A Comprehensive Review on the Development of Titanium Complexes as Cytotoxic Agents

After the discovery of cis-platin, the first metal-based anticancer drugs, budotitane, and titanocene dichloride entered clinical trials. These two classes of complexes were effective against those cell lines that are resistant to cis-platin and other platinum-based drugs. However, the main limitation of these complexes is their low hydrolytic stability. After these two classes, a third generation titanium based complex, i.e. diaminebis(phenolato)bis(alkoxo) titanium(IV), was invented, which showed more hydrolytic stability and high cytotoxicity than budotitane and titanocene dichloride. The Hydrolytic stability of complexes plays an important role in cytotoxicity. Earlier research showed that hydrolytically less stable complexes decompose rapidly into non-bioavailable moiety and become inactive. The mechanism of Ti(IV) complexes of diaminebis(phenolato) bis(alkoxo) is under investigation and is presumed to involve Endoplasmic Reticulum (ER) stress, which leads to apoptosis. The proposed mechanism involves the removal of ligands from the titanium complex and the binding of the Ti center to transferrin protein and its release inside the cell. Also, the structure of the ligand plays a key role in the cytotoxicity of complexes; as the bulkiness of the ligand increased, the cytotoxic nature of complexes decreased.