New Insights on the Active Species and Mechanism of Cytotoxicity of Salan-Ti(IV) Complexes: A Stereochemical Study

Abstract

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.

Cytotoxicity of a Ti(IV) compound is independent of serum proteins

“…HBED is a cell-permeable molecule that is a promising candidate for iron-overload disease therapy because of its high Fe(III) affinity (41). Ti(IV) compounds of diamine-bis(phenolato) ligands, which are related to HBED but lack the carboxylate appendages, display cytotoxic properties in different cell lines in vitro (14,17,19,28,(42)(43)(44) and in a mouse cancer model in vivo (35). It is feasible that Ti(IV) compounds of citrate and HBED could use ligand-specific mechanisms for transport into cells.…”

“…Another study shows that substitutions ortho to the binding phenolato unit of salan-type ligands influences the cytotoxicity of these types of Ti(IV) compounds because of electronic and steric effects (27). In addition, both the chirality of ligands (28) and ligand coordination to Ti(IV) (28,29) can affect the cytotoxicity of Ti(IV) compounds.…”

Bringing Radiotracing to Titanium-Based Antineoplastics: Solid Phase Radiosynthesis, PET and ex Vivo Evaluation of Antitumor Agent [45Ti](salan)Ti(dipic)

“…However, recent advances in titanium-stabilizing ligands have led to a new class of cytotoxic Ti-based antineoplastics 5 . Prominently, introduction of the ligand salan, a diamine bisphenalato compound, conferred excellent hydrolytic stability to Ti(IV) alkoxide complexes, as presented by Tshuva and co-workers (Chart 1, 1) [6][7][8][9][10][11][12][13] . Many of these compounds also demonstrated micro-and submicromolar antiproliferative activity against HT29 and OVCAR-1 cancer cell lines in vitro.…”

Cytotoxic O-bridged inert titanium(IV) complexes of phenylenediamine-bis(phenolato) ligands

“…Complexes of Ti IV , budotitane ((bzac) 2 Ti(OEt 2 ), titanocene dichloride (Cp 2 TiCl 2 ) and their derivatives exhibited high anti-cancer properties against a range of cell lines with relatively minor side effects; nevertheless, rapid hydrolysis of the complexes in biologically relevant solutions to multiple unidentified species inhibited their utility [2][3][4][5][6][7][8][9][10][11][12][13]. Previously we have presented the diaminobis(phenolato) Ti IV complexes with particularly high cytotoxic activity, demonstrating higher hydrolytic stability than that of budotitane and titanocene dichloride [14][15][16][17][18][19][20][21][22][23][24][25]. Structure-activity relationship studies revealed that, for example, methyl groups on the nitrogen atoms (N-Me) greatly improve the hydrolytic stability of the complexes compared with no substitution (N-H) [22].…”

“…Structure-activity relationship studies revealed that, for example, methyl groups on the nitrogen atoms (N-Me) greatly improve the hydrolytic stability of the complexes compared with no substitution (N-H) [22]. Subsequent studies suggested that the active species are polynuclear O-bridged hydrolysis products [26]: trinuclear species for N-Me complexes [15,16] and binuclear species for N-H complexes [22,23], thus eliminating the need for labile ligands. The polynuclear hydrolysis products mostly showed anticancer activity only in particular nano-formulations, due to diminished accessibility and solubility [26,27].…”