Synthesis and X-ray structure analysis of cytotoxic 2-picolylamino-type HfIV-bis-chelated complexes†
Abstract
Eight novel heteroleptic HfIV 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 HfIV 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 HfIV 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 HfIV 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.