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. 2025 Apr 1;10(14):13829-13838.
doi: 10.1021/acsomega.4c06972. eCollection 2025 Apr 15.

Piperazine-Based Co(III), Ni(II), Cu(II), and Zn(II) Carbodithioate Complexes as Potential Anticancer Agent

Seema Gupta  1 , Alok Shukla  2 , Shivendra Kumar Pandey  1 , Shalini Jha  1 , Berhanu Zewde  3 , Arbind Acharya  2 , Raymond John Butcher  3 , M K Bharty  1
Affiliations

Piperazine-Based Co(III), Ni(II), Cu(II), and Zn(II) Carbodithioate Complexes as Potential Anticancer Agent

Seema Gupta et al. ACS Omega. .

Abstract

The development of facile and cost-effective anticancer metallodrugs possessing minimal side effects is urgently needed. Piperazine-containing anticancer drugs are already available on the market. A piperazine-based potassium 4-(ethoxycarbonyl)piperazine-1-carbodithioate [pecpcdt] (L) ligand and its metal complexes [Co(ecpcdt)3] (1), [Ni(ecpcdt)2] (2), [Cu(ecpcdt)2] (3), and [Zn(ecpcdt)2] (4) were synthesized. These compounds were characterized by different spectroscopic methods and single-crystal X-ray crystallography data. Ni(II) and Cu(II) complexes have distorted square planar geometry, whereas the Co(III) complex has distorted octahedral geometry around the metal ions. Complexes are weakly fluorescent in the solution compared to the free ligand. The complexes were further examined for their in vitro anticancer activities against the primary Dalton's lymphoma (DL) cells along with standard drug cisplatin. The anticancer studies of metal complexes have been performed through various biochemical assays, and the findings thus obtained suggest that they demonstrate an effective anticancer activity. [Co(ecpcdt)3] (1) shows superior cytotoxicity against DL cells than complexes [Cu(ecpcdt)2] (3), [Zn(ecpcdt)2] (4), and cisplatin. The superiority preferences of these complexes follows [Co(ecpcdt)3] (1) > [pecpcdt] > [Cu(ecpcdt)2] (3) > [Ni(ecpcdt)2] (2) > [Zn(ecpcdt)2] (4). Further assays were performed on a cobalt(III) complex having the highest efficacy to gain insights into the mechanism of cell death and showed that reduced mitochondrial membrane potential and increased mitochondrial ROS production, highlighting mitochondrial-dependent apoptosis as the major mechanism for tumor cell death. On the other hand, the viability of normal splenocytes was minimally affected by the [Co(ecpcdt)3] (1) treatment.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Synthesis of [pecpcdt] and Its Co(III), Ni(II), Cu(II), and Zn(II) Complexes
Figure 1
Figure 1
ORTEP Diagram of [Co(ecpcdt)3] (1) at the 40% Probability Level. Hydrogen Atoms Are Omitted for Clarity.
Figure 2
Figure 2
ORTEP diagram of [Cu(ecpcdt)2] (3) at the 40% probability level. Only the main contributing part is shown. H atoms and other disordered parts are omitted.
Figure 3
Figure 3
Cell viability was evaluated using the standard MTT assay detailed in the materials and methods. Tumor cells were subjected to 24 h treatments with varying concentrations of [pecpcdt] (1) (A), [Co(ecpcdt)3] (1) (B), [Ni(ecpcdt)2] (2) (C), [Cu(ecpcdt)2] (3) (D), [Zn(ecpcdt)2] (4) (E), and cisplatin (F). The cytotoxic effects were quantified, and the results are presented in a bar diagram, indicating the percentage of mean ± SD. Statistical analysis involved a one-way analysis of variance, followed by Bonferroni’s multiple comparison post-test, across at least three independent experiments. Significance levels were denoted as **p < 0.01 and ***p < 0.001.
Figure 4
Figure 4
Morphological features of apoptosis, necrosis, and plasma membrane integrity were evaluated through AO/EB dual staining. (A) Images were captured using DIC, FITC, and TRITC channels on a confocal microscope (Zeiss LSM 780) at 60× magnification. (B) Mean fluorescent intensity of AO/EB in control, cobalt-complex-treated, and cisplatin-treated tumor cells is represented in a bar diagram. Statistically significant at *p < 0.1.
Figure 5
Figure 5
Tumor cells were treated with specified concentrations of the cobalt complex and the standard anticancer drug cisplatin separately for 24 h. A quantitative assessment of apoptosis induced by the cobalt complex was conducted using Annexin-V/PI staining followed by flow cytometry. (A) Flow cytometry dot plot illustrating the counts of live, early apoptotic, late apoptotic, and necrotic cells in control, [Co(ecpcdt)3] (1)-treated and cisplatin-treated groups. (B) Bar diagram depicting the percentage of apoptotic tumor cells in all three groups, with statistical significance measured at ***p < 0.001.
Figure 6
Figure 6
Flow cytometry analysis of mitochondrial membrane potential using the JC-1 assay in tumor cells treated with the cobalt complex. (A) FACS quadrant illustrating a shift in the cell percentage toward green fluorescence, indicating reduced mitochondrial potential. (B) Bar diagram depicting the percentage of tumor cells emitting red fluorescence (JC-1’s J aggregates) and green fluorescence (JC-1 monomer). Statistical significance was measured at **p < 0.01, ***p < 0.001.
Figure 7
Figure 7
Impact of cobalt complex treatment on ROS production in tumor cells was evaluated by using the H2DCFDA assay. ROS levels were analyzed via flow cytometry using the FL-1 channel. (A) Flow cytometry histogram displays increased ROS production, evident from the right shift in overlaid histograms. (B) Bar diagram illustrates the enhancement in the geomean during flow cytometry. Statistically significant at **p < 0.01, ***p < 0.001.
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