Complexities of the Interaction of NiII, PdII and PtII Pyrrole-Imine Chelates with Human Serum Albumin**

Abstract

Human serum albumin (HSA) efficiently transports drugs in vivo: most are organic. Here, HSA binding affinity and site specificity are shown to depend on the identity of the d⁸ metal ion in Ni^II, Pd^II and Pt^II chelates of the bis(pyrrole-imine) ligand H₂PrPyrr. Fluorescence quenching data for native and probe-bound HSA showed sites close to Trp-214 (subdomain IIA) are targeted. The Stern-Volmer constants, K_SV, ranged from 10⁴ M⁻¹ to 10⁵ M⁻¹ while the affinity constants, K_a, ranged from ∼3.5×10³ M⁻¹ to ∼1×10⁶ M⁻¹ at 37 °C, following the order Pd(PrPyrr) > Pt(PrPyrr) > Ni(PrPyrr) > H₂PrPyrr. Ligand uptake is enthalpically driven, hinging mainly on London dispersion forces. Induced CD spectra for the protein-bound ligands could be simulated by hybrid QM:MM TD-DFT methods, proving that the metal chelates neither decompose nor demetallate after uptake by HSA. Transport and delivery of the metal chelates by HSA in vivo could therefore be feasible.