Vanadium Chloro-Substituted Schiff Base Catecholate Complexes are Reducible, Lipophilic, Water Stable, and Have Anticancer Activities

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 V-51 and H-1 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 (IC50 = 4.1 +/- 0.5 mu M DTB, 34 +/- 7 mu M 3-MeCat, and 19 +/- 2 mu M Cat). Furthermore, upon aging, the complexes formed less toxic decomposition products (IC50 = 9 +/- 1 mu M DTB, 18 +/- 3 mu M 3-MeCat, and 8.1 +/- 0.6 mu M 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.

Automated summary

A hydrophobic Schiff base catecholate vanadium complex with superior anticancer properties to cisplatin has been discovered and found suitable for intratumoral administration. Compared to simpler catecholato complexes, this complex has higher stability. Three new chloro-substituted Schiff base complexes of vanadium(V) with catecholates as co-ligands were synthesized and compared to their non-chlorinated counterparts. The chloro-substituted vanadium(V) complexes displayed increased hydrophobicity, stability, and anticancer activity, with the most sterically hindered complex showing an order of magnitude higher activity than cisplatin under the same conditions.