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Chemistry. 2016 Jul 11;22(29):9986-95. doi: 10.1002/chem.201601389. Epub 2016 Jun 20.

Specific Design of Titanium(IV) Phenolato Chelates Yields Stable and Accessible, Effective and Selective Anticancer Agents.

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The Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, 9190401, Israel), Fax: (+972) 2-6584282.
Department of Cell and Developmental Biology, Alexander Silberman Institute of Life Science, The Hebrew University of Jerusalem, Jerusalem, 9190401, Israel.
NCATS Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA.
The Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, 9190401, Israel), Fax: (+972) 2-6584282.


Octahedral titanium(IV) complexes of phenolato hexadentate ligands were developed and showed very high stability for days in water solutions. In vitro cytotoxicity studies showed that, whereas tetrakis(phenolato) systems are generally of low activity presumably due to inaccessibility, smaller bis(phenolato)bis(alkoxo) complexes feature high anticancer activity and accessibility even without formulations, also toward a cisplatin-resistant cell line. An all-aliphatic control complex was unstable and inactive. A leading phenolato complex also revealed: 1) high durability in fully aqueous solutions; accordingly, negligible loss of activity after preincubation for three days in medium or in serum; 2) maximal cellular accumulation and induction of apoptosis following 24-48 h of administration; 3) reduced impact on noncancerous fibroblast cells; 4) in vivo efficacy toward lymphoma cells in murine model; 5) high activity in NCI-60 panel, with average GI50 of 4.6±2 μm. This newly developed family of Ti(IV) complexes is thus of great potential for anticancer therapy.


N,O ligands; antitumor agents; drug design; ligand design; titanium

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