Phenolato Ti(iv) hexacoordinate complexes for anticancer chemotherapy: enhancement of solubility, hydrolytic stability, and cytotoxicity

Abstract

A new series of five titanium(IV) complexes based on diaminobis(phenolato)-bis(alkoxo) ligands with different substitutions was synthesized and characterized. All complexes were analyzed by X-ray crystallography, and all structures indicated C₂ symmetrical octahedral compounds. All complexes exhibited enhanced solubility in aqueous media compared with the parent methylated derivative phenolaTi (up to 0.4 vs. 0.05 mg ml⁻¹ of phenolaTi) due to halogen and alkoxo/hydroxo substitutions, with particularly enhanced water solubility for the methoxylated and hydroxylated derivatives. In particular, high hydrolytic stability was recorded for all derivatives, with the t_½ for ligand hydrolysis of more than 8 days, as established by ¹H NMR and HR-MS. All complexes were cytotoxic toward human ovarian A2780, colon HT-29, and cervical HeLa cancer cell lines (IC₅₀ values in the range of 0.3–40 μM), with negligible activity toward non-cancerous MRC-5 cells. The halogenated compounds of this series exhibit the best combination of stability and activity, making them highly promising for anticancer applications.