Synthesis of asymmetrical diaminobis(alkoxo)-bisphenol compounds and their C1-symmetrical mono-ligated titanium(iv) complexes as highly stable highly active antitumor compounds

Abstract

Asymmetrical 2,2'-((ethane-1,2-diylbis((2-hydroxyethyl)azanediyl))bis(methylene))diphenol substituted compounds and their C₁-symmetrical diaminobis(phenolato)-bis(alkoxo) titanium(iv) complexes were synthesized, with one symmetrical analogue. X-ray crystallography corroborated tight ligand binding. Different substitutions on the two aromatic rings enabled fine-tuning of the complex properties, giving enhanced solubility, high anticancer activity (IC₅₀ < 4 μM), and significant hydrolytic stability.

Scheme 1. Ti(iv) complexes with bis(phenolato) salan ligand (left), and with bis(phenolato)-bis(alkoxo) ligand (right).

Scheme 2. Synthesis of asymmetrical diaminobis(phenolato)-bis(alkoxo) ligands and their Ti(iv) complexes.

Fig. 1. ORTEP drawing of L^3,4Ti with 50% probability ellipsoids; H atoms and solvent were omitted for clarity. Selected bond lengths (Å) and angels (°): Ti(1)–O(1) 1.871(2), Ti(1)–O(2) 1.876(2), Ti(1)–O(3) 1.880(2), Ti(1)–O(4) 1.886(2), Ti(1)–N(1) 2.205(2), Ti(1)–N(2) 2.241(2); O(1)–Ti(1)–O(4) 107.19(7), O(2)–Ti(1)–O(3) 157.76(8), N(1)–Ti(1)–N(2) 81.33(7).

Fig. 2. Dependence of HT-29 (top), A2780 (middle), and A2780cp (bottom) cell viability based on the MTT assay following a three day incubation period with administered concentration of LTi; in parenthesis: relative IC₅₀ values (μM), maximal cell growth inhibition (MI) (%).