Active Cytotoxic Reagents Based on Non-metallocene Non-diketonato Well-Defined C₂-Symmetrical Titanium Complexes of Tetradentate Bis(phenolato) Ligands

Abstract

A new family of non-Cp-based non-diketonato-based C 2-symmetrical octahedral Ti(IV) complexes of dianionic diamine bis(phenolato) ligands, which are conveniently obtained as single isomers in quantitative yields, leads to appreciable cytotoxicity against colon and ovarian cells with a non-transferrin-dependent cell penetration mechanism. The ligand structural features including steric demands, symmetry, and aromaticity strongly influence activity, supporting its role in the biological mechanism of action.

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.…”

Synthesis, Characterization, Cytotoxicity, and Hydrolytic Behavior of C2‐ and C1‐Symmetrical TiIV Complexes of Tetradentate Diamine Bis(Phenolato) Ligands: A New Class of Antitumor Agents

“…[23] We have recently introduced a new family of cytotoxic agents based on readily accessible Ti IV complexes of diamine bis(phenolato) ligands. [33] These complexes demonstrate some resemblance to the active budotitane in terms of covalent donor types, coordination number, and general symmetry; however, unlike budotitane, they are obtained quantitatively in a single step as single (racemic) isomers [17,34] and include a single tetradentate dianionic ligand instead of two monoanionic ones. Some members of this 2 ] n = 1 or 2) exhibit higher activity against colon HT-29 and ovarian OVCAR-1 cells than those measured for titanocene dichloride, budotitane, and cisplatin, which is independent of transferrin.…”

“…[32] The reactivity is, however, strongly dependent on the particular ligand employed, since bulkier ligands ([Ti(L 3 )A C H T U N G T R E N N U N G (OiPr) 2 ]), aliphatic ligands, and ligands of branched donor connectivity that produce complexes of different symmetry all lead to substantially reduced activity. [33] Herein we elaborate on this family of complexes, discussing the effect of structural parameters on cytotoxicity and hydrolytic behavior of the complexes, while pointing to a connection between the two.…”

Anticancer Metal Complexes: Synthesis and Cytotoxicity Evaluation by the MTT Assay

“…The data received from the MTT assay is analyzed to evaluate the cytotoxicity of the compound 18,21 . First, subtraction of the blank control absorbance value from all the other values is performed.…”

“…Ti (IV) complexes were the first to enter clinical trials after cisplatin due to these properties; however, they have failed the trials due to formulation difficulties and hydrolytic instability. There is thus a current need to develop improved derivatives of these metal complexes that may combine high anticancer activity with water resistance 15,[17][18][19][20][21] .…”