Basic coordination chemistry relevant to DNA adducts formed by the cisplatin anticancer drug. NMR studies on compounds with sterically crowded chiral ligands

Academic Article


  • Me4DABPtG2 adducts with the bulky C 2-symmetric chiral diamine, Me4DAB (N,N,N′,N′- tetramethyl-2,3-diaminobutane with R,R and S,S configurations at the chelate ring C atom, G = guanine derivative), exhibit slow conformer interchange and are amenable to characterization by NMR methods. The investigation of the cis-PtA2G2 adducts formed by clinically widely used anticancer drugs [A2 = diaminocyclohexane, (NH3) 2] is impeded by the rapid conformer interchange permitted by the low A2 bulk near the inner coordination sphere. Me 4DABPtG2 adducts exist as a mixture of exclusively head-to-tail (HT) conformers. No head-to-head (HH) conformer was observed. The Me4DAB chirality significantly influences which HT chirality is favored (ΔHT for S,S and ΛHT for R,R). For simple G ligands, the ratio of favored HT conformer to less favored HT conformer is ∼2:1. For guanosine monophosphate (GMP) ligands, the phosphate group cis G N1H hydrogen bonding favors the ΛHT and the ΔHT conformers for 5′-GMP and 3′-GMP adducts, respectively. For both HT conformers of cis-PtA 2G2 adducts, the G nucleobase plane normally cants with respect to the coordination plane in the same direction, left or right, for a given A2 chirality. In contrast, the results for Me 4DABPtG2 adducts provide the first examples of a change in the canting direction between the two HT conformers; this unusual behavior is attributed to the fact that canting always gives long G O6 to N-Me distances and that these Me4DAB ligands have bulk both above and below the coordination plane. These results and ongoing preliminary studies of Me 4DABPt adducts with G residues linked by a phosphodiester backbone, which normally favors HH conformers, all indicate that a high percentage of HT conformer is present. Collectively, these findings advance fundamental concepts in Pt-DNA chemistry and may eventually help define the role of the carrier-ligand steric effects on anticancer activity. © 2010 American Chemical Society.
  • Digital Object Identifier (doi)

    Author List

  • Saad JS; Benedetti M; Natile G; Marzilli LG
  • Start Page

  • 5573
  • End Page

  • 5583
  • Volume

  • 49
  • Issue

  • 12