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

Abstract

AbstractTwo new series of complexes with pyridine‐containing Schiff bases, [VVO(SALIEP)L] and [VVO(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 1H and 51V NMR and UV‐Vis spectroscopies confirmed that: 1) most complexes form two major geometric isomers in solution, and [VVO(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 VIV 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 VIV occurred for the unsubstituted‐catecholato VV complexes on dissolution in DMSO. By contrast, the pyridine moiety within the Schiff base significantly improved the hydrolytic stability of [VVO(SALIEP)(DTB)] compared with [VVO(HSHED)(DTB)]. [VVO(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 [VVO(SALIEP)(DTB)] a potential drug candidate for the treatment of advanced gliomas by intracranial injection.