Ti(IV) Asymmetric Acetyl-Substituted Phenolato Hexacoordinate Complexes as Anticancer Chemotherapy of Enhanced Bioavailability

Abstract

A series of four titanium(IV) complexes based on asymmetric diaminobis(phenolato)-bis(alkoxo) ligands with different substitutions and acetyl functional groups was synthesized and characterized. All complexes were analyzed by ¹H NMR,¹³C NMR, and HRMS. Three complexes were analyzed by X-ray crystallography; interestingly, whereas two complexes were similar to previously published structures showing C₁ asymmetrical mononuclear octahedral coordination sphere, one structure of a bulky iodinated complex indicated formation of a unique pseudo-C₂ symmetrical hepta-coordinated dimer, where computational studies indicated mostly subtle solvent and temperature effects. High hydrolytic stability was recorded for all derivatives, with t_½ of more than 3 days for hydrolysis in 10% D₂O organic solutions, with enhanced solubility in PBS/DMSO (up to 0.25 mg/mL in <0.5% DMSO aqueous solution). All complexes were highly cytotoxic toward human ovarian A2780 and colon HT-29 cancer cell lines (IC₅₀ values in the range of 0.5–10 µM). Cellular uptake studies showed that the studied complexes possess marked membrane permeability, pointing to high potential as anticancer therapeutics.