Basic coordination chemistry relevant to DNA adducts formed by the cisplatin anticancer drug. NMR studies on compounds with sterically crowded chiral ligands.
Me(4)DABPtG(2) adducts with the bulky C(2)-symmetric chiral diamine, Me(4)DAB (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-PtA(2)G(2) adducts formed by clinically widely used anticancer drugs [A(2) = diaminocyclohexane, (NH(3))(2)] is impeded by the rapid conformer interchange permitted by the low A(2) bulk near the inner coordination sphere. Me(4)DABPtG(2) adducts exist as a mixture of exclusively head-to-tail (HT) conformers. No head-to-head (HH) conformer was observed. The Me(4)DAB chirality significantly influences which HT chirality is favored (DeltaHT for S,S and LambdaHT for R,R). For simple G ligands, the ratio of favored HT conformer to less favored HT conformer is approximately 2:1. For guanosine monophosphate (GMP) ligands, the phosphate group cis G N1H hydrogen bonding favors the LambdaHT and the DeltaHT conformers for 5'-GMP and 3'-GMP adducts, respectively. For both HT conformers of cis-PtA(2)G(2) adducts, the G nucleobase plane normally cants with respect to the coordination plane in the same direction, left or right, for a given A(2) chirality. In contrast, the results for Me(4)DABPtG(2) 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 Me(4)DAB ligands have bulk both above and below the coordination plane. These results and ongoing preliminary studies of Me(4)DABPt 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.
Saad
Jamil S
JS
Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803, USA. saad@uab.edu
Benedetti
Michele
M
Natile
Giovanni
G
Marzilli
Luigi G
LG
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D002945:Cisplatin / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D018736:DNA Adducts / Q000138:chemical synthesis* / Q000737:chemistry; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D018736:DNA Adducts; D008024:Ligands; D002945:Cisplatin