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

Abstract: 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.