Dithiocarbazate ligands and their Ni(II) complexes with potential biological activity: Structural, antitumor and molecular docking study

Abstract

In the search for new metal complexes with antitumor potential, two dithiocarbazate ligands derived from 1,1,1-trifluoro-2,4-pentanedione (H₂L¹) and (H₂L²) and four Ni(II) complexes, [Ni(L¹)PPh₃] (1), [Ni(L¹)Py] (2), [Ni(L²)PPh₃] (3), and [Ni(L²)Py] (4), were successfully synthesized and investigated by physical-chemistry and spectroscopic methods. The crystal structure of the H₂L¹ and the Ni(II) complexes has been elucidated by single-crystal X-ray diffraction. The obtained structure from H₂L¹ confirms the cyclization reaction and formation of the pyrazoline derivative. The results showed square planar geometry to the metal centers, in which dithiocarbazates coordinated by the ONS donor system and a triphenylphosphine or pyridine molecule complete the coordination sphere. Hirshfeld surface analysis by d _norm function was investigated and showed π-π stacking interactions upon the molecular packing of H₂L¹ and non-classical hydrogen bonds for all compounds. Fingerprint plots showed the main interactions attributed to H⋅H C⋅H, O⋅H, Br⋅H, and F⋅H, with contacts contributing between 1.9% and 38.2%. The mass spectrometry data indicated the presence of molecular ions [M + H]⁺ and characteristic fragmentations of the compounds, which indicated the same behavior of the compounds in solution and solid state. Molecular docking simulations were studied to evaluate the properties and interactions of the free dithiocarbazates and their Ni(II) complexes with selected proteins and DNA. These results were supported by in vitro cytotoxicity assays against four cancer cell lines, showing that the synthesized metal complexes display promising biological activity.

Keywords: Hirshfeld surface; Ni(II) complexes; antitumor activity; crystal structure; dithiocarbazate; mass spectrometry.

FIGURE 1

Synthesis of the Ni(II) complexes (1–4).

FIGURE 2

Molecular structure of H₂L¹ with crystallographic labeling (30% probability displacement). The intramolecular interaction is shown as a dashed line.

FIGURE 3

Projection view of H₂L¹ showing an intramolecular hydrogen bond and the π⋅⋅⋅π stacking interactions (as a dashed line).

FIGURE 4

Molecular structure of the complexes (1–4) with crystallographic labeling (30% probability displacement).

FIGURE 5

Hirshfeld surface of the complexes (1–4) mapped with d _norm .

FIGURE 6

Hirshfeld surface mapped in shape index for H₂L¹.

FIGURE 7

Percentage contribution of close contacts for H₂L¹ and the complexes (1–4).

FIGURE 8

ESI(+)-MS/MS spectrum for H₂L¹.

FIGURE 9

ESI(+)-MS/MS spectrum for (1).

FIGURE 10

ESI(+)-MS/MS spectrum for (2).

FIGURE 11

Evaluation of cytotoxic effects by MTT/resazurin assay. Concentrations lower than 4.68 µM were deleted since their effects were negligible. The asterisk indicates that cell viability is significantly different from the respective DMSO control (p < 0.5, Kruskal–Wallis followed by Dunn’s comparison test). DMSO at 0.01% did not affect the cell viability of any cell line.

FIGURE 12

Concentration–response curves of all tested compounds in each cell line after 72 h exposure. Concentrations were shown as logarithms to perform the non-linear regression of data, allowing the calculation of concentration able to inhibit 50% of cell viability in cultures (IC_50%).

FIGURE 13

Molecular docking results of NALM-6 target. (A) Active site regions of UDP and DI-39 inhibitors and main residues of the DCK protein (4KCG) (Nathanson et al., 2014). (B) 2D representation of the interactions carried out between the best-ranked inhibitor, 2, and the UDP active site. (C) Main nearest residues of both active sites of the 4KCG receptor (distance till 6.0 Å) and all the six compounds studied.

FIGURE 14

Molecular docking results of the 697 cell type target. (A) Binding active site regions of the Linkers A and B of the protein–DNA complex (7DW5) (Zhang et al., 2021). (B) 2D representation of the interactions carried out between the best-ranked inhibitor, 4, and the active site. (C) Main nearest residues of both active sites of the 7DW5 receptor (distance till 6.0 Å) and all the six compounds studied.

FIGURE 15

Molecular docking results of the U251 cell type target. (A) Binding active site regions of the CDK6 kinase protein (6OQO) (Bronner et al., 2019), the DFG catalytic triad, and the gatekeeper residue His100 are also represented. (B) 2D representation of the interactions carried out between the best-ranked inhibitor, 2, and the active site. (C) Main nearest residues of both active sites of the 6OQO receptor (distance till 6.0 Å) and all the six compounds studied.

FIGURE 16

Molecular docking results of the MDA-MB-231 cell type target. (A) Binding active site regions of the CA protein (6VJ3) (Petreni et al., 2020). (B) 2D representation of the interactions carried out between the best-ranked inhibitor, 2, and the residues of the active site of the receptor. (C) Main nearest residues of both active sites of the 6VJ3 receptor (distance till 6.0 Å) and all the six compounds studied.