Abstract 5496: ‘Salan’ titanium(IV) complexes: A new class of anti-cancer agents.

Abstract

Abstract Early attempts at using titanium compounds (derivatives of titanocene dichloride and budotitane) as anti-cancer treatment were essentially unsuccessful. The main reason was their rapid hydrolysis in biological media, leading to a variety of unidentified products that hampered the elucidation of mechanistic aspects. Lately, we have introduced a new class of Ti(IV) complexes of salan type diamino bis(phenolato) ligands. These compounds demonstrate substantially enhanced hydrolytic stability, as well as cytotoxic activity towards a variety of cancer cell lines in vitro. The IC50 of different derivatives of these compounds towards murine mammary carcinoma, lymphoma, multi-drug resistant lymphoma, as well as human leukemia, melanoma and pancreatic cancer cell lines, is in the range of 0.6 - 5.7μM, as compared to 70-100μM of the older titanium compounds and to 50-60μM of cisplatin (Manna C.M. et al. ChemMedChem, 7, 703 (2012)). Exposure of murine T-69 and human OVCAR-1 and HT-29 cell lines to one of the salan Ti(IV) compounds resulted in increased levels of p53 and growth arrest in G-1 of the cell cycle implying activation of the apoptotic pathway in response to Ti(IV) complexes.The well-identified and highly stable hydrolysis products of the titanium compounds, which had previously been formulated into nanoparticles to enhance solubility and assist cellular penetration (Meker, S. et al. Angew. Chem. Int. Ed. 51,10515 (2012)), were active both in vitro (IC50 -0.45μM) in murine lymphoma and in vivo (50% tumor growth inhibition) of the same lymphoma cells following their introduction into syngeneic mice. These findings suggest the potential use of solubilized active titanium compound derivatives as a new class of anti-cancer agents. Citation Format: Ori Braitbard, Sigalit Meker, Maya Stolarov, Jacob Hochman, Edit Tshuva. ‘Salan’ titanium(IV) complexes: A new class of anti-cancer agents. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5496. doi:10.1158/1538-7445.AM2013-5496