FULL PAPER DOI:10.1002/ejic.201301463 Cytotoxic Titanium(IV) Complexes of Chiral Diaminobis(phenolato) Ligands: Better Combination of Activity and Stability by the Bipyrrolidine Moiety Maya Miller [a] and Edit Y. Tshuva* [a] Keywords: Cytotoxicity / Anticancer agents / Titanium / Chiral induction / Hydrolysis Racemic and enantiomerically pure titanium(IV) complexes with ortho-bromo-para-methyl-substituted diaminobis(phen- olato) ligands were prepared with NH-, NMe-, and bipyrrol- idine-based diamino bridges through ligand-to-metal chiral induction. The hydrolytic stability of the complexes was evaluated, and their cytotoxicity was measured using HT-29 human colon cancer cells based on the MTT assay. All stereochemical forms of the NMe-based complexes, although demonstrating the highest hydrolytic stability, were biolo- Introduction Titanium(IV) complexes often demonstrate appreciable cytotoxic properties, and represent an attractive alternative to platinum-based anticancer drugs due to their wide range of activities and potentially reduced side effects. [1] Follow- ing reports on the cytotoxic activity of Cp- and diketonato- based titanium(IV) complexes, compounds of salan-type di- aminobis(phenolato) ligands were investigated (Scheme 1) and showed promising results both in vitro and in vivo, [2–5] where: (a) they were markedly more active than cisplatin toward various cancer cell lines; [5] (b) they demonstrated little to no effect on non-cancerous cells; [5] and (c) they dis- played enhanced hydrolytic stability. [3,5,6] Structure–activity relationship (SAR) investigations have revealed that cytoto- xicity generally correlates with hydrolytic stability; ortho- halogenation increases the stability, whereas increased steric bulk negatively influences the cytotoxic activity. [3,6] Scheme 1. Salan titanium(IV) complexes. Bis(alkoxo) salan titanium(IV) complexes generally pos- sess C 2 -symmetry, rendering them chiral. Evaluation of separate enantiomers is essential for further exploration of [a] Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel E-mail: edit.tshuva@mail.huji.ac.il http://chem.ch.huji.ac.il/~tshuva/ Eur. J. Inorg. Chem. 2014, 1485–1491 © 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1485 gically inactive. For the NH and bipyrrolidine-based active complexes, the pure enantiomers exhibited high cytotoxicity whereas the racemic mixtures were inactive, supporting the involvement of a polynuclear active species. The bipyrrol- idine complexes appear to provide the best combination of hydrolytic stability and biological activity, presumably by mi- nimizing steric bulk and consequently enabling biological accessibility. compounds as potential pharmaceuticals. Previous studies with trans-cyclohexyldiamine-based ligands have afforded enantiomerically pure complexes by ligand-to-metal chiral induction. [7–10] Different cytotoxicities for optically pure complexes versus their racemates support the notion that the active species is a polynuclear compound composed of several chiral centers. [7,8] Later evidence for the cytotoxic activity of the insoluble salan-bound polynuclear hydrolysis products of related complexes, when formulated into nano- particles, supports their participation as the active species in the cell. [11] Additionally, cyclohexyl-based complexes with NH donors have generally shown higher activity for the enantiomerically pure species relative to the racemic mixtures, whereas for N-methylated complexes, the racemic mixtures were generally the most active. [7,8] Moreover, N- methylated complexes, although substantially more stable to hydrolysis, have demonstrated a stronger dependence of cytotoxicity on steric bulk probably due to the additive influence of the methyl substitutions and the cyclohexyl rings, which was a limiting factor. A possible explanation for these observations may relate to the nature of the hy- drolysis product that participated in the biological interac- tions. N-methylated complexes in water afforded salan- bound trinuclear clusters, which are bulkier than the di- meric products of the NH complexes. [2,3,6] The large steric bulk is presumed to hamper accessibility of the compounds to their cellular target. [11] This paper presents optically pure derivatives of salan- type titanium(IV) complexes that are based on the more compact bipyrrolidine chiral moiety, enabling ligand-to- metal chiral induction for isolation of pure enantiomers. [12] This moiety is shown to provide a better combination of