Anti-tumoral Titanium^(IV) Complexes Stabilized with Phenolato Ligands and Structure-Activity Relationship

Titanocene dichloride and budotitane have opened a new chapter in medicinal chemistry of titanium^(IV) complexes being novel non-platinum antitumor metallic agents. Numerous efforts have led to the discovery of the diamino bis-phenolato titanium^(IV) complexes. Among which, the [ONNO] and [ONON] type ligands namely Salan, Salen and Salalen coordinated titanium^(IV) alkoxyl complexes have demonstrated significantly enhanced aqueous stability, their in vitro and in vivo antitumor efficacy, mechanism of action, structure-activity relationships and combined tumor therapy have been intensively investigated. Replacement of the labile alkoxyls with a second chelator resulted in structural rigid titanium^(IV) complexes, which showed exceedingly good aqueous stability and potent antitumor activity both in vitro and in vivo. The unique ligand system successfully allowed the access of isotopic [⁴⁵Ti]Titanium^(IV) complexes, post-synthetic modification, facile synthetic protocols and antitumor congeneric zirconium^(IV) and hafnium^(IV) complexes. This review presents recent research progress in the field of antitumor group 4 metal complexes stabilized with phenolato ligands; especially their structure-activity relationships are summarized.