Exploring the Universality of Unusual Conformations of the 17-Membered Pt(d(G*pG*)) Macrochelate Ring. Dependence of Conformer Formation on a Change in Bidentate Carrier Ligand from an sp³to an sp²Nitrogen Donor

Abstract

Early studies on cis-PtA2(d(G*pG*)) (A2 = diamine or two amines, G* = N7-platinated G) and cis-Pt(NH3)2(d(G*pG*)) models for the key cisplatin−DNA cross-link suggested that they exist exclusively or mainly as the HH1 conformer (HH1 = head-to-head G* bases, with 1 denoting the normal direction of backbone propagation). These dynamic models are difficult to characterize. Employing carrier A2 ligands designed to slow dynamic interchange of conformers, we found two new conformers, ΔHT (head-to-tail G* bases with a Δ chirality) and HH2 (with 2 denoting the backbone propagation direction opposite to normal). However, establishing that the non-HH1 conformations exist as an intrinsic feature of the 17-membered Pt(d(G*pG*)) ring requires exploring a range of different carrier ligands. Here we employ the planar aromatic sp2 N-donor 5,5‘-Me 2 bipy (5,5‘-dimethyl-2,2‘-bipyridine) ligand, having a shape very different from those of previously used nonplanar sp3 N-donor bidentate carrier ligands, which often bear NH groups. The 5,5‘-Me 2 bipy H6 and H6‘ protons project toward the d(G*pG*) moiety and hinder the dynamic motion of 5,5‘-Me 2 bipyPt(d(G*pG*)). We again found HH1, HH2, and ΔHT conformers with typical properties, supporting the conclusions that the new ΔHT and HH2 conformers exist universally in dynamic cis-PtA2(d(G*pG*)) adducts, including cis-Pt(NH3)2(d(G*pG*)), and that the carrier ligand typically has little influence on the overall structure of the Pt(d(G*pG*)) macrocyclic ring of a given conformer. The sizes of the G* H8 to H6/H6‘ NOE cross-peaks indicate little base canting in all 5,5‘-Me 2 bipyPt(d(G*pG*)) conformers, suggesting that carrier-ligand NH groups favor the canting of one G* base in the HH1 and HH2 conformers of typical cis-PtA2(d(G*pG*)) adducts.

Single-Stranded Oligonucleotide Adducts Formed by Pt Complexes Favoring Left-Handed Base Canting: Steric Effect of Flanking Residues and Relevance to DNA Adducts Formed by Pt Anticancer Drugs

“…5,29,42,44 The similarity of the 31 P NMR resonance observed at À2.83 ppm ( Figure 5) to chemical shifts observed for (S,R,R,S)-BipPt(d(G*pG*)) 27 and other LPt(d(G*pG*)) adducts confirmed the HH1 conformer assignment. 5,26,29 For the less stable conformer (still abundant at 1 day), no H8ÀH8 NOE cross-peak was detected, indicating an HT arrangement of the G* bases. 5,27À29,42,44 The more downfield H8 signal (7.77 ppm) had a strong NOE cross-peak to a peak at 6.00 ppm, which showed NOE cross-peaks with signals at 2.65 and 3.31 ppm.…”

“…This downfield H2 0 shift has also been observed for the ΔHT1 3 0 -G* residue in many other adducts. 5,20,27,29,42,44 In the Results section, all solutions were at pH ≈ 4 unless otherwise noted. For each (S,R,R,S)-BipPt(oligo) complex, we present general conformer features found by 1D NMR spectroscopy ( 1 H and 31 P).…”

“…26À28 Minor shift variations (0.1À0.2 ppm) observed for H8 signals of the HH1 conformer as the carrier ligand changes can be attributed to secondary factors, such as carrier-ligand influence on the inductive effect of the Pt(II) center. 5,44 Comparison of the G* H8 shifts of the (S,R,R,S)-BipPt(oligo) adducts to those of the parent (S,R,R,S)-BipPt(d(G*pG*)) adduct (Table 1 and Figure 9) is the standard approach for assessing the influence of the flanking residue type (phosphate group or complete T residue) or the length of the flanking nucleotide chain (T or TTT) on base canting of the HH1 conformer. We must factor out the relative contribution of through-space anisotropic effects of flanking residues on the G* H8 shifts.…”

Solution Structures of a DNA Dodecamer Duplex with and without a Cisplatin 1,2-d(GG) Intrastrand Cross-Link: Comparison with the Same DNA Duplex Containing an Oxaliplatin 1,2-d(GG) Intrastrand Cross-Link,

“…The difference in the chemical shift of the G7 H8 proton is particularly interesting because it could theoretically arise from a difference in the canting of the 3′ G residue in relation to the 5′ G residue for the OX-GG and CP-GG adducts. The degree of base canting for both the 5′ and 3′ G residues was determined by measuring the C5-N7-Pt-cis N and C8-N7-Pt-cis N dihedral angles (48) (Table S4 of the Supporting Information). However, no significant differences were observed in these dihedral angles for the OX-GG and CP-GG adducts.…”

1H, 13C, 195Pt and 15N NMR structural correlations in Pd(II) and Pt(II) chloride complexes with various alkyl and aryl derivatives of 2,2′‐bipyridine and 1,10‐phenanthroline

“…In this work we present the 1 H, 13 C, 15 N and 195 Pt NMR spectra of analogous Pd(II) and Pt(II) chloride complexes with some other alkyl and aryl derivatives of bpy and phen (LL): 6,6 -dimethyl-bpy (6,6 -dmbpy), 5,5 -dimethyl-bpy (5,5 -dmbpy), 4,4 -di-tert-butylbpy (4,4 -dbbpy), 2,9-dimethyl-phen (2,9-dmphen), 2,9-dimethyl-4,7-diphenyl-phen (2,9-dm-4,7-dpphen), 3,4,7,8-tetramethyl-phen (3,4,7,8- . Some of them were already studied by 1 H and/or 13 C NMR (1a, [10,11] 2a, [2] 3a, [12 -15] 4a, [16,17] 5a, [18] 1b, [10] 2b, [19] 3b, [1,20 -26] 4b, [17,27,28] 5b, [28] 6b [22,28] ) (Table S1, Supporting Information); however, no systematic comparison of their 1H coord and 13C coord coordination shifts ( coord = δ complex − δ ligand ) was performed. The 15 N and 195 Pt NMR spectra of the title complexes were never reported (although the former were published for the related organometallics: [Pd(2,9-dmphen )(bis(anisylimino)acenapthene)(CH 3 …”