In vitro and in vivo antitumor activities of three novel binuclear platinum(II) complexes with 4′-substituted-2,2′:6′,2″-terpyridine ligands

Abstract

Herein, we report the design and synthesis of three novel binuclear platinum(II) complexes, [Pt(tpbtpy)Cl][Pt(DMSO)Cl3] (tpbtpy-Pt), [Pt(dthbtpy)Cl][Pt(DMSO)Cl3]⋅CH3OH (dthbtpy-Pt), and [Pt(qlbtpy)Cl][Pt(DMSO)Cl3]⋅CH3OH (qlbtpy-Pt) with 4′-(3-thiophenecarboxaldehyde)-2,2′:6′,2″-terpyridine (tpbtpy), 4′-(3,5-bis (1,1-dimethylethyl)-2-hydroxy-benzaldehyde)-2,2′:6′,2″-terpyridine (dthbtpy) and 4′-(2-quinolinecarboxaldehyde)-2,2′:6′,2″-terpyridine (qlbtpy) as ligands, respectively. All three novel binuclear platinum(II) complexes tpbtpy-Pt, dthbtpy-Pt, and qlbtpy-Pt were characterized by single-crystal X-ray diffraction analysis, spectroscopic analysis (ESI-MS, IR, 1H NMR), and elemental analysis. Additionally, the cytotoxicity of tpbtpy-Pt, dthbtpy-Pt and qlbtpy-Pt was assessed with human non-small cell lung cancer cell line (NCIH460 cells), yielding IC50 values in the range of 0.35–12.09 μM with tpbtpy-Pt as the most potent and qlbtpy-Pt as the least potent complexes. Mechanistic studies indicated that tpbtpy-Pt and dthbtpy-Pt induced apoptosis through mitochondrial dysfunction and telomerase inhibition. In a NCIH460 xenograft model, when administered at 10.0 mg kg−1 every 2 days, tpbtpy-Pt was shown to significantly reduce tumor growth (tumor growth inhibition rate (IR) = 70.1%, p < 0.05). Therefore, tpbtpy-Pt is a promising Pt(II) complex for further translational studies and clinical evaluation as an antitumor agent.