New insights on the active species and mechanism of cytotoxicity of salan-Ti(IV) complexes: A stereochemical study

Following the discovery of cisplatin, much effort has been devoted to the exploration of transition metal complexes as cytotoxic agents. We have recently introduced the highly efficient C ₂-symmetrical salan-Ti(IV) family of complexes, demonstrating high cytotoxicity toward colon and ovarian cells and enhanced hydrolytic stability in mixed organic/water solutions. The effect of stereochemistry is hereby reported, by comparing the cytotoxic activity and hydrolysis of pure enantiomers and their racemic mixture for four complexes of this family with different aromatic substitutions: para-Me, para-Cl, ortho-Cl, and ortho-OMe. These complexes include the trans-diaminocyclohexyl bridge, which enables ligand-to-metal chiral induction to give solely the Δ isomer when starting from the R,R ligand and vice versa. Different activity is obtained for the different stereochemical forms (Δ, Λ, and rac) in two of the four complexes, where for the other two either all forms are inactive or all are highly active. Additionally, where not all are of similar activity, the racemic mixture is the least active of the three. We therefore conclude that the salan ligand is essential for the fruitful biological interaction, which probably involves a chiral cellular target. The activity of the racemate differing from that expected from a simple mixture of enantiomers operating separately may be explained by the involvement of a polynuclear active species, where different metal centers might be of different configurations. This is particularly supported by the different polynuclear products of hydrolysis obtained from an optically pure complex and from the racemic one, as analyzed crystallographically. The former is an all-R,R chiral C ₁-symmetrical homodimer, while the latter is an achiral R,R-S,SC _i-symmetrical heterodimer obtained through chiral recognition.