Highly Effective and Hydrolytically Stable Vanadium(V) Phenolato Antitumor Agents: The Role of the Ligand in the Cytotoxic Pathway

Today numerous metal compounds are being investigated worldwide in order to resolve the limited activity range and severe toxicity of the antitumor drug cisplatin. One of the most promising metals studied today is vanadium. Vanadium compounds were found to exert favorable properties for use in therapy, but the complicated aquatic chemistry of vanadium compounds impeded the potential of vanadium as an antitumor agent. Therefore, the development of compounds with improved hydrolytic stability is essential for therapeutic utilization. In previous work we developed a family of oxo-vanadium(V) complexes with pentadentate diamino tris(phenolato) ligands, and no labile ligands, which therefore exhibited remarkable resistance towards hydrolysis. Importantly, these compounds displayed exceptional cytotoxic activity, higher than that of cisplatin by up to two orders of magnitude, which was preserved during incubation in DMSO for several weeks and in aqueous medium for a few days. These complexes also displayed therapeutic potential through preliminary in vivo results, in which a representative complex achieved promising anti-tumor effects with no sign of clinical toxicity.¹

However, ¹⁹F-NMR measurements of cells treated with a representative compound indicate that the complex decomposes in the presence of cells and releases the free ligand, which also possesses cytotoxic activity. To answer the question whether the free ligand might be the active species inside the cell mechanistic investigation is being conducted. In addition, structural changes to the ligand are being applied to increase the stability of the obtained complex. Preliminary results and insights regarding both objectives will be presented.

1. L. Reytman, O. Braitbard, J. Hochman, E. Y. Tshuva, Inorg. Chem. 2016, 55, 610–618.