Factors Influencing Conformer Equilibria in Retro Models of Cisplatin−DNA Adducts As Revealed by Moderately Dynamic (N,N‘-Dimethyl-2,3-diaminobutane)PtG₂ Retro Models (G = a Guanine Derivative)

Abstract

Typical cis-PtA(2)G(2) models of key DNA lesions formed by cis-type Pt anticancer drugs are very dynamic and difficult to characterize (A(2) = diamine or two amines; G = guanine derivative). Retro models have A(2) carrier ligands designed to decrease dynamic motion without eliminating any of three possible conformers with bases oriented head-to-tail (two: DeltaHT and LambdaHT) or head-to-head (one: HH). All three were found in NMR studies of eight Me(2)DABPtG(2) retro models (Me(2)DAB = N,N'-dimethyl-2,3-diaminobutane with S,R,R,S and R,S,S,R configurations at the chelate ring N, C, C, and N atoms, respectively; G = 5'-GMP, 3'-GMP, 5'-IMP, and 3'-IMP). The bases cant to the left (L) in (S,R,R,S)-Me(2)DABPtG(2) adducts and to the right (R) in (R,S,S,R)-Me(2)DABPtG(2) adducts. Relative to the case in which the bases are both not canted, canting will move the six-membered rings closer in to each other ("6-in" form) or farther out from each other ("6-out" form). Interligand interactions between ligand components near to Pt (first-first sphere communication = FFC) or far from Pt (second-sphere communication = SSC) influence stability. In typical cases at pH < 8, the "6-in" form is favored, although the larger six-membered rings of the bases are close. In minor "6-out" HT forms, the proximity of the smaller five-membered rings could be sterically favorable. Also, G O6 is closer to the sterically less demanding NH part of the Me(2)DAB ligand, possibly allowing G O6-NH hydrogen bonding. These favorable FFC effects do not fully compensate for possibly stronger FFC dipole effects in the "6-in" form. SSC, phosphate-N1H cis G interactions favor LambdaHT forms in 5'-GMP and 5'-IMP complexes and DeltaHT forms in 3'-GMP and 3'-IMP complexes. When SSC and FFC favor the same HT conformer, it is present at >90% abundance. In six adducts [four (S,R,R,S)-Me(2)DABPtG(2) and (R,S,S,R)-Me(2)DABPtG(2) (G = 3'-GMP and 3'-IMP)], the minor "6-out" HT form at pH approximately 7 becomes the major form at pH approximately 10, where G N1H is deprotonated, because the large distance between the negatively charged N1 atoms minimizes electrostatic repulsion and probably because the G O6-(NH)Me(2)DAB H-bond (FFC) is strengthened by N1H deprotonation. At pH approximately 10, phosphate-negative N1 repulsion is an unfavorable SSC term. This factor disfavors the LambdaHT R form of two (R,S,S,R)-Me(2)DABPtG(2) (G = 5'-GMP and 5'-IMP) adducts to such an extent that the "6-in" DeltaHT R form remains the dominant form even at pH approximately 10.

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

“…Crystallization of the LHT conformer could also be favored by utilizing neutral pH, at which the phosphates carry a double-negative charge and the LHT rotamer of 5'-GMP adducts has the highest stability relative to the DHT rotamer. [55,58] Under these conditions, the [Pt- 2 ] adduct gives a solution composition of about 75 % LHT and only 25 % DHT. This strategy proved to be successful and allowed us to grow X-ray-quality crystals containing the LHT conformer.…”

“…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))-…”

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).…”

“…Finally, FSC (first-to-second sphere communication) involves interactions between residues, one far from (nucleotide) and the other close to (cis-amine) the metal center (i.e., the hydrogen-bond interaction between the 5'-phosphate of a nucleotide and the NÀH group of the cis-amine). [23] We have focused on highly dynamic [Pt(dach)G 2 ] complexes. NMR spectroscopy is not useful for elucidating the interligand interactions due to fast interconversion between rotamers.…”