Three bis(pyrrolide-imine) Pt(II) chelates were synthesised and characterized with different bridging alkyl groups, specifically 2-hydroxypropyl (1), 2,2-dimethylpropyl (2), and 1,2-(S,S)-(+)-cyclohexyl (3). Novel compounds 1 and 2 were analysed by single-crystal X-ray diffraction (space group P[1 with combining macron]). The asymmetric unit of 1 comprises three independent molecules linked by hydrogen bonds involving the OH groups, forming a trimeric supramolecular structure. The Pt(II) chelates were reacted with human serum albumin (HSA) to investigate how the ligand bound to the Pt(II) ion influences the compound's affinity for HSA. Fluorescence quenching data obtained for native HSA and HSA bound to site-specific probes (warfarin, subdomain IIA; ibuprofen, subdomain IIIA) indicated that the three Pt(II) chelates bind close enough (within ∼30 Å) to Trp-214 to quench its intrinsic fluorescence. The bimolecular quenching constant (kq) was 103–104 -fold higher than the maximum diffusion-controlled collision constant in water (1010 M s−1) at 310 K, while the affinity constants, Ka, ranged from ∼5 × 103 to ∼5 × 105 at 310 K, and followed the order 1 > 3 > 2. The reactions of 1 and 3 with HSA were enthalpically driven, while that for 2 was entropically driven. Macromolecular docking simulations (Glide XP) and binding site specificity assays employing site-specific probes and UV-vis CD spectroscopy indicated that 1 and 2 target Sudlow's site II in subdomain IIIA, minimally perturbing the tertiary structure of the protein. Well-resolved induced CD signals from 1 and 2 bound to HSA in subdomain IIIA were adequately simulated by hybrid QM:MM TD-DFT methods. We conclude that the structure of the bis(pyrrolide-imine) Pt(II) chelate measurably affects its uptake by HSA without detectable decomposition or demetallation. Such compounds could thus serve as metallodrug candidates capable of utilising an HSA-mediated cellular uptake pathway.
CORE (COnnecting REpositories)
CORE (COnnecting REpositories)