Basic Coordination Chemistry Relevant to DNA Adducts Formed by the Cisplatin Anticancer Drug. NMR Studies on Compounds with Sterically Crowded Chiral Ligands

Abstract

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.

Response of Cisplatin Resistant Skov-3 Cells to [Pt(O,O′-Acac)(γ-Acac)(DMS)] Treatment Revealed by a Metabolomic 1H-NMR Study

“…It is well known that cisplatin can cross the cell membrane by passive diffusion [ 32 , 33 , 34 ], or using selected ion channels [ 35 ]. Once inside the cytosol, aquation processes activate the drug, increasing its reactivity toward DNA (essentially at the purines N7 electron donors, which are considered the main pharmacological targets of cisplatin) [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ].…”

Ameliorative efficacy of quercetin against cisplatin-induced mitochondrial dysfunction: Study on isolated rat liver mitochondria

“…The exact mechanism underlying CP-induced toxicity remains to be fully elucidated. Previous studies have demonstrated that the anticancer behavior of CP originates from its capacity to attach to the N-7 position of purine bases of cellular DNA causing mono-adducts formation, which are converted into inter-and intra-strand cross links with a reaction at the secondary reactive site of drug together with the second nucleobase (3)(4)(5). Mitochondria have been revealed to be the cellular power plants (6,7).…”

Guanine Nucleobase Adducts Formed by [Pt(di-(2-picolyl)amine)Cl]Cl: Evidence That a Tridentate Ligand with Only in-Plane Bulk Can Slow Guanine Base Rotation

“…In Pt(II) adducts with DNA, the G* nucleobase orientation is strongly influenced by a combination of the DNA structure and the steric interactions of the nucleobase with the carrier ligand. 29,30 Considerable effort has been expended in studying Pt(L)(G) 2 models and in comparing results to related G*G* intrastrand models with short oligonucleotides. 12,20,29,31−33 Both model types can have as many as two head-to-head (HH) and two head-to-tail (HT) rotamers, depending on the bulk and symmetry of L ( Figure 2).…”