Synthesis and X-ray Structure Analysis of Cytotoxic 2-Picolylamino type Hf IV-bis-Chelated Complexes

Abstract

Eight novel heteroleptic Hf^IV complexes containing differently substituted 2-picolylamino-bis-phenolate and 2,6-dipicolinic acid (Dipic) as chelating ligands were synthesized and characterized with yields higher than 80%. These [ONON] type Hf^IV complexes have good aqueous stability and potent anti-tumor activity against Hela S3 (human cervical adenocarcinoma) and Hep G2 (human derived hepatoma) cells. In particular, the complexes demonstrated selective inhibitory activity against Hep G2 cells. The IC₅₀ of the most cytotoxic complex [L₁Hf^IVDipic^4-Cl] (0.9 ± 0.4 μM) was ten fold higher than that of cisplatin (11.2 ± 2.1 μM) on Hep G2 cells, being the most cytotoxic anti-tumor Hf^IV complex to date. Furthermore, [L₁Hf^IVDipic^4-Cl] could inhibit tumor cell migration, induce reactive oxygen species generation (particullarly HO•), loss of mitochondrial membrane potential and almost exclusive early apoptosis in Hela S3 cells. [L₁Hf^IVDipic^4-Cl] exhibited rapid cellular uptake by Hela S3 cells, and when in aqueous media, these Hf^IV complexes slowly hydrolyzed, releasing non-toxic phenolato ligands as the product of hydrolysis. Overall, these rare earth complexes, particularly [L₁Hf^IVDipic^4-Cl], show promising potential as novel anticancer agents with significant efficacy against human liver cancer cells and favorable selectivity profiles for further therapeutic development.