Conformational preferences, rotational barriers and energetics of purine nucleobase rotation and dissociation in square planar platinum(II) antitumour complexes: Structure–activity correlation

Abstract

The structural, energetic and electronic properties of a series of square planar platinum(II) complexes of formula cis-[PtL₂Cl(G)]⁺ (where L₂ is two unidentate ligands or one bidentate amine ligand and G is the guanine base molecule) were computed at an improved modified ASED-MO level of theory. The reliability of the ASED-MO model was checked by DFT calculations at the B3LYP level of theory on the parent complex of the series, namely cis-[Pt(NH₃)₂Cl(G)]⁺. Particular emphasis was paid to the role of the carrier amine ligands in the rotation of the purine ligand about the Pt–N7 coordination bond. The computed rotational barriers have been found to be significantly influenced by the nature of the carrier amine ligands, as a result of steric interactions. The conformational energy maps exhibit two distinct minima corresponding to two stable conformers. The interconversion processes of the two conformers either through the transition state of the lower or the transition state of the higher energy are dominated by steric interactions between purine and cis-amine and chloride ligands, while the electronic contribution to the rotational barrier is negligible. The purine base torsion in these complexes can be described as a “spiral” type motion along the Pt–N7 coordination bond. Finally, correlation of the computed energetic and electronic parameters of the complexes with experimentally determined biological parameters illustrated that the rotational barriers, the Pt–N7 bond dissociation energies and the net atomic charges on Pt and N atoms are key modulators of the cytostatic activity and toxicity of the platinum(II)-containing cytostatics.