Titanocene-derivative complex modified with a myristic-like aliphatic chain exhibits anticancer activity in vitro and in vivo by cisplatin-alternative mechanisms

Titanium coordination compounds have emerged as promising agents in the treatment of cisplatin-resistant tumors. To address the instability and solubility issues of these compounds, we synthesized a new titanocene-derived complex, [TiCp₂(OOC)₂py-O-myr] (Myr-Ti), with improved stability and high albumin affinity. Its cytotoxic effect was higher compared with TiCp₂Cl₂ in cisplatin resistant tumor cells, and it seems to be related to an increased uptake of our Ti (IV) compound by tumor cells. In addition, Myr-Ti showed higher selectivity and resistance factor than cisplatin. Unlike conventional DNA-binding chemotherapeutics, such as cisplatin, Myr-Ti exhibits low affinity for DNA. Its mechanism of action involves cell cycle arrest, leading to apoptosis without causing oxidative stress or endoplasmic reticulum stress. In vivo studies on xenografted mice have shown promising results, with significant tumor reduction and no damage to primary organs. Myr-Ti exhibited consistent efficacy across both cellular and animal systems. These findings support further exploration to determine whether Myr-Ti may become a useful therapeutic candidate in the future.