Differential impact on oral cancer cell viability for three carboxylate-stabilized rhenium(I) tricarbonyl centers supported by 2,2′-bipyridine: One-pot synthesis, a structure, and proton-catalyzed carboxylate ligand substitution

Abstract

A set of six carboxylate-stabilized rhenium(I) tricarbonyl complexes supported by a 2,2′-bipyridine (bpy) ligand, Re(O2CR)(CO)3(bpy) (R = H, CH3, CHF2, R- or S-CHBrCH(CH3)2, and C5H11), were prepared by acidolysis of the complex Re(OCO2C5H11)(CO)3(bpy) with the appropriate carboxylic acid and characterized by 1H and 13C-{1H} NMR and IR spectroscopy. The crystal structure of the complex, Re[R-O2CCHBrCH(CH3)2](CO)3(bpy), was determined by X-ray crystallography. An alternate one-pot route to the carboxylate-stabilized rhenium(I) complexes Re(O2CR’)(CO)3(bpy) (R’ = CH3 or C6H5) and Re(O2CCH3)(CO)3(1,10-pheanthroline), which starts with Re2(CO)10 and in which an ester solvent serves as the source of the carboxylate ligand, was also developed. Cell viability tests on three carboxylate-stabilized rhenium(I) complexes (R = H, CH3, or CHF2), using the HSC-2 oral cancer cell line, found different levels of cytotoxicity for each complex. NMR studies of the carboxylate ligand substitution reaction found that the reaction is catalyzed by protons. In a chloride-rich NMR solution, substitution of the carboxylate ligand leads to either a chloride-stabilized neutral complex (major product) or to a water-stabilized cation (minor product). Cytotoxicity results correlate positively with the Kb value of the carboxylate ligand. Apparently, the more substitutionally inert the carboxylate-stabilized complex is in a chloride-rich environment (similar to extracellular fluid) the greater the amount of cytotoxic [Re(CO)3(bpy)(H2O)]+ that forms in the cytosol.