Effects of Six-Membered-Ring Conformation on the Rotamer Distribution and Rate of Atropisomerization in Platinum(II)−Guanine Compounds:  2,4-Bis(methylamino)pentane Complexes

Abstract

NMR and CD spectroscopy and molecular mechanics and dynamics (MMD) calculations were used to characterize (Me2DAP)Pt(G)2 complexes (G = N9-substituted guanine derivative; Me2DAP = 2,4-bis(methylamino)pentane with N, C, C, and N stereochemistries of S,R,S,R, S,R,R,R, and R,R,R,R). NMR and MMD results indicated that the favored Me2DAP chelate ring conformations were chair. There are two possible head-to-tail rotamers (ΔHT and ΛHT) and, depending on the Me2DAP stereochemistry, one or two head-to-head (HH) rotamers. Rotation of the G bases around the Pt−N7 bond was found to be rapid on the NMR time scale for all compounds in D2O at room temperature; in contrast, slow rotation was reported for (Me2DAB)Pt(G)2 (Me2DAB = 2,3-bis(methylamino)butane by Xu et al.) Because of the additional flexibility of the six-membered chelate ring in the Me2DAP systems versus the five-membered ring in Me2DAB, the N-methyl groups of Me2DAP can occupy more pronounced axial positions, allowing a low-energy path to rotation as suggested by MMD calculations. The fast rotation necessitated that the rotamer preference be assessed by CD spectroscopy. For the S,R,S,R complexes, the G N9 substituent strongly influenced which HT rotamer was preferred. The ΛHT rotamer was favored for the R,R,R,R complexes at pH 3 regardless of the G used. MMD calculations on the [(R,R,R,R)-(Me2DAP)Pt(9-EtG)2]2+ complex suggested amine-O6 hydrogen bonding in the ΛHT rotamer and indicated an unfavorable nonbonded interaction between the G O6 and an axial cis C-methyl group in the ΔHT rotamer. This nonbonded interaction was also observed in calculated structures of the [(S,R,R,R)-(Me2DAP)Pt(9-EtG)2]2+ complex, for which experimental data showed a preference for the ΛHT rotamer as well. Thus, the orientations of the N- and C-methyl groups appear to be important in determining both the rate of rotation and the rotamer preference of the (Me2DAP)Pt(G)2 systems.

The First Pure ΛHT Rotamer of a Complex with a cis‐[Metal(nucleotide)2] Unit: A cis‐[Pt(amine)2(nucleotide)2] ΛHT Rotamer with Unique Molecular Structural Features

“…Structural models with both 5'-GMP nucleo-A C H T U N G T R E N N U N G tides in the anti conformation suggested that the 5'-phosphates are directed toward the cis amines in the DHT conformer and toward the cis nucleotide in the LHT conformer. Therefore, phosphate interactions with the cis amine (hydrogen-bond interaction) and with the platinum core (electrostatic interactions) will favor the DHT conformer, whereas phosphate interactions with the cis guanine (hydrogen-bond interaction with cis-5'-GMP N1H) [55][56][57][58] will favor the LHT conformer. However, even for those cases in which our choice of carrier ligand restricted the rotation about the PtÀN7 bond, these adducts are rendered very dynamic by rapid motions involving rotation about the N9 À C1' and the C4' À C5' bonds, and interchange among a very broad range of sugar puckers.…”

“…We employed neutral pH because the phosphate group is fully deprotonated, favoring hydrogen bonding and the LHT conformer. [55][56][57][58] With this strategy we were able to obtain, for the first time, crystals of a pure LHT rotamer, [bis(guanosine-5'-monophosphate(-2))-…”

Conformation of 2-Aminomethylpyrrolidine and 2-Aminomethylpiperidine in Ternary Platinum(II) Complexes: Regulation of Conformation of the Diamine by the Coexisting Ligand

“…In the case of the Pt(II) complexes with L 1 ϭpipda, the general feature is similar to those of the octahedral complexes with L 2 ϭ(NH 3 ) 2 or cbdca, the chemical shifts of H 7a and H 7e are reversed for L 2 ϭbpy or phen. Though the 13 C-NMR spectrum of [Pt(bpy)(pipda)] 2ϩ was reported two decades ago, 12) the resolution of the spectrum at that time was not sufficient to establish the condensation modes of the chelate ring and the piperidine ring. The authors assumed that the trans-fused structure for this chelate on the basis of a model.…”

“…11) Using NMR spectroscopy, a conformational study of platinum(II) complexes with pipda was undertaken two decades ago 12) and several studies using derivatives of its enantiomeric form have been reported recently in conjunction with the orientations of nucleosides that coordinate as the ligands. [13][14][15][16] For the platinum(II) complex with pyrda, several X-ray studies have also been reported. 17,18) However, the conformations of these diamines in metal complexes in solution and in the crystal state may not be the same.…”

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

“…These interactions have been grouped into three classes: FFC, SSC and FSC. [21][22][23] FFC (first-to-first sphere communication) involves internucleotide and nucleotide-amine interactions close to the metal center (e.g., the dipole-dipole interaction between cis-guanines, and hydrogen-bond formation between the guanine O6 atom and NÀ H of the cis-amine). SSC (second-to-second sphere communication) involves interactions far from the metal center and between cis-nucleotides (i.e., the hydrogen-bond interaction between the phosphate of a nucleotide and the N1 À H group of the cis-guanine).…”