Strong in vitro and vivo cytotoxicity of novel organoplatinum(II) complexes with quinoline-coumarin derivatives

Abstract

A series of novel organoplatinum(II) complexes, [Pt^II(QC1)(H-QC1)Cl] (Pt1), [Pt^II(QC2)(H-QC2)Cl] (Pt2), [Pt^II(QC3)(H-QC3)Cl] (Pt3), [Pt^II(QC4)(H-QC4)Cl]⋅CH₃OH (Pt4), [Pt^II(QC5)(H-QC5)Cl] (Pt5), [Pt^II(H-QC6)(DMSO)Cl₂] (Pt6), [Pt^II(H-QC7)(DMSO)Cl₂]⋅H₂O (Pt7), [Pt^II(H-QC8)(DMSO)Cl₂] (Pt8), [Pt^II(H-QC9)(DMSO)Cl₂]⋅CH₃OH (Pt9), [Pt^II(H-QC10)(DMSO)Cl₂] (Pt10) and [Pt^II(H-QC11)(DMSO)Cl₂] (Pt11), bearing quinoline-coumarin derivatives (H-QC1-H-QC11) have been first designed. Complexes Pt1-Pt11 selectively displayed obvious cytotoxicities in comparison to cisplatin for A549/DDP (cisplatin-resistant human lung adenocarcinoma) cells and HeLa cervical carcinoma cells, with IC₅₀ values as low as 100 nM-10.33 μM. In addition, Pt4 and Pt5 display a green-colored luminescent properties, targeted mitochondrial membrane and, thereby induced mainly mitochondria-mediated cell apoptosis was in the following order: Pt4 > Pt5. The different anti-cancer activity of quinoline-coumarin complexes Pt4 (100 nM) and Pt5 (250 nM) were correlate with the presence of 3-(2'-quinolyl)-6-hydroxy-coumarin (H-QC4) ligand. The quinoline-coumarin complex Pt4 (2.0 mg/kg per 2 days) also displayed potent in vivo anti-tumor effect after 21 days-treated. In contrast, the H-QC4 ligand highly enhances the anti-tumor activity and selectivity of organoplatinum(II) complexes in comparison to other previously reported coumarin derivatives metal complexes.

Keywords: Cell apoptosis; Mitochondria dysfunction; Organoplatinum(II) complexes; quinoline-coumarin derivatives.