Complexities of the interaction of Ni(II), Pd(II) and Pt(II) 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, KSV, ranged from 10^4 M^(-1) to 10^5 M^(-1) while the affinity constants, Ka, ranged from 3.5 x 10^3 M^(-1) to 1 x 10^6 M^(-1) at 37 degrees Centigrade, 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.

Spectroscopic and computational study of the interaction of Pt(ii) pyrrole-imine chelates with human serum albumin

“…S22 and S23 †). Significantly, and in contrast to similar chelates of Pd(II), 29 1-3 were substitution-inert and did not hydrolyse to form aqua or hydroxo species. The titrimetric data for 1-3 with HSA thus reflect reactions of the intact, tetradentate Pt(II) chelates with the protein target.…”

“…47 The small red shifts in the emission maximum for 2 and 3 are comparable to that of Pt(PrPyrr). 29 Two potential explanations…”

“…The K SV values are consistent with those of other Pt(II) complexes interacting with HSA. 29,53,54 A summary of K SV and k q values obtained for the interaction of the three Pt(II) complexes with HSA is reported in Table 2. The 2).…”

“…28 By employing isoelectronic Ni(II), Pd(II), and Pt(II) (nd 8 ) chelates of the propyl-bridged structural congener of 1 (R = CH 2 CH 2 CH 2 ; H 2 PrPyrr), we recently showed that the thermodynamics governing complex uptake by HSA depended on the identity of the metal ion. 29 Specifically, TΔS/ΔG and ΔH/ΔG together became increasingly positive (enthalpically driven) in the order Pt(II) < Pd(II) < Ni(II) < H 2 PrPyrr, thereby inversely tracking the metal ionic radii and polarizability order (5d > 4d > 3d). 29 A key question emerging from this study was whether varying the ligand chelated to a given metal ion (e.g., Pt 2+ ) affects its uptake by HSA and, if so, how?…”

“…29 Specifically, TΔS/ΔG and ΔH/ΔG together became increasingly positive (enthalpically driven) in the order Pt(II) < Pd(II) < Ni(II) < H 2 PrPyrr, thereby inversely tracking the metal ionic radii and polarizability order (5d > 4d > 3d). 29 A key question emerging from this study was whether varying the ligand chelated to a given metal ion (e.g., Pt 2+ ) affects its uptake by HSA and, if so, how? To answer this question, we synthesized three structurally-related, yet discrete, bis ( pyrrole-imine) Schiff base ligands, namely 1,3-bis{[(1E)-1Hpyrrol-2-ylmethylene]amino}propan-2-ol, 2,2-dimethyl-N,N′-bis [(1E)-1H-pyrrol-2-ylmethylene]propane-1,3-diamine and (1S,2S)-N,N′-bis[(1E)-1H-pyrrol-2-ylmethylene]cyclohexane-1,2diamine.…”