Water-Soluble, Titanocene-Based Prodrugs with Thiosemicarbazones as Cytotoxic Agents

Prodrugs that improve drug delivery in the body are highly desirable because they increase drug solubility and activity, thereby reducing drug concentration and side effects compared to the actual active compound. In this work, we demonstrate the impact of titanocene scaffolds on active thiosemicarbazones (TSCN). Two routes toward cationic Ti-(IV) TSCN complexes were established either by the reaction of titanocene bis-(trimethylsilyl)-acetylene with TSCN and subsequent oxidation of the resulting Ti-(III) complex with ferrocenium triflate or by ligand exchange of the triflato ligands in titanocene-(IV) triflate with TSCN. The solubility and stability of the complexes in aqueous media were evaluated by NMR and ultraviolet/visible (UV/vis) spectroscopy. A selection of cationic Ti-(IV) TSCN complexes exhibit improved water solubility, stability and increased cytotoxicity at lower concentrations compared to pure TSCN, cisplatin and 5-FU in human colon cancer cells in vitro.