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. 2018 Jun 28;7(5):987-993.
doi: 10.1039/c8tx00127h. eCollection 2018 Sep 1.

Less toxic zinc(ii), diorganotin(iv), gallium(iii) and cadmium(ii) complexes derived from 2-benzoylpyridine N, N-dimethylthiosemicarbazone: synthesis, crystal structures, cytotoxicity and investigations of mechanisms of action

Yan Fang  1 , Jie Li  1 , Pei-Pei Han  1 , Qiu-Xia Han  1 , Ming-Xue Li  1
Affiliations

Less toxic zinc(ii), diorganotin(iv), gallium(iii) and cadmium(ii) complexes derived from 2-benzoylpyridine N, N-dimethylthiosemicarbazone: synthesis, crystal structures, cytotoxicity and investigations of mechanisms of action

Yan Fang et al. Toxicol Res (Camb). .

Abstract

Four metal complexes based on 2-benzoylpyridine N,N-dimethylthiosemicarbazone (Bp44mT) were designed. Free ligand and zinc(ii), diorganotin(iv), gallium(iii) and cadmium(ii) complexes all demonstrated pronounced activity, which was indicated using the growth inhibition test in vitro. Interestingly, most of the compounds were found to be selective against hepatocellular carcinoma (HepG2) cells but had little effect on normal hepatocyte (QSG7701) cells. In particular, Zn(Bp44mT)2 (1) exhibited toxicity on QSG7701 cells which approximately 12-fold lower than that on HepG2 cells. The studies of mechanisms of action indicated that 1 induced reactive oxygen species (ROS) generation in a dose-dependent manner via the mitochondria transduction pathway. Protein analyses showed that 1 significantly promoted p21 and p53 gene expression, causing caspase-3 activation.

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Figures

Scheme 1
Scheme 1. The synthetic reactions of complexes 1–4.
Fig. 1
Fig. 1. The cytotoxicity of the tested compounds against hepatocellular carcinoma HepG2 cells and normal hepatocyte QSG7701 cells. All the data are expressed as the mean ± standard deviation (SD) from four separate determinations.
Fig. 2
Fig. 2. Cell morphology was observed using phase contrast microscope (×200 magnification, bar = 20 μm) after treatment with 2 μM 1 for 24 h.
Fig. 3
Fig. 3. Effects of 1 on intracellular ROS in HepG2 cells. n = 4, Mean ± SD, p < 0.05 versus control group.
Fig. 4
Fig. 4. Significant reduction in MMP was induced by 1 in HepG2 cells. After treating with the indicated concentration of 1, the cells were loaded with membrane-sensitive probe, Rh123. Flow cytometry was applied for determining the rhodamine retention. On this basis, the linear graph of the corresponding fluorescence activated cell sorting (FACS) histogram is given. n = 4, mean ± SD, p < 0.05 versus control group.
Fig. 5
Fig. 5. Effects of 1-induced activation of caspase-3. The HepG2 cells were treated with the indicated concentrations of 1 for 24 h, and the expression levels of caspase-3 were detected using indirect immunofluorescence. n = 4, mean ± SD, p < 0.05 versus control group.
Fig. 6
Fig. 6. Effects of 1 on the activation of the p53 gene in HepG2 cells using an in vitro kinase test. n = 4, mean ± SD, p < 0.05 versus control group.
Fig. 7
Fig. 7. Effects of 1 on the activation of the p21 gene in HepG2 cells using an in vitro kinase test. n = 4, mean ± SD, p < 0.05 versus control group.
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