Synthesis and X-ray structure analysis of cytotoxic 2-picolylamino-type Hf^IV-bis-chelated complexes

Eight novel heteroleptic Hf^IV complexes containing differently substituted 2-picolylamino-bis-phenolate and 2,6-dipicolinic acid (Dipic) groups 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 value of the most cytotoxic complex [L1HfIVDipic4-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, [L1HfIVDipic4-Cl] could inhibit tumor cell migration, induce reactive oxygen species generation (particularly HO˙), loss of mitochondrial membrane potential and almost exclusive early apoptosis in HeLa S3 cells. [L1HfIVDipic4-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 [L1HfIVDipic4-Cl], show promising potential as novel anticancer agents with significant efficacy against human liver cancer cells and favorable selectivity profiles for further therapeutic development.