Chemotherapeutic Activities of New η6- p-Cymene Ruthenium(II) and Osmium(II) Complexes with Chelating SS and Tridentate SNS Ligands

Abstract

A series of new chelating bidentate (SS) alkylimidazole-2-thione-Ru(II)/Os(II) complexes (3a_i, 3a_ii, 3a_iii, 3b_ii/4a_iii, 4b_i, 4b_ii), and the tridentate (SNS) pyridine-2,6-diylimidazole-2-thione-Ru(II)/Os(II) complexes (5b_i, 5c_iv/6bi, 6c_i, 6c_iv) in the forms [M^II(cym)(L)Cl]PF₆ and [M^II(cym)(L)]PF₆ (M = Ru or Os, cym = η⁶-p-cymene, and L = heterocyclic derivatives of thiourea) respectively, were successfully synthesized. Spectroscopic and analytical methods were used to characterize the complexes and their ligands. Solid-state single-crystal X-ray diffraction analyses revealed a "piano-stool" geometry around the Ru(II) or Os(II) centers in the respective complexes. The complexes were investigated for in vitro chemotherapeutic activities against human cervical carcinoma (HeLa) and the non-cancerous cell line (Hek293) using the MTT assay. The compounds 3a_ii, 5c_iv, 5b_i, 4a_iii, 6c_i, 6c_iv, and the reference drug, 5-fluorouracil were found to be selective toward the tumor cells; the compounds 3a_i, 3a_iii, 3b_ii, 4b_i, 4b_ii, and 6b_i, which were found not to be selective between normal and tumor cell lines. The IC₅₀ value of the tridentate half-sandwich complex 5b_i (86 ± 9 μM) showed comparable anti-proliferative activity with the referenced commercial anti-cancer drug, 5-fluorouracil (87 ± 15 μM). The pincer (SNS) osmium complexes 6c_i (36 ± 10 μM) and 6c_iv (40 ± 4 μM) were twice as effective as the reference drug 5-fluorouracil at the respective dose concentrations. However, the analogous pincer (SNS) ruthenium complex 5c_iv was ineffective and did not show anti-proliferative activity, even at a higher concentration of 147 ± 1 μM. These findings imply that the higher stability of the chelating (SS) and the pincer (SNS) ligand architectures in the complexes improves the biological (anti-proliferative) activity of the complexes by reducing the chance of ligand dissociation under physiological conditions. In general, the pincer (SNS) osmium complexes were found to be more cytotoxic than their ruthenium analogues, suggesting that the anti-proliferative activity of the imidazole-2-thione-Ru/Os complexes depends on the ligand's spatial coordination, the nature of the metal center, and the charge of the metal complex ions.

Keywords: anti-cancer; half-sandwich complexes; imidazole-2-thiones; molecular structures; osmium; ruthenium.