Vanadium(V) Pyridine-Containing Schiff Base Catecholate Complexes are Lipophilic, Redox-Active and Selectively Cytotoxic in Glioblastoma (T98G) Cells

Abstract

Two new series of complexes with pyridine-containing Schiff bases, [V^V O(SALIEP)L] and [V^V O(Cl-SALIEP)L] (SALIEP=N-(salicylideneaminato)-2-(2-aminoethylpyridine; Cl-SALIEP=N-(5-chlorosalicylideneaminato)-2-(2-aminoethyl)pyridine, L=catecholato(2-) ligand) have been synthesized. Characterization by ¹ H and ⁵¹ V NMR and UV-Vis spectroscopies confirmed that: 1) most complexes form two major geometric isomers in solution, and [V^V O(SALIEP)(DTB)] (DTB=3,5-di-tert-butylcatecholato(2-)) forms two isomers that equilibrate in solution; and 2) tert-butyl substituents were necessary to stabilize the reduced V^IV species (EPR spectroscopy and cyclic voltammetry). The pyridine moiety within the Schiff base ligands significantly changed their chemical properties with unsubstituted catecholate ligands compared with the parent HSHED (N-(salicylideneaminato)-N'-(2-hydroxyethyl)-1,2-ethanediamine) Schiff base complexes. Immediate reduction to V^IV occurred for the unsubstituted-catecholato V^V complexes on dissolution in DMSO. By contrast, the pyridine moiety within the Schiff base significantly improved the hydrolytic stability of [V^V O(SALIEP)(DTB)] compared with [V^V O(HSHED)(DTB)]. [V^V O(SALIEP)(DTB)] had moderate stability in cell culture media. There was significant cellular uptake of the intact complex by T98G (human glioblastoma) cells and very good anti-proliferative activity (IC₅₀ 6.7±0.9 μM, 72 h), which was approximately five times higher than for the non-cancerous human cell line, HFF-1 (IC₅₀ 34±10 μM). This made [V^V O(SALIEP)(DTB)] a potential drug candidate for the treatment of advanced gliomas by intracranial injection.

Keywords: Schiff bases; anti-cancer complexes; hydrophobic complexes; non-innocent metal complexes; redox-active complexes; vanadium.