Major impact of N-methylation on cytotoxicity and hydrolysis of salan Ti(IV) complexes: sterics and electronics are intertwined

Abstract

A series of Ti(IV) complexes containing diamino bis(phenolato) "salan" type ligands with NH coordination were prepared, and their hydrolysis and cytotoxicity were analyzed and compared to the N-methylated analogues. Substituting methyl groups on the coordinative nitrogen donor of highly active and stable Ti(IV) salan complexes with H atoms has two main consequences: the hydrolysis rate increases and the cytotoxic activity diminishes. In addition, the small modification of a single replacement of Me with H leads to a different major hydrolysis product, where a dinuclear Ti(IV) complex with two bridging oxo ligands is obtained, as characterized by X-ray crystallography, rather than a trinuclear cluster. A partial hydrolysis product containing a single oxo bridge was also crystallographically analyzed. Investigation of a series of complexes with NH donors of different steric and electronic effects revealed that cytotoxicity may be restored by fine tuning these parameters even for complexes of low stability.

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

“…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]. 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.…”

“…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.…”