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)

Academic Article


  • Typical cis-PtA2G2 models of key DNA lesions formed by cis-type Pt anticancer drugs are very dynamic and difficult to characterize (A2 = diamine or two amines; G = guanine derivative). Retro models have A2 carrier ligands designed to decrease dynamic motion without eliminating any of three possible conformers with bases oriented head-to-tail (two: ΔHT and ΔHT) or head-to-head (one: HH). All three were found in NMR studies of eight Me2DABPtG2 retro models (Me2DAB = 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)-Me2DABPtG2 adducts and to the right (R) in (R,S,S,R)-Me2DABPtG2 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 06 is closer to the sterically less demanding NH part of the Me2DAB 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 ΔHT forms in 5′-GMP and 5′-IMP complexes and ΔHT 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)-Me2DABPtG2 and (R,S,S,R)-Me2DABPtG2 (G = 3′-GMP and 3′-IMP)], the minor "6-out" HT form at pH ∼7 becomes the major form at pH ∼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)Me2DAB H-bond (FFC) is strengthened by N1H deprotonation. At pH ∼10, phosphate-negative N1 repulsion is an unfavorable SSC term. This factor disfavors the ΔHT R form of two (R,S,S,R)-Me2DABPtG2 (G = 5′-GMP and 5′-IMP) adducts to such an extent that the "6-in" ΔHT R form remains the dominant form even at pH ∼10.
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    Author List

  • Saad JS; Scarcia T; Natile G; Marzilli LG
  • Start Page

  • 4923
  • End Page

  • 4935
  • Volume

  • 41
  • Issue

  • 19