New titanocene derivative with improved stability and binding ability to albumin exhibits high anticancer activity

Abstract

Titanium-based therapies have emerged as a promising alternative for the treatment of cancer patients, particularly those with cisplatin resistant tumors. Unfortunately, some titanium compounds show stability and solubility problems that have hindered their use in clinical practice. Here, we designed and synthesized a new titanium complex containing a titanocene fragment, a tridentate ligand to improve its stability in water, and a long aliphatic chain, designed to facilitate a non-covalent interaction with albumin, the most abundant protein in human serum. The stability and human serum albumin affinity of the resulting titanium complex was investigated by UV-Vis absorption and fluorescence spectroscopy techniques. Complex [TiCp₂{(OOC)₂py-O-myr}] (3) (myr = C₁₄H₂₉, py = pyridine) and its analogous [TiCp₂{(OOC)₂py-OH}] (4), lacking the aliphatic chain, showed improved stability in phosphate saline buffer compared with [TiCp₂Cl₂] (1). 3 showed a strong interaction with human serum albumin in a 1:1 stoichiometry. The cytotoxic effect of 3 was higher compared to [TiCp₂Cl₂] in tumor cell lines and showed potential tumor selectivity when assayed in non-tumor human epithelial cells. Finally, 3 showed an antiproliferative effect on cancer cells, decreasing the population in the S phase, and increasing apoptotic cells in a significant manner. All this makes the novel Ti(IV) compound 3 a firm candidate to continue further studies of its therapeutic potential in vitro and in vivo.

Keywords: Albumin; Antitumor agents; Cytotoxicity; Ligand design; Metallodrugs; Titanium complex.