Titanium salan complexes displays strong antitumor properties in vitro and in vivo in mice

Abstract

The anticancer activity of titanium complexes has been known since the groundbreaking studies of Köpf and Köpf-Maier on titanocen dichloride. Unfortunately, possibly due to their fast hydrolysis, derivatives of titanocen dichloride failed in clinical studies. Recently, the new family of titanium salan complexes containing tetradentate ONNO ligands with anti-cancer properties has been discovered. These salan complexes are much more stabile in aqueous media. In this study we describe the biological activity of two titanium salan complexes in a mouse model of cervical cancer. High efficiency of this promising complex family was demonstrated for the first time in vivo. From these data we conclude that titanium salan complexes display very strong antitumor properties exhibiting only minor side effects. Our results may influence the chemotherapy with metallo therapeutics in the future.

Figure 1. Synthesis of the salan ligands and titanium salan complexes.

The halo-salan ligands L¹ and L² were synthesised via a Mannich-condensation of the respective phenol, formaldehyde and N,N'-ethylenediamine. The ligands were then metallated with Ti(OⁱPr)4 in toluene to give complexes 1 and 2.

Figure 2. Viability of C3 cells after incubation for 48 h with complexes 1 and 2.

Dose-response curves were obtained using an AlamarBlue assay. Measuring the fluorescence and comparison to a negative control gave the relative amount of cells surviving the treatment. The shown dose-effect curves result from three independent test series done in four replicates.