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We recently introduced a new class of bis(isopropoxo)-Ti(IV) complexes with diamine bis(phenolato) ligands that possess antitumor activity against colon HT-29 and ovarian OVCAR-1 cells that is higher than that of the known Ti(IV) compounds titanocene dichloride and budotitane as well as that of cisplatin. Herein, we elaborate on this family of compounds; we discuss the effect of structural parameters on the cytotoxic activity and hydrolytic behavior of these complexes, seeking a relationship between the two. Whereas complexes with small steric groups around the metal center possess high activity and lead mostly to formation of O-bridged polynuclear complexes with bound bis(phenolato) ligand upon water addition, bulky complexes hydrolyze to release all free ligands and are inactive. Slightly increasing the size of the N-donor substituents probably weakens the ligand binding in solution, and, thus, rapid hydrolysis is observed, leading to a lack of cytotoxicity, supporting the requirement for ligand inertness. Replacing the two isopropoxo ligands with a single catecholato unit gives a complex with a different geometry that exhibits slower hydrolysis and reduced cytotoxicity, suggesting some participation of labile ligand hydrolysis in the cytotoxicity mechanism. A crystallographically characterized O-bridged polynuclear species obtained from a biologically active bis(isopropoxo) complex upon water addition is inactive, which rules out its participation as the active species, yet suggests some role of the particular steric and electronic requirements allowing its formation in the activity mechanism. Additional measurements support rapid formation of the active species in the presence of cells prior to O-bridged Ti(IV) cluster formation.

Novel amine bis(phenolate) zirconium dibenzyl complexes were synthesized in quantitative yields from a versatile family of chelating amine−bis((2-hydroxyaryl)methyl) ligand precursors, their X-ray structures solved, and their reactivity in the polymerization of 1-hexene in the presence of B(C6F5)3 studied. Several minor peripheral structural modifications were studied and found to have a major influence on the catalyst performance. Thus, a variety of reactivities, ranging from extremely high to negligible, were obtained, demonstrating a unique structure−reactivity relationship. This relationship is partially revealed from the crystal structures of the precatalysts, indicating similar [ONO] ligand cores in all structures solved. A correlation between the solid and the solution structures is obtained from 1H NMR spectra, which reveal a rigid binding of the ligand to the metal. The solid structures are therefore proposed to serve as reliable references when studying structure−reactivity relationships. The most significant structural parameter was found to be the existence of an extra donor located on a pendant arm. [ONO]-type pentacoordinate complexes lacking such an additional donor are rapidly deactivated and lead only to traces of oligomers. On the other hand, hexacoordinate complexes based on [ONNO]-type ligands, in which strong donation of a side donor to the metal is obtained through formation of a five-membered chelate, lead to extremely reactive polymerization catalysts. The nitrogen hybridization and aromatic ring substituents have a more subtle effect on reactivity. Increasing the chelate size results in either no binding of the side donor, yielding negligible reactivity, or strong binding yet moderate polymerization reactivity. Increasing the steric bulk on the donor results in weakening of the metal−donor bond, leading to a moderate oligomerization catalyst. The sidearm nitrogen is therefore proposed to play a crucial role in determining the propagation process rate, as well as the propagation/termination rate ratio.

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.