Kinetic Overview of Polynuclear Platinum(II) Complexes in Heparan Sulfate Substitution: Mimetic Model Analysis and Mechanistic Perspectives

Polynuclear platinum(II) complexes (PPCs) represent a promising class of anticancer agents, offering enhanced efficacy and reduced toxicity compared with traditional mononuclear platinum drugs. Their interactions extend beyond DNA to include noncovalent and covalent binding with biologically relevant anions, such as sulfates and carboxylates, in glycosaminoglycans (GAGs) like heparan sulfate (HS) and chondroitin sulfate. This study investigates the chloride substitution mechanisms in PPCs using a Cl–PtN3 model, evaluating both aquation-driven and direct substitution pathways with GAG mimetic models of iduronic acid, IdoA(2S), and glucose, GlcNS(6S). A computational benchmarking analysis identified the double-hybrid DFT functional B2PLYP as the most accurate method, displaying an absolute deviation of only 1.05 kcal mol–1 from the DLPNO–CCSD(T) reference. Free energy profiles revealed similar energy transition-state species ranging from ca. 26 to 30 kcal mol–1, while direct substitutions exhibit lower activation barriers but are thermodynamically less favorable. The inclusion of explicit water molecules in the solvation layer was also addressed and significantly drove the results toward experimental data, with a better description of the active complex. These findings, added to our microkinetic analysis, provide insight into PPC ligand-exchange mechanisms, contributing to the rational design of next-generation platinum-based anticancer therapeutics.