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

Abstract

cis-[PtA2(nucleotide)2] complexes (A2 stands for two amines or a diamine) have been extensively investigated as model compounds for key cisplatin-DNA adducts. All cis-[metal(nucleotide/nucleoside)2] complexes with guanine and related purines characterized in the solid state thus far have the DeltaHT conformation (head-to-tail orientation of the two bases and right-handed chirality). In sharp contrast, the LambdaHT conformation (left-handed chirality) dominates in acidic and neutral aqueous solutions of cis-[PtA2(5'-GMP)2] complexes. Molecular models and solution experiments indicate that the LambdaHT conformer is stabilized by 5'-phosphate/N1H hydrogen-bond interactions between cis nucleotides with the normal anti conformation. However, this evidence, while compelling, is indirect. At last, conditions have been defined to allow crystallization of this elusive conformer. The structure obtained reveals three unique features not present in all other cis-[PtA2(nucleotide)2] solid-state structures: a LambdaHT conformation, very strong hydrogen-bond interactions between the phosphate and N1H of cis nucleotides, and a very small dihedral angle between the planes of the two guanines lying nearly perpendicular to the coordination plane. These new results indicate that, because there are no local base-base repulsions precluding the LambdaHT conformer, global forces rather than local interactions account for the predominance of the DeltaHT conformer over the LambdaHT conformer in the solid state and in both inter- and intrastrand HT crosslinks of oligonucleotides and DNA.

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 ].…”

A Very Rare Example of a Structurally Characterized 3′-GMP Metal Complex. NMR and Synthetic Assessment of Adducts Formed by Guanine Derivatives with [Pt(Ltri)Cl]Cl Complexes with an N,N′,N″ Tridentate Ligand (Ltri) Terminated by Imidazole Rings

“…Other relevant structures with one Pt–N7 bond do not contain a nucleotide; these are [Pt­(dien)­(guanosine)]­(ClO 4 ) 2 , [Pt­(dien)­(inosine)]­(NO 3 ) 2 ·H 2 O, [Pt­(NH 3 ) 3 (9-methylhypoxanthine)]­Cl­(NO 3 )·1.5H 2 O, [Pt­(NH 3 ) 3 (9-ethylhypoxanthine)]­Cl­(NO 3 )·H 2 O, and cis -[Pt­(NH 3 ) 2 ( N 2 , N 2 -dimethyl-9-methylguanine)­Cl]­PF 6 . In contrast, there are many reported structures of complexes with two cis Pt–N7 bonds to G ligands, quite often 5′-GMP. ,− …”

Nucleic Acid-Metal Ion Interactions in the Solid State

“…Metal bonding to guanine O6 is less favored but there are some examples [ 32,41,[63][64][65][66][67] involving the N7-metal-O6 chelation [63][64][65] . Amino substituents at N6 of adenine, N2 of guanine, and N4 of cytosine have never participated in the metal coordination, though these groups become good ligands when they are deprotonated.…”

“…In guanine nucleotides, such as Na 2 [Pt(Me 4 dae)(5'-GMP) 2 ]·7H 2 O [ 32 ] , a seven-coordinated [Na(H 2 O)] + ion binds directly to symmetry-related four GMP molecules through O6 of the base, hydroxyl O2' and O3' of the sugar, and three phosphate oxygens. The Na + -O6 bonding is also observed in [Na 2 (5'-dGMP)]·4H 2 O [ 41 ] .…”