Modern cytotoxic titanium(IV) complexes; Insights on the enigmatic involvement of hydrolysis

Abstract

In this paper, we describe our recent results with three families of Ti(IV) complexes, elaborating on their cytotoxic activity, hydrolytic behavior, and the potential connection between the two. Complexes of diamine bis(phenolato) ligands, particularly those of ligands of sequential arrangement of donor atoms, demonstrate appreciable activity towards colon HT-29 and ovarian OVCAR-1 cell, which is higher than that of titanocene dichloride, budotitane and cisplatin. Strong dependence of activity on the particular ligand is observed, where small modifications relating to steric bulk at various locations, electronic effects, ligand lability, general symmetry of the complex and more, have a major effect on the cytotoxic activity. An interesting correlation between cytotoxic activity and hydrolytic behavior is observed. Complexes of cytotoxic activity lead upon addition of water to defined O-bridged clusters within several hours, which is a particularly slow period for such processes, where the bulk of the substituents located near the metal site affects the rate of hydrolysis. In contrast, complexes that are inactive biologically either decompose rapidly, or possess steric bulk too large to form the O-bridged cluster. Additional mechanistic investigations revealed that the activity is independent of transferrin, and that the cell penetration of the active species by an alternative mode occurs relatively rapidly prior to its decomposition to give inactive complexes, among which, the O-bridged cluster. Thus, a relatively inert ligand is required to allow this process and stabilize the active species, while hydrolysis of the more labile groups seems to be essential for its formation. These conclusions are also supported by additional studies conducted with hydroxylamino-triazine compounds, which proved them to be excellent ligands for Ti(IV) forming especially short Ti–N coordinative bonds, thus leading to exceptionally high hydrolytic stability. Some cytotoxic activity was observed for highly inert homoleptic Ti[ONO] 2 complexes of this family, while lack of activity was obtained with analogous substantially more rigid [ONNO]Ti(OiPr) 2 complexes featuring weaker ligand binding and thus hydrolytic instability. Well-defined Ti(IV) complexes of bis(carboxylato) ligands are more difficult to obtain due to the ability of the carboxylato groups to bind in a bidentate mode and bridge two metal centers, nevertheless, such complexes are in general more hydrolytically instable and lack cytotoxic activity.