Interaction of the anticancer gallium(III) complexes of 8-hydroxyquinoline and maltol with human serum proteins

Abstract

Tris(8-quinolinolato)gallium(III) (KP46) and tris(maltolato)gallium(III) (GaM) are promising orally active antitumor metallodrugs currently undergoing clinical trials. Their interaction with human serum albumin (HSA) and transferrin (Tf) was studied in detail in aqueous solution by the combination of various methods such as spectrofluorometry, UV-vis spectrophotometry, (1)H and saturation transfer difference NMR spectroscopy, and ultrafiltration-UV-vis spectrophotometry. Binding data were evaluated quantitatively. Tf was found to replace the original ligand much less efficiently in KP46 than in GaM, whereas a significant noncovalent binding of KP46 with HSA (log K' = 4.04) retaining the coordination environment around gallium(III) was found. The interaction between HSA and KP46 was also confirmed by protein-complex modeling calculations. On the basis of the conditional stability constants, the distribution of gallium(III) in serum was computed and compared for these metallodrugs under physiological conditions, and revealed the prominent role of HSA in the case of KP46 and that of Tf for GaM.

Speciation of Metal Complexes of Medicinal Interest: Relationship between Solution Equilibria and Pharmaceutical Properties

“…The interaction of KP46 with HSA is reversible and does not change the original coordination mode of the complex, which might be beneficial with respect to increased half life and solubility. This finding also suggests a Tf-independent gallium uptake mechanism of KP46 [100]. …”

“…These features have a profound effect on their binding processes with serum proteins [100]. GaM was GaM and KP46 in the presence of HSA and Tf were performed; and an unequivocally different speciation was obtained (Fig.…”

Development of the application of speciation in chemistry

“…The binding of KP46 to HSA is reversible and does not alter the original coordination mode of the complex, which might increase its solubility and half-life. This finding also suggests a Tfindependent gallium uptake mechanism for KP46 [35]. Adapted from Ref.…”

“…However, protein-metal equilibria cannot be excluded, especially in faster complexation processes with the proteins. Indeed, protein interactions were included in computer simulations of the distributions of Al(III) [32], V(IV)O [33], Zn(II) [34], Ga(III) [35], and Gd(III) [36] complexes in serum. In the case of speciation in natural/industrial waters, the redox processes, solubility properties, and adsorption interactions must also be considered (see Section 4.2).…”

“…Adapted from Ref. [35] Therefore, in addition to investigating the reaction rate, the extent of binding (determination of binding constants when an equilibrium is reached) and the nature of the binding event (non-covalent/coordinative) are important for successful drug development.…”