Understanding the formation mechanism and structural aspects of anti-cancer drug platinum uracil blue by quantum...

The mechanism of the reaction between the hydrolysis product of cisplatin ([Pt(NH₃)₂(OH₂)₂]) and uracil leading to the formation of di- and tetra-valent platinum complexes with varying oxidation states, such as Pt(2+), Pt(2.25+), Pt(2.5+), and Pt(3+), was investigated using density functional theory (DFT). The formation of the dimer of cis-[Pt₂(NH₃)₄(Ur)₂]²⁺ (Ur = deprotonated uracil) from cis-[Pt(NH₃)₂(OH₂)₂]²⁺ proceeded through a four-step mechanism. In the first and second steps, two water molecules were successively replaced by two Ur to form cis-[Pt(NH₃)₂(Ur)₂]. In the third step, cis-[Pt(NH₃)₂(Ur)₂] dimerised to the diplatinum complex [Pt₂(NH₃)₄(OH₂)(Ur)(µ-Ur)]²⁺ using one exocyclic oxygen of uracil via a bridged bond, which subsequently formed [Pt₂(NH₃)₄(µ-Ur)₂]²⁺ in the fourth step. Pentacoordinated platinum transition states (TSs) and other stationary points on the potential energy surface were optimized and characterized. In the gas phase, the activation energy barriers for the formation of the head-to-head orientation increased progressively across the reaction steps. In contrast, in the solvent phase, although the barriers were generally comparable, the clear stepwise progression observed in the gas phase was not maintained. Time-dependent DFT (TD-DFT) was employed to examine the spectral changes from monomer to dimer to tetramer forms. Intermolecular interactions in tetramers were characterized using reduced density gradient (RDG). Furthermore, quantum theory of atoms in molecules (QTAIM) analysis was employed to compare the binding character of Pt(2+)₄ and Pt(2.25+)₄.