Mitochondria-localizing dicarbohydrazide Ln complexes and their mechanism of in vitro anticancer activity

• Published in: Dalton transactions : an international journal of inorganic chemistry Vol. 49; no. 14; pp. 4404 - 4415
• Main Authors: Meng, Ting, Liu, Tong, Qin, Qi-Pin, Chen, Zi-Lu, Zou, Hua-Hong, Wang, Kai, Liang, Fu-Pei
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 07.04.2020
• Subjects: Anticancer properties; Apoptosis; Cancer; Crystallography; Fluorescence; Ligands; Mitochondria; Structural analysis; Toxicity
• ISSN: 1477-9226; 1477-9234
• DOI: 10.1039/d0dt00210k

In this study, two novel organic ligands, bis(salicylaldehyde)pyrazino-1,10-phenanthroline-7,10-dicarbohydrazide (L) and bis(salicylaldehyde)-1,10-phenanthroline-7,10-dicarbohydrazide (L1), were synthesized. These ligands were used to react with lanthanide(iii) acetate to obtain complexes 1-6, namely, [Dy5(L)2(CH3COO)5(CH3OH)(μ3-OH)(μ2-OH)(H2O)]·2CH3OH (1), [Tb5(L)2(CH3COO)5(CH3OH)(μ3-OH)(μ2-OH)(H2O)]·3CH3OH (2), [Gd5(L)2(CH3COO)5(CH3OH)(μ3-OH)(μ2-OH)(H2O)]·3CH3OH (3), [Dy5(L1)2(μ2-OH)(μ3-OH)(CH3COO)5(CH3OH)(H2O)2]·2H2O (4), [Dy5(L1)2(μ3-OH)(CH3COO)6(CH3OH)3]·CH3OH (5), and [Dy5(L1)2(μ2-OH)2(μ3-OH)(CH3COO)4(CH3OH)(H2O)2]·CH3OH (6). Fluorescence studies demonstrated that complexes 1-6 show appreciable fluorescence in the yellow-green region. In vitro antitumor screening revealed that complex 1 exhibits better inhibitory activities than the commercial anticancer drug cisplatin against SK-OV-3 and A549 tumor cell lines, with IC50 values of 8.09 ± 1.25 and 13.26 ± 0.39 μM, respectively. All six complexes showed low cytotoxicity toward normal human liver HL-7702 cells compared with cisplatin. Complexes 1 and 3 induced the highest apoptosis rate of SK-OV-3/DDP cells. They also bind to DNA via an intercalative mode with the binding constant Kq values of 1.6 × 104 and 1.19 × 104 L mol-1, respectively. Confocal fluorescence imaging ascertained that complexes 1 and 3 are primarily localized in the mitochondria. Further studies revealed that these complexes trigger SK-OV-3/DDP cell apoptosis via a mitochondrial dysfunction pathway, which is probably caused by the reduction of the mitochondrial membrane potential and the induction of reactive oxygen species production.