HH1 R, but (S,R,R,S)-BipPt(GpG) is a mixture of anti,anti HH1 L and anti,syn ΔHT1 L forms, both new low pH forms for a GpG adduct. This HT variant grew to dominance after ∼3 d at pH ∼10 (both G N1's deprotonated). By pH jump experiments, we obtained NMR and deconvoluted CD spectra of both L variants of (S,R,R,S)-BipPt(GpG) at low and high pH. Spectral features of these L variants are present in cis-Pt(NH3)2(GpG) spectra, suggesting that the anti,anti HH1 R variant is not exclusively present but that ∼30% of other variants are present; N1H deprotonation alters the distribution of forms as found also for retro models. The results suggest that the spectroscopic and structural properties for retro models are directly relevant to cisplatin adducts.

Rotamer Stability in cis‐[Pt(diA)G2] Complexes (diA=Diamine Derivative and G=Guanine Derivative) Mediated by Carrier‐Ligand Amine Stereochemistry as Revealed by Circular Dichroism Spectroscopy

“…However, the canting effect is second order, and CD spectra of HH rotamers are generally much less intense than those of HT rotamers. [26][27][28] [Pt(dach)(9-EtG) 2 ]…”

DNA fragment conformations in adducts with Kiteplatin

“…In this case there is quite an intense H8-H1′ crosspeak. The presence of a H8-H1′ cross-peak indicates either a partial syn character [58][59][60]64,91,94 for the 3′-G of the dominant conformer or, more likely, the existence of a minor ΔHT1 conformer in dynamic equilibrium with the dominant HH1 conformer. Such a dynamic equilibrium would explain the somewhat broad nature of the H8 signals, even at −5°C (Fig.…”

“…17,[46][47][48]53,55,59,64 The stereochemistry of the Bip carrier ligand influences both the conformer distribution and the cross-link handedness. For example, ((R,S,S,R)-Bip)Pt(d(GpG)) was shown to have two abundant right-handed conformers (HH1 R, HH2 R), and ((S,R,R,S)-Bip)Pt(d(GpG)) was shown to have two abundant lefthanded conformers (HH1 L, ΔHT1 L).…”

Ligands Rock & Roll: Stepwise Twisting of Two cis‐Coordinated Lopsided N‐Heterocycles in an Octahedral Bis(2‐phenylazopyridine)–Ruthenium(II) Complex with Seven Atropisomers

“…In cis-bisadducts of square-planar four-coordinate Pt II complexes with guanine derivatives, this phenomenon has been nominated the "dynamic motion problem", and to solve this problem Pt II complexes with large (backbone) ligand systems have been designed to increase the steric hindrance and lower the rotation speed of the ligands. [16,17,53] The dynamic motion problem of 1 is actually addressed by changing the sterical aspects of the (rotating) ligands instead of changing the ligand backbone, that is, by comparison of the data of 1 and 2. As the MeBim ligands in 2 are rotating rapidly around their RuÀN axes when just above room temperature, vide infra, it is reasonable to assume the smaller MeIm ligands also do so at this temperature.…”