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

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 NiII, PdII and PtII 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, KSV, ranged from 104 M−1 to 105 M−1 while the affinity constants, Ka, 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.