Different ortho and para Electronic Effects on Hydrolysis and Cytotoxicity of Diamino Bis(Phenolato) “Salan” Ti(IV) Complexes

Abstract

Bis(isopropoxo) Ti(IV) complexes of diamino bis(phenolato) "salan" ligands were prepared, their hydrolysis in 1:9 water/THF solutions was investigated, and their cytotoxicity toward colon HT-29 and ovarian OVCAR-1 cells was measured. In particular, electronic effects at positions ortho and para to the binding phenolato unit were analyzed. We found that para substituents of different electronic features, including Me, Cl, OMe, and NO(2), have very little influence on hydrolysis rate, and all para-substituted ortho-H complexes hydrolyze slowly to give O-bridged clusters with a t(1/2) of 1-2 h for isopropoxo release. Consequently, no clear cytotoxicity pattern is observed as well, where the largest influence of para substituents appears to be of a steric nature. These complexes exhibit IC(50) values of 2-18 μM toward the cells analyzed, with activity which is mostly higher than those of Cp(2)TiCl(2), (bzac)(2)Ti(OiPr)(2) and cisplatin. On the contrary, major electronic effects are observed for substituents at the ortho position, with an influence that exceeds even that of steric hindrance. Ortho-chloro or -bromo substituted compounds possess extremely high hydrolytic stability where no major isopropoxo release as isopropanol occurs for days. In accordance, very high cytotoxicity toward colon and ovarian cells is observed for ortho-Cl and -Br complexes, with IC(50) values of 1-8 μM, where the most cytotoxic complexes are the ortho-Cl-para-Me and ortho-Br-para-Me derivatives. In this series of ortho-substituted complexes, the halogen radius is of lesser influence both on hydrolysis and on cytotoxicity, while OMe substituents do not impose similar effect of hydrolytic stability and cytotoxicity enhancement. Therefore, hydrolytic stability and cytotoxic activity are clearly intertwined, and thus this family of readily available Ti(IV) salan complexes exhibiting both features in an enhanced manner is highly attractive for further exploration.

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

“…This rearrangement would change the overall charge of the compound from neutral to positive and may facilitate direct interaction with the DNA backbone through ionic interactions resulting in cell death (26). 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.…”

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

“…Nevertheless, numerous attempts to isolate pure LTiX 2 precursors failed; the water presumably originating from ligand preparation despite extensive purifications attempts (see SI), was sufficient to yield only hydrolysis products. The hydrolytic stability of the binuclear complexes was analyzed by 1 H NMR, adding 10% D 2 O to a DMSO-d 6 solution of the complexes, as previously described [15,16]. All salophan-Ti IV complexes were found to be highly stable, with t 1/2 above 100 h as expected for O-bridged clusters with no labile ligands [15,16,22,23,26].…”

“…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].…”

“…The organic phase was evacuated to give the red product, which was heated overnight at 60°C (0.33 g, 26%). 1 LTi(OiPr) 2 compounds [16,22] by mixing the ligand with 1 equiv. of Ti(OiPr) 4 in THF at room temperature and stirring for at least 2 h. 2 The complexes were analyzed by 1 H NMR that suggested the formation of binuclear Ti IV compounds with similar number of signals but at different chemical shifts, without any indications of labile isopropoxo ligands.…”