Highly Effective and Hydrolytically Stable Vanadium(V) Phenolato Antitumor Agents: Development, Analysis and Mechanistic Investigation

Lilia Reytman, The Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel
Edit Y. Tshuva, The Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel

In the field of anti-cancer chemotherapeutic research, 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 new family of vanadium(V) complexes with tetradentate diamino bis(phenolato) "salan" ligands with favorable cytotoxic activity. Nevertheless, theses complexes exhibited mild water stability. Appreciable cytotoxic activity was measured for an isolated hydrolytsis product that was found to exhibit a dimeric structure with no labile ligands [1].

Herein we developed a family of oxo-vanadium(V) complexes with pentadentate diamino tris(phenolato) ligands, which do not contain any labile ligands, and therefore exhibit remarkable resistance towards hydrolysis. Importantly, these compounds display exceptional cytotoxic activity, higher than that of cisplatin by up to two orders of magnitude, which is preserved during incubation in DMSO for several weeks [2]. These properties, along with promising in vivo results for a representative complex, encourage further development and investigation regarding the mechanism of action of this family of complexes. Preliminary evidence of possible cellular pathways of these complexes will be discussed, as well as properties of selectivity towards cancer cells and structure-activity studies concerning different substituents on the phenolato rings.

1.         Reytman L, Braitbard O, Tshuva, EY (2012) Dalton Trans 41: 5241-5247

2.         Reytman L, Tshuva EY In preparation