Cytotoxic homoleptic Ti() compounds of ONO-type ligands: synthesis, structures and anti-cancer activity

• Published in: Dalton transactions : an international journal of inorganic chemistry 2019, Vol.48 (1), p.34-314
• Main Authors: Manne, Rajesh, Miller, Maya, Duthie, Andrew, Guedes da Silva, M. Fátima C, Tshuva, Edit Y, Basu Baul, Tushar S
• Format: Article
• Language: English
• Subjects: Anticancer properties; Cancer; Colon; Crystallography; Crystals; Cytotoxicity; Dependence; Dichloromethane; Hydroxybenzaldehydes; Lead compounds; Ligands; Oxygen atoms; Single crystals; Titanium; Toxicity; X-ray diffraction
• ISSN: 1477-9226; 1477-9234
• DOI: 10.1039/c8dt03747g

Eight Ti( iv ) compounds 1-8 , of the type [Ti(L n ) 2 ] where L n is a variously substituted dianionic tridentate acylhydrazone, were synthesized by reacting the appropriate hydrazide with 2-hydroxybenzaldehyde or 2′-hydroxyacetophenone and titanium( iv ) tetra(isopropoxide) in a 2 : 2 : 1 molar ratio. The solid-state structures of 1-6 and 7 ·CH 2 Cl 2 were deduced from the single crystal X-ray diffraction data, which indicated that each L 2− ligand is fully deprotonated and coordinated to the Ti( iv ) cation via the enolic oxygen, the imino nitrogen and the phenolic oxygen atoms (ONO donor set) in an enol tautomeric form, the metal assuming the distorted octahedral geometry. The structures of pro-ligands H 2 L 3 and H 2 L 5 are also reported. All complexes displayed high hydrolytic stability. In vitro cytotoxicity assays towards human ovarian A2780 and colon HT-29 cancer cell lines revealed the activity dependence on the acylhydrazone substituents, with electron-donating groups on the phenolato units enhancing the solubility and promoting cytotoxicity. The lead compound 5 of this study presents IC 50 values of 2.5 ± 0.2 and 4.2 ± 0.6 μM for ovarian A2780 and colon HT-29 human cancer cells, respectively. Reacting variously substituted dianionic tridentate ONO-type acylhydrazone ligands with titanium( iv ) tetra(isopropoxide) gave a new class of eight homoleptic titanium( iv ) compounds showing exceptional stability and promising cytotoxicity.