Skip to main content
NCBI home page
ACS Medicinal Chemistry Letters logoLink to ACS Medicinal Chemistry Letters
. 2021 Feb 26;12(3):467–476. doi: 10.1021/acsmedchemlett.0c00680

Novel Copper(II) Complex with a 4-Acylpyrazolone Derivative and Coligand Induce Apoptosis in Liver Cancer Cells

Marhaba Nurmamat †, Haili Yan †, Ru Wang †, Huixin Zhao †, Yanhong Li †, Xiaojing Wang †, Kaidirye Nurmaimaiti †, Tamasha Kurmanjiang †, Difang Luo †, Jumagul Baodi †, Guancheng Xu ‡,*, Jinyu Li †,*
PMCID: PMC7957940  PMID: 33738074

Abstract

graphic file with name ml0c00680_0009.jpg

A novel pyrazolone-based copper complex [CuL(phen)(CH3OH)][CuL(phen)]·CH3CH2OH·CH3OH (P-FAH-Cu-phen) was synthesized and characterized. The asymmetric structural unit of P-FAH-Cu-phen was composed of two independent complex units [CuL(phen)(CH3OH)] and [CuL(phen)]:Cu12+ center with six coordination mode and Cu22+ center with five coordination mode. The growth of BEL-7404 cells and H22 cells was significantly inhibited by P-FAH-Cu-phen with IC50 values of 1.175 μg/mL and 1.097 μg/mL, respectively, which were much lower than IC50 of cisplatin for BEL-7404 cells (23.32 μg/mL) and H22 cells (27.5 μg/mL). P-FAH-Cu-phen induced cell cycle arrest at G2/M and apoptosis in BEL-7404 cells through mitochondria- and endoplasmic reticulum stress-associated pathways. Moreover, P-FAH-Cu-phen significantly suppressed the migration of BEL-7404 cells and the tumor growth in H22 tumor mouse model without severe side effects and improved the survival of tumor mice. The results suggested that P-FAH-Cu-phen might be a potential drug candidate for the treatment of live cancer.

Keywords: Pyrazolone-based copper complex, structure, antitumor effect, apoptosis

Primary liver cancer is the fifth most common cancer and the second leading cause of cancer mortality worldwide with 841 080 new cases diagnosed and 781 631 deaths in 2018.1,2 Africa, East Asia, and Southeast Asia are high-risk areas for liver cancer, nearly half of which occur in China.3 Around 85–90% of primary liver cancer is hepatocellular carcinoma (HCC). Owing to the lack of clinical symptoms, HCC patients often progress to the advanced stage when diagnosed, and they are not suitable for early surgical treatment.4 Currently, there are limited therapies for advanced HCC patients. The 5-year survival rate of advanced HCC patients decreased to 1%, which is the lowest among all solid tumors.5 Sorafenib and lenvatinib are often first-line options for the treatment of advanced HCC, but only a few patients can gain long-term benefits from them. Besides, high drug resistance and toxicity further limit the advantages of their treatments.6 Therefore, it is urgent to develop novel drugs with low side effect for advanced HCC.

Since Rosberg discovered the antitumor activity of cisplatin in 1969, platinum-based antitumor drugs including cisplatin, carboplatin, and oxaliplatin have been broadly used in the clinical treatment of cancers.7,8 However, these drugs often develop drug resistance and cause severe side effects. The development of other non-platinum metal drugs with low side effects has drawn more and more attention in the treatment of cancers.9 A large number of non-platinum transition metal compounds, such as ruthenium, titanium, and copper, have been extensively evaluated for their antitumor activity in vitro and in vivo, and some of them have already entered phase I and phase II trials.10,11 Among the metal compounds, copper complexes have been considered as one of the best alternatives to cisplatin.12 Compared with platinum drugs, copper complexes may be more effective anticancer agents, which not only reduce drug resistance and toxicity but also may resensitize platinum drug resistant cancer cells.13

Over the years, metal complexes with Schiff base have been successfully incorporated into new drugs and therapeutic agents.14,15 Great attention has been paid to pyrazolone Schiff base derivatives due to their advantages including many coordination atoms and multiple coordination modes,16,17 as well as a wide range of biological activities.18,19 A novel pyrazolone-based cadmium(II) complex was able to induce apoptosis in Eca-109 cells by the production of reactive oxygen species (ROS) and mitochondria-dependent pathway.20 Four mixed ligand Cu(II) complexes derived from 4-acylpyrazolone could induce apoptosis in A549 cells via a Bcl-2 independent pathway.21 Recently, we synthesized three cadmium(II) complexes with a 4-acylpyrazolone derivative, which showed higher cytotoxic activity on HeLa and Eca-109 cells compared with cisplatin.22 These results indicated that the metal complexes of 4-acylpyrazolone derivative have the potential for the development of anticancer drugs.

In this study, we synthesized a novel copper complex of pyrazolone derivative [CuL(phen)(CH3OH)][CuL(phen)]·CH3CH2OH·CH3OH, (H2L = N-(1-phenyl-3-methyl-4-(4-chlorobenzoyl)-5-pyrazolone)-2-furan carboxylic acid hydrazide, phen = 1,10-phenanthroline) (P-FAH-Cu-phen). The antitumor effects of P-FAH-Cu-phen on HCC cells both in vitro and in vivo were detected, and its potential molecular mechanism was also investigated.

The copper(II) complex P-FAH-Cu-phen was synthesized in 65% yield by reaction of methanolic solution of Cu(OAc)2·H2O and N-(1-phenyl-3-methyl-4-(4-chlorobenzoyl)-5-pyrazolone-2-furoic acid hydrazide (Figure 1A) in a mixture of methanol/ethanol 7:3 with 1,10-phenanthroline in 1:1:1 molar ratio upon slow evaporation at room temperature for 1 week. The result of single crystal X-ray diffraction study of the complex is shown in Figure 1B. The complex crystallized in a centrosymmetric triclinic space group P-1. Its asymmetric structural unit consists of two independent complex units [CuL(phen)(CH3OH)] and [CuL(phen)]. The Cu12+ center is six-coordinate, while the Cu22+ center is five-coordinate.

Figure 1.

Figure 1

Open in a new tab

Structure of ligand H2L (A) and crystal structure of P-FAH-Cu-phen (B).

In the structural unit of the Cu12+ center, each Cu12+ ion is hexacoordinated by the O2, O3, N4 atoms from a ligand anion L2– and N1 and N2 atoms from 1,10-phenanthroline and O7 atom from the coordinated methanol molecule to form a CuN3O3 coordination environment. Moreover, O2, O3, N1, and N4 atoms consist of an equatorial plane. The bond lengths of Cu1–O2, Cu1–O3, Cu1–N1, and Cu1–N4 are 1.974 (2) Å, 1.950 (2) Å, 2.030 (3) Å, and 1.948 (3) Å, respectively, which are in the normal range. The axial positions are occupied by O7 and N2 atoms, and the bond lengths of Cu1–O7 and Cu1–N2 are 2.566 (5) Å and 2.339 (3) Å, respectively. The bond angles of O3–Cu1–O2, O7–Cu1–N2, and N4–Cu1–N1 are 169.45 (10)°, 167.49 (2)°, and 171.01 (11)°, respectively, which deviate from the theoretical value of 180°. These data indicated that the coordination geometry of Cu12+ ion can be regarded as a distorted octahedron.23

In the structural unit of the Cu22+ center, each Cu22+ ion is pentacoordinated by O5, O6, N8 atoms from a ligand anion L2– and N11 and N12 atoms from 1,10-phenanthroline to form a square pyramid geometry. The base plane is composed of O5, O6, N8, and N12 atoms, and the bond lengths of Cu2–O5, Cu2–O6, Cu2–N8, and Cu2–N12 are 1.942 (2) Å, 1.961 (2) Å, 1.945 (3) Å, and 2.010 (3) Å, respectively. The apex of the square pyramid is occupied by N11 atom, and the bond length of Cu2–N11 is 2.254 (3) Å. The bond angles of O5–Cu2–O6 and N8–Cu2–N12 are 161.25 (10)° and 173.08 (11)°, respectively. The coordination configuration of Cu22+ ions should be a distorted square pyramid with a CuN3O2 donor set, which is reflected by the τ value (0.20) defined by Addison et al. (τ = 0 for an ideal square pyramid and τ = 1 for an ideal trigonal bipyramid).23

To investigate the antitumor effect of P-FAH-Cu-phen on HCC cells, P-FAH-Cu-phen was used to treat BEL-7404 and H22 cells in vitro. After 24 h, the morphological changes of BEL-7404 cells were observed by an inverted microscope. As shown in Figure 2A, the cell morphology gradually became round and shrunk with the increase of concentration. Next, the viability of BEL-7404 and H22 cells was determined by MTT assay after P-FAH-Cu-phen treatment. P-FAH-Cu-phen significantly reduced cell viability of BEL-7404 and H22 cells in a dose- and time-dependent manner (Figure 2B and Figure 2C). The IC50 values of P-FAH-Cu-phen on BEL-7404 and H22 cells at 24 h were 1.175 ± 0.19 μg/mL and 1.097 ± 0.17 μg/mL, respectively, which were much lower than IC50 of cisplatin for BEL-7404 cells (23.32 ± 1.62 μg/mL) and H22 cells (27.5 ± 1.54 μg/mL). These data indicated that P-FAH-Cu-phen had higher cytotoxicity against HCC cells compared with cisplatin. The cytotoxic effect of P-FAH-Cu-phen on mouse normal liver cell NCTC1469 was also detected by MTT assay after treatment for 24 h (Figure 2D). Although P-FAH-Cu-phen showed the cytotoxic effect on NCTC1469 cells, the IC50 (2.95 μg/mL) was 2.5–3 times higher than that of BEL-7404 and H22 cells, suggesting that P-FAH-Cu-phen had stronger cytotoxic effect on HCC cells compared with normal liver cells.

Figure 2.

Figure 2

Open in a new tab

Effects of P-FAH-Cu-phen on the growth of HCC and normal liver cells. BEL-7404 and H22 cells were treated with different concentrations of P-FAH-Cu-phen for 24, 48, and 72 h. (A) The cell morphology was observed by inverted microscopy at 24 h. (B) The cell viability was detected by MTT assay. (C) The inhibitory rate was calculated. Data are from three independent experiments and analyzed by ANOVA. (D) NCTC1469 cells were treated with different concentrations of P-FAH-Cu-phen for 24 h. The cell viability was detected by MTT assay. ***p < 0.001 compared to control group.

In order to detect the antitumor effect of P-FAH-Cu-phen on drug resistant tumor cells, 5-fluorouracil and paclitaxel (taxol) resistant colorectal carcinoma cell lines (HCT-15/Fu and HCT-15/paclitaxel) were treated with different doses of P-FAH-Cu-phen for 24 h. The results showed that 300 μg/mL of 5-fluorouracil and paclitaxel did not reduce the viability of HCT-15/5-Fu and HCT-15/paclitaxel, respectively, while 1.5 μg/mL of P-FAH-Cu-phen significantly decreased the viability of the two cell lines (Supplementary Figure 1). These data indicated that P-FAH-Cu-phen could inhibit the proliferation of drug resistant tumor cells.

The effect of P-FAH-Cu-phen on cell cycle distribution of BEL-7404 cells was detected after treatment with P-FAH-Cu-phen for 24 h. As shown in Figure 3A, P-FAH-Cu-phen dose-dependently increased the proportions of BEL-7404 cells at the G2/M phase and decreased the proportions of BEL-7404 cells at the S phase. Cyclin B1, as a cyclin in the G2 phase, activates and forms a complex with cyclin-dependent protein kinases (CDKs), which promotes the G2/M phase transition of cells.24 Consistently, P-FAH-Cu-phen decreased the levels of cyclin B1 compared with control (Figure 3B). The results suggested P-FAH-Cu-phen induced cell cycle arrest at G2/M in BEL-7404 cells.

Figure 3.

Figure 3

Open in a new tab

P-FAH-Cu-phen induced cell cycle arrest in BEL-7404 cells. BEL-7404 cells were treated with different concentrations of P-FAH-Cu-phen for 24 h. (A) Cell cycle distribution was analyzed by flow cytometry after PI staining. *p < 0.05; **p < 0.01 compared to control group (ANOVA). (B) The proteins were isolated, and the levels of cyclin B1 were detected by Western blot.

To investigate whether the inhibitory effect of P-FAH-Cu-phen on BEL-7404 cells is mediated by the induction of apoptosis, cells were stained with Annexin V-FITC and PI after treatment with P-FAH-Cu-phen for 24 h. The results showed that the frequencies of apoptotic BEL-7404 cells (both early and late apoptosis) were significantly increased, while the percentages of necrotic cells were not significantly changed by P-FAH-Cu-phen treatment (Figure 4A). The apoptotic phenotype of BEL-7404 cells was further evaluated by Hoechst 33258 staining. As shown in Figure 4B, cells in control and DMSO groups showed a uniform nuclear staining distribution, while cells treated with P-FAH-Cu-phen showed bright nuclear staining characterized by chromatin condensation and fragmentation. We subsequently observed that P-FAH-Cu-phen dose-dependently up-regulated and down-regulated the expressions of proapoptotic Bcl-2-associated X protein (Bax) and antiapoptotic B cell lymphoma 2 (Bcl-2), respectively (Figure 4C). The results indicated that P-FAH-Cu-phen induced apoptosis in BEL-7404 cells.

Figure 4.

Figure 4

Open in a new tab

P-FAH-Cu-phen induced apoptosis in BEL-7404 cells. BEL-7404 cells were treated with different concentrations of P-FAH-Cu-phen for 24 h. (A) The apoptosis and necrosis of BEL-7404 cells were analyzed by flow cytometry. **p < 0.01; ***p < 0.001 compared to control group (ANOVA). (B) The nuclear morphology of BEL-7404 cells was observed by inverted fluorescence microscopy after staining with Hoechst 33258. The arrows indicated the chromosomal condensation. (C) The proteins were isolated, and the levels of Bcl-2 and Bax were detected by Western blot.

Apoptosis can be induced by three main signaling pathways including extrinsic pathway mediated by death receptor and intrinsic pathways mediated by mitochondria or endoplasmic reticulum (ER), which trigger the activation of promoter caspase-8, -9, and -12, respectively.25 Thc Δψm is considered to be a hallmark of the mitochondrial apoptosis pathway,26 which is strictly regulated by Bcl-2 family proteins including Bcl-2 and Bax.27,28 We observed that the percentages of FL-1+FL-2– cells were significantly increased in a dose-dependent manner (Figure 5A), suggesting that P-FAH-Cu-phen decreased Δψm in BEL-7404 cells. As a result, the levels of cytochrome c were increased upon P-FAH-Cu-phen treatment (Figure 5B). Consequently, caspase-9 was activated by cytochrome c, which further activated caspase-3 and then induced the cleavage of poly(ADP-ribose) polymerase (PARP) to prevent the repair of DNA damage. In addition, the activation of caspase-8 was inhibited by P-FAH-Cu-phen treatment (Figure 5B).

Figure 5.

Figure 5

Open in a new tab

P-FAH-Cu-phen activated mitochondria-dependent apoptosis pathway and increased ROS generation. BEL-7404 cells were treated with different concentrations of P-FAH-Cu-phen for 24 h. (A) Cells were stained with JC-1, and the fluorescence changes were detected by flow cytometry. (B) The proteins were isolated and the levels of cytochrome c and cleaved-caspases and -PARP were detected by Western blot. (C) Cells were stained with DCFH-DA and analyzed by flow cytometry. *p < 0.05; **p < 0.01; ***p < 0.001 compared to control group (ANOVA).

ROS is involved in apoptosis caused by mitochondrial dysfunction mediated by the loss of Δψm.29 As shown in Figure 5C, P-FAH-Cu-phen dose-dependently increased the levels of ROS, which could further decrease Δψm.25 The results suggested that P-FAH-Cu-phen induced mitochondria-dependent apoptosis in BEL-7404 cells.

ROS can exert a direct or indirect effect on ER stress, which can affect mitochondria-mediated apoptosis.30 Continued ER stress mainly mediates cell apoptosis through activation of caspase-12, JNK/p38, and CCAAT-enhancer-binding protein homologous protein (CHOP) pathways.31 After P-FAH-Cu-phen treatment, the levels of caspase-12 and cleaved-caspase-12 were up-regulated compared to control (Figure 6). We also found that the levels of p38, phosphorylated p38 (P-p38), c-Jun N-terminal kinase (JNK), and phosphorylated JNK (P-JNK) were increased. ER stress can also promote cell survival by regulating the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and their downstream signaling pathway.32 Consistently, the level of phosphorylated p44/42 (P-p44/42) was decreased upon P-FAH-Cu-phen treatment (Figure 6). The results suggested that P-FAH-Cu-phen induced ER stress in BEL-7404 cells.

Figure 6.

Figure 6

Open in a new tab

P-FAH-Cu-phen caused ER stress in BEL-7404 cells. BEL-7404 cells were treated with different concentrations of P-FAH-Cu-phen for 24 h, and then the proteins were isolated and the levels of JNK, phosphorylated (P)-JNK, p38, P-p38, p44/42, P-p44/42, caspase-12, and cleaved-caspase-12 were detected by Western blot.

Metastasis is a leading cause of failure to treat malignancies. Wound-healing assay was used to evaluate the effect of P-FAH-Cu-phen on the migration of BEL-7404 cells. Compared to control, the migration of BEL-7404 cells was significantly suppressed by P-FAH-Cu-phen treatment in a dose- and time-dependent manner (Figure 7A). Matrix metalloproteinases (MMPs) are family members of zinc- or calcium-dependent endopeptidases that can degrade extracellular matrix and are considered crucial protein hydrolases involved in the invasion and metastasis of tumor.33 Consistently, the levels of MMP-2 were decreased after P-FAH-Cu-phen treatment. In addition, the decrease of vascular endothelial growth factor (VEGF) was also observed (Figure 7B). The results suggested that P-FAH-Cu-phen might inhibit the invasion and metastasis of BEL-7404 cells.

Figure 7.

Figure 7

Open in a new tab

P-FAH-Cu-phen inhibited the migration of BEL-7404 cells in vitro. BEL-7404 cells were treated with different concentrations of P-FAH-Cu-phen. (A) After 24 and 48 h, the migration of cells was observed by inverted microscope and analyzed by ImageJ. The percentages of wound healing were shown in lower panels. *p < 0.05; ***p < 0.001 compared to control group (ANOVA). (B) After 24 h, the proteins were isolated to detect the levels of MMP-2 and VEGF by Western blot.

After treatment with P-FAH-Cu-phen or cisplatin, the body weight of tumor mice had no significant difference among control and both doses of P-FAH-Cu-phen treated groups, while it was significantly reduced in cisplatin group (Figure 8A). Compared with control group, tumor growth was significantly suppressed in groups treated with both doses of P-FAH-Cu-phen and cisplatin (Figure 8B). At the end of this experiment (72 days), all mice in the control group were dead. 2 of 8 mice in 0.5 mg/kg P-FAH-Cu-phen group and cisplatin group were dead, and the survival rate of both groups was 75%. 3 of 8 mice in 2 mg/kg of P-FAH-Cu-phen group were dead, and the survival rate is 62.5% (Figure 8C). These data suggested that P-FAH-Cu-phen not only suppressed tumor growth but also improved the survival of tumor mice.

Figure 8.

Figure 8

Open in a new tab

In vivo antitumor effect of P-FAH-Cu-phen. Tumor mouse model was established by injection of H22 cells. After 3 days, tumor mice were treated with DMSO, cisplatin, and 0.5 and 2 mg/kg P-FAH-Cu-phen, respectively. Body weight (A), tumor volume (B), and survival rate (C) of tumor mice were monitored at the indicated time points. *p < 0.05; **p < 0.01; ***p < 0.001 compared to control group (ANOVA). (D) Pathological changes of liver tissues. Livers were isolated on day 25 and observed by inverted fluorescence microscopy after H&E staining.

On day 25, 6 mice were randomly selected from each group and sacrificed to collect the organs and calculate the organ indexes. Compared with the control group, P-FAH-Cu-phen did not significantly change organ indexes including heart, spleen, liver, lung, kidney, and thymus except lung index in 2 mg/kg of P-FAH-Cu-phen group, suggesting that high dose of P-FAH-Cu-phen might cause some side effects in lung tissues. This could be correlated with the poor antitumor effect of high dose P-FAH-Cu-phen compared with a low dose one. Cisplatin significantly increased the liver and lung indexes (Table 1). The pathological changes of liver tissues were further characterized by H&E staining. Both doses of P-FAH-Cu-phen groups showed intact lobular architecture with regular cell organization, which was similar to the control group. However, the cisplatin group exhibited disordered cell organization with necrotic or apoptotic areas (Figure 8D). The results indicated that cisplatin induced severe side effects in mice, such as the decrease of body weight, the increase of liver and lung indexes, and the pathological changes of liver tissues, although it showed similar antitumor effect with P-FAH-Cu-phen. Therefore, P-FAH-Cu-phen might be more suitable than cisplatin in the development of antitumor drug for liver cancer.

Table 1. Organ Indexes of Tumor Mice after 25 Days of P-FAH-Cu-phen Treatmenta.

  organ indexes (mg/g)
treatment spleen liver lung thymus kidney heart
control 0.43 ± 0.16 6.40 ± 0.34 0.52 ± 0.04 0.14 ± 0.04 1.71 ± 0.24 0.43 ± 0.07
cisplatin 0.31 ± 0.08 7.22 ± 0.52** 0.76 ± 0.13** 0.09 ± 0.05 1.59 ± 0.12 0.42 ± 0.05
0.5 mg/kg P-FAH-Cu-phen 0.44 ± 0.13 6.65 ± 0.33 0.61 ± 0.09 0.09 ± 0.06 1.67 ± 0.10 0.43 ± 0.04
2.0 mg/kg P-FAH-Cu-phen 0.41 ± 0.09 6.39 ± 0.61 0.68 ± 0.22* 0.10 ± 0.07 1.88 ± 0.20 0.45 ± 0.03
Open in a new tab
a

Values are the mean ± SD (n = 6). *p < 0.05, **p < 0.01 compared with control.

In conclusion, P-FAH-Cu-phen inhibited the growth of HCC cells both in vitro and in vivo without or with low side effects and induced apoptosis in BEL-7404 cells via mitochondria- and ER stress-mediated pathways. P-FAH-Cu-phen might be a promising antitumor drug candidate.

Acknowledgments

This work was financially supported by Doctoral Research Initiation Fund (Grant XJNUBS1815) of Xinjiang Normal University, Key Laboratory of Special Environment Biodiversity Application and Regulation in Xinjiang (Grant XJTSWZ-2017-03), Xinjiang Key Laboratory of Special Species Conservation and Regulatory Biology (Grant XJDX1414-2018-02), Key Laboratory of Plant Stress Biology in Arid Land, the “13th Five-Year” Plan for Key Discipline Biology, Xinjiang Normal University.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00680.

  • Synthesis and characteristics of the compounds and details of biological assay protocol (PDF)

  • Tables of crystallographic information (PDF)

  • Figure showing viability (PDF)

Author Contributions

§ M.N., H.Y., and R.W. contributed equally.

The authors declare no competing financial interest.

Supplementary Material

ml0c00680_si_001.pdf (128.8KB, pdf)
ml0c00680_si_002.pdf (449.9KB, pdf)
ml0c00680_si_003.pdf (222.5KB, pdf)

References

  1. Bray F.; Ferlay J.; Soerjomataram I.; Siegel R. L.; Torre L. A.; Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca-Cancer J. Clin. 2018, 68, 394–424. 10.3322/caac.21492. [DOI] [PubMed] [Google Scholar]
  2. Wang L.; Wang F. S. Clinical immunology and immunotherapy for hepatocellular carcinoma: current progress and challenges. Hepatol. Int. 2019, 13, 521–533. 10.1007/s12072-019-09967-y. [DOI] [PubMed] [Google Scholar]
  3. Wang F. S.; Fan J. G.; Zhang Z.; Gao B.; Wang H. Y. The global burden of liver disease: the major impact of China. Hepatology 2014, 60, 2099–2108. 10.1002/hep.27406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Vilchez V.; Turcios L.; Marti F.; Gedaly R. Targeting Wnt/beta-catenin pathway in hepatocellular carcinoma treatment. World J. Gastroentero. 2016, 22, 823–832. 10.3748/wjg.v22.i2.823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Siegel R. L.; Miller K. D.; Jemal A. Cancer statistics, 2019. Ca-Cancer J. Clin. 2019, 69, 7–34. 10.3322/caac.21551. [DOI] [PubMed] [Google Scholar]
  6. De Mattia E.; Cecchin E.; Guardascione M.; Foltran L.; Di Raimo T.; Angelini F.; D’Andrea M.; Toffoli G. Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma. World J. Gastroenterol. 2019, 25, 3870–3896. 10.3748/wjg.v25.i29.3870. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Wheate N. J.; Walker S.; Craig G. E.; Oun R. The status of platinum anticancer drugs in the clinic and in clinical trials. Dalton Trans 2010, 39, 8113–8127. 10.1039/c0dt00292e. [DOI] [PubMed] [Google Scholar]
  8. Wang D.; Lippard S. J. Cellular processing of platinum anticancer drugs. Nat. Rev. Drug Discovery 2005, 4, 307–320. 10.1038/nrd1691. [DOI] [PubMed] [Google Scholar]
  9. Ott I.; Gust R. Non platinum metal complexes as anti-cancer drugs. Arch. Pharm. (Weinheim, Ger.) 2007, 340, 117–126. 10.1002/ardp.200600151. [DOI] [PubMed] [Google Scholar]
  10. Lazarevic T.; Rilak A.; Bugarcic Z. D. Platinum, palladium, gold and ruthenium complexes as anticancer agents: Current clinical uses, cytotoxicity studies and future perspectives. Eur. J. Med. Chem. 2017, 142, 8–31. 10.1016/j.ejmech.2017.04.007. [DOI] [PubMed] [Google Scholar]
  11. Ceresa C.; Bravin A.; Cavaletti G.; Pellei M.; Santini C. The combined therapeutical effect of metal-based drugs and radiation therapy: the present status of research. Curr. Med. Chem. 2014, 21, 2237–2265. 10.2174/0929867321666140216125721. [DOI] [PubMed] [Google Scholar]
  12. Ramakrishnan S.; Shakthipriya D.; Suresh E.; Periasamy V. S.; Akbarsha M. A.; Palaniandavar M. Ternary dinuclear copper(II) complexes of a hydroxybenzamide ligand with diimine coligands: the 5,6-dmp ligand enhances DNA binding and cleavage and induces apoptosis. Inorg. Chem. 2011, 50, 6458–6471. 10.1021/ic1024185. [DOI] [PubMed] [Google Scholar]
  13. Denoyer D.; Masaldan S.; La Fontaine S.; Cater M. A. Targeting copper in cancer therapy: ‘Copper That Cancer’. Metallomics 2015, 7, 1459–1476. 10.1039/C5MT00149H. [DOI] [PubMed] [Google Scholar]
  14. Hameed A.; Al-Rashida M.; Uroos M.; Abid Ali S.; Khan K. M. Schiff bases in medicinal chemistry: a patent review (2010-2015). Expert Opin. Ther. Pat. 2017, 27, 63–79. 10.1080/13543776.2017.1252752. [DOI] [PubMed] [Google Scholar]
  15. Zhang Z.; Wang H.; Yan M.; Wang H.; Zhang C. Novel copper complexes as potential proteasome inhibitors for cancer treatment (Review). Mol. Med. Rep. 2017, 15, 3–11. 10.3892/mmr.2016.6022. [DOI] [PubMed] [Google Scholar]
  16. Karrouchi K.; Radi S.; Ramli Y.; Taoufik J.; Mabkhot Y. N.; Al-aizari F. A.; Ansar M. h. Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review. Molecules 2018, 23, 134. 10.3390/molecules23010134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Casas J. S.; García-Tasende M. S.; Sánchez A.; Sordo J.; Touceda Á. Coordination modes of 5-pyrazolones: A solid-state overview. Coord. Chem. Rev. 2007, 251, 1561–1589. 10.1016/j.ccr.2007.02.010. [DOI] [Google Scholar]
  18. Pettinari R.; Marchetti F.; Pettinari C.; Petrini A.; Scopelliti R.; Clavel C. M.; Dyson P. J. Synthesis, structure, and antiproliferative activity of ruthenium(II) arene complexes with N,O-chelating pyrazolone-based beta-ketoamine ligands. Inorg. Chem. 2014, 53, 13105–13111. 10.1021/ic502274b. [DOI] [PubMed] [Google Scholar]
  19. Idemudia O. G.; Sadimenko A. P.; Hosten E. C. Metal Complexes of New Bioactive Pyrazolone Phenylhydrazones; Crystal Structure of 4-Acetyl-3-methyl-1-phenyl-2-pyrazoline-5-one phenylhydrazone Ampp-Ph. Int. J. Mol. Sci. 2016, 17, 687. 10.3390/ijms17050687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Zhao J.; Zhang L.; Li J.; Wu T.; Wang M.; Xu G.; Zhang F.; Liu L.; Yang J.; Sun S. A novel pyrazolone-based derivative induces apoptosis in human esophageal cells via reactive oxygen species (ROS) generation and caspase-dependent mitochondria-mediated pathway. Chem.-Biol. Interact. 2015, 231, 1–9. 10.1016/j.cbi.2015.02.004. [DOI] [PubMed] [Google Scholar]
  21. Jadeja R. N.; Vyas K. M.; Upadhyay K. K.; Devkar R. V. In vitro apoptosis-inducing effect and gene expression profiles of mixed ligand Cu(ii) complexes derived from 4-acyl pyrazolones on human lung cancer cells. RSC Adv. 2017, 7, 17107–17116. 10.1039/C7RA01025G. [DOI] [Google Scholar]
  22. Luo H.-Y.; Li J.-Y.; Li Y.; Zhang L.; Li J.-Y.; Jia D.-Z.; Xu G.-C. Cadmium (II) complexes with a 4-acyl pyrazolone derivative and co-ligands: crystal structures and antitumor activity. RSC Adv. 2016, 6, 114997–115009. 10.1039/C6RA23938B. [DOI] [Google Scholar]
  23. Addison A. W.; Rao T. N.; Reedijk J.; van Rijn J.; Verschoor G. C. Synthesis, structure, and spectroscopic properties of copper(II) compounds containing nitrogen-sulphur donor ligands; the crystal and molecular structure of aqua[1,7-bis(N-methylbenzimidazol-2’-yl)-2,6-dithiaheptane]copper(II) perchlorate. J. Chem. Soc., Dalton Trans. 1984, 7, 1349–1356. 10.1039/DT9840001349. [DOI] [Google Scholar]
  24. Bulavin D. V.; Amundson S. A.; Fornace A. J. p38 and Chk1 kinases: different conductors for the G(2)/M checkpoint symphony. Curr. Opin. Genet. Dev. 2002, 12, 92–97. 10.1016/S0959-437X(01)00270-2. [DOI] [PubMed] [Google Scholar]
  25. Redza-Dutordoir M.; Averill-Bates D. A. Activation of apoptosis signalling pathways by reactive oxygen species. Biochim. Biophys. Acta, Mol. Cell Res. 2016, 1863, 2977–2992. 10.1016/j.bbamcr.2016.09.012. [DOI] [PubMed] [Google Scholar]
  26. Green D. R.; Reed J. C. Mitochondria and apoptosis. Science 1998, 281, 1309–1312. 10.1126/science.281.5381.1309. [DOI] [PubMed] [Google Scholar]
  27. Wu H.; Medeiros L. J.; Young K. H. Apoptosis signaling and BCL-2 pathways provide opportunities for novel targeted therapeutic strategies in hematologic malignances. Blood Rev. 2018, 32, 8–28. 10.1016/j.blre.2017.08.004. [DOI] [PubMed] [Google Scholar]
  28. Sharpe J. C.; Arnoult D.; Youle R. J. Control of mitochondrial permeability by Bcl-2 family members. Biochim. Biophys. Acta, Mol. Cell Res. 2004, 1644, 107–113. 10.1016/j.bbamcr.2003.10.016. [DOI] [PubMed] [Google Scholar]
  29. Circu M. L.; Aw T. Y. Reactive oxygen species, cellular redox systems, and apoptosis. Free Radical Biol. Med. 2010, 48, 749–762. 10.1016/j.freeradbiomed.2009.12.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Malhotra J. D.; Kaufman R. J. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword?. Antioxid. Redox Signaling 2007, 9, 2277–2293. 10.1089/ars.2007.1782. [DOI] [PubMed] [Google Scholar]
  31. Liu K.-s.; Peng Z.-h.; Cheng W.-j.; Dai C.-f.; Tong H. Endoplasmic reticulum stress-induced apoptosis in the development of reproduction. J. Reprod. Contracept. 2016, 27, 51–59. 10.7669/j.issn.1001-7844.2016.01.0051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Yang H. J.; Zhuang R. J.; Li Y. B.; Li T.; Yuan X.; Lei B. B.; Xie Y. F.; Wang M. Cold-inducible protein RBM3 mediates hypothermic neuroprotection against neurotoxin rotenone via inhibition on MAPK signalling. J. Cell. Mol. Med. 2019, 23, 7010–7020. 10.1111/jcmm.14588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Foda H. D.; Zucker S. Matrix metalloproteinases in cancer invasion, metastasis and angiogenesis. Drug Discovery Today 2001, 6, 478–482. 10.1016/S1359-6446(01)01752-4. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ml0c00680_si_001.pdf (128.8KB, pdf)
ml0c00680_si_002.pdf (449.9KB, pdf)
ml0c00680_si_003.pdf (222.5KB, pdf)

Articles from ACS Medicinal Chemistry Letters are provided here courtesy of American Chemical Society

RESOURCES