A hydrophobic Schiff base catecholate vanadium complex was recently discovered to have anticancer properties superior to cisplatin and suited for intratumoral administration. This [VO(HSHED)(DTB)] complex, where HSHED is N-(salicylideneaminato)-N′-(2-hydroxyethyl)-1,2-ethanediamine and the non-innocent catecholato ligand is di-t-butylcatecholato (DTB), has higher stability compared to simpler catecholato complexes. Three new chloro-substituted Schiff base complexes of vanadium(V) with substituted catecholates as co-ligands were synthesized for comparison with their non-chlorinated Schiff base vanadium complexes, and their properties were characterized. Up to four geometric isomers for each complex were identified in organic solvents using 51 V and 1 H NMR spectroscopies. Spectroscopy was used to characterize the structure of the major isomer in solution and to demonstrate that the observed isomers are exchanged in solution. All three chloro-substituted Schiff base vanadium(V) complexes with substituted catecholates were also characterized by UV−vis spectroscopy, mass spectrometry, and electrochemistry. Upon testing in human glioblastoma multiforme (T98g) cells as an in vitro model of brain gliomas, the most sterically hindered, hydrophobic, and stable compound [t 1/2 (298 K) = 15 min in cell medium] was better than the two other complexes (IC 50 = 4.1 ± 0.5 μM DTB, 34 ± 7 μM 3-MeCat, and 19 ± 2 μM Cat). Furthermore, upon aging, the complexes formed less toxic decomposition products (IC 50 = 9 ± 1 μM DTB, 18 ± 3 μM 3-MeCat, and 8.1 ± 0.6 μM Cat). The vanadium complexes with the chloro-substituted Schiff base were more hydrophobic, more hydrolytically stable, more easily reduced compared to their corresponding parent counterparts, and the most sterically hindered complex of this series is only the second non-innocent vanadium Schiff base complex with a potent in vitro anticancer activity that is an order of magnitude more potent than cisplatin under the same conditions.

The vanadium(V) complexes have been investigated as potential anticancer agents which makes it essential to evaluate their toxicity for safe use in the clinic. The large-scale synthesis and the acute oral toxicity in mice of the oxidovanadium(V) Schiff base catecholate complex, abbreviated as [VO(HSHED)dtb] containing a redox-active ligand with tridentate Schiff base (HSHED = N-(salicylideneaminato)-N’-(2-hydroxyethyl)-1,2-ethylenediamine) and dtb = 3,5-di-(t-butyl)catechol ligands were carried out. The body weight, food consumption, water intake as well biomarkers of liver and kidney toxicity of the [VO(HSHED)dtb] were compared to the precursors, sodium orthovanadate, and free ligand. The 10-fold scale-up synthesis of the oxidovanadium(V) complex resulting in the preparation of material in improved yield leading to 2–3 g (79%) material suitable for investigating the toxicity of vanadium complex. No evidence of toxicity was observed in animals when acutely exposed to a single dose of 300 mg/kg for 14 days. The toxicological results obtained with biochemical and hematological analyses did not show significant changes in kidney and liver parameters when compared with reference values. The low oral acute toxicity of the [VO(HSHED)dtb] is attributed to redox chemistry taking place under biological conditions combined with the hydrolytic stability of the oxidovanadium(V) complex. These results document the design of oxidovanadium(V) complexes that have low toxicity but still are antioxidant and anticancer agents.