Homoleptic Ti[ONO]₂ type complexes of amino‐acid‐tethered phenolato Schiff‐base ligands: Synthesis, characterization, time‐resolved fluorescence spectroscopy, and cytotoxicity against ovarian and colon cancer cells

Abstract

Six homoleptic Ti(IV) compounds of dianionic tridentate Schiff base ligands were synthesized from chiral amino acids, 2-hydroxybenzaldehyde and Ti(OiPr)4. The compounds were spectroscopically characterized and the molecular geometries were established by X-ray crystallography. The ligands coordinated the titanium via carboxylate-O-, imine-N-, and phenoxide-O atoms. Two isomers were identified; each based on a trans-N2O4 donor set, but one with trans carboxylate-O atoms and another with each carboxylate-O atom trans to a phenoxide-O atom. Photophysical profiles exhibited faster excited-state relaxation in the solid phase than in solution. Marked cytotoxicities were recorded toward human ovarian A2780 and colon HT-29 cancer cells with IC50 values ranging between 23±2 and 103±3 µM. Comparative hydrolytic stability studies by NMR in 10% D2O solutions provided t1/2 values of up to 15±2 h, with little correlation to cytotoxicity implying a role of hydrolysis products in the reactivity and identifying steric bulk as a contributor to stability and solubility.

Automated and Efficient Generation of General Molecular Aggregate Structures

“…To demonstrate the general applicability and efficiency of the aISS algorithm and to validate the resulting structures, we investigated a variety of currently researched dimers and trimers (Figure 2). [35–40] …”

“…To demonstrate the general applicability and efficiency of the aISS algorithm and to validate the resulting structures, we investigated a variety of currently researched dimers and trimers (Figure 2). [35][36][37][38][39][40] These small to medium-sized systems contain up to 300 atoms including heavy main-group elements and transition metals, which are usually challenging or not even included for common force fields that do not employ electronic information. Thus, the default GFN2-xTB [41] was chosen for the final geometry optimizations in the aISS algorithm (aISS//GFN2-xTB).…”

Hydrolytically Stable and Cytotoxic [ONON]2Ti(IV)-Type Octahedral Complexes

“…32 ligands were observed only for tridentate [ONO]-type ligands (Scheme 1, bottom) 25,33,34 and were mostly unstable and inactive, although some related complexes of mono-phenolato ligands exhibit stability and cytotoxicity. 25,36,37 Herein, we report on octahedral [ONON] 2 Ti complexes, obtained from [ONON]-type ligands without binding of the side amine donor (Scheme 2). In particular, heating provided an entropic drive for second ligand binding without coordination of the dangling N donor.…”

“…A ligand with ortho- and para-dimethylated aromatic rings and a diethylated side amine donor arm (Scheme , middle: R = Me, R′ = Et) is bound similarly to give an LTiX 2 -type complex, despite the relatively long Ti–N bond (2.46 Å) leading to negligible stability and activity . Homoleptic L 2 Ti complexes of bis­(phenolato) ligands were observed only for tridentate [ONO]-type ligands (Scheme , bottom) ,, and were mostly unstable and inactive, although some related complexes of mono-phenolato ligands exhibit stability and cytotoxicity. ,, …”

“… 32 Homoleptic L 2 Ti complexes of bis(phenolato) ligands were observed only for tridentate [ONO]-type ligands ( Scheme 1 , bottom) 25 , 33 , 34 and were mostly unstable and inactive, although some related complexes of mono-phenolato ligands exhibit stability and cytotoxicity. 25 , 36 , 37 …”