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Article

Structural, Antioxidant, and Protein/DNA-Binding Properties of Sulfate-Coordinated Ni(II) Complex with Pyridoxal-Semicarbazone (PLSC) Ligand

by
Violeta Jevtovic
1,
Luka Golubović
2,
Odeh A. O. Alshammari
1,
Munirah Sulaiman Alhar
1,
Tahani Y. A. Alanazi
1,
Aleksandra Radulović
3,
Đura Nakarada
2,
Jasmina Dimitrić Marković
2,
Aleksandra Rakić
2 and
Dušan Dimić
2,*
1
Department of Chemistry, College of Science, University Ha’il, Ha’il 81451, Saudi Arabia
2
Faculty of Physical Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia
3
Department of Prosthodontics, School of Medicine, 78000 Banja Luka, Bosnia and Herzegovina
*
Author to whom correspondence should be addressed.
Inorganics 2024, 12(11), 280; https://doi.org/10.3390/inorganics12110280
Submission received: 2 October 2024 / Revised: 24 October 2024 / Accepted: 28 October 2024 / Published: 30 October 2024
(This article belongs to the Special Issue Metal Complexes Containing Bioactive Ligands: Structure and Biological Evaluation)
Browse Figures
Figure 1
<p>Different binding modes of PLSC ligand.</p> "> Figure 2
<p>(<b>a</b>) Molecular diagram of [Ni(PLSC)(SO<sub>4</sub>)(H<sub>2</sub>O)<sub>2</sub>], with non-hydrogen atoms represented by 50% displacement ellipsoids and hydrogen atoms as spheres of arbitrary size. (<b>b</b>) The ball and stick representation shows part of the hydrogen bonding between the molecules. (Hydrogen-white, carbon-gray, nitrogen-blue, oxygen-red, sulfur-lilac, nickel-light blue).</p> "> Figure 3
<p>Cell packing is viewed down the b-axis, and the 3D hydrogen-bonded network is shown as comprising parallel layers of the Ni(PLSC) structural units.</p> "> Figure 4
<p>(<b>a</b>) Hirshfeld surface and (<b>b</b>) optimized structure (hydrogen atoms are omitted for clarity) at the B3LYP/6-311++G(d,p)(H,C,N,O,S)/LanL2DZ(Ni) level of theory of [Ni(PLSC)(SO<sub>4</sub>)(H<sub>2</sub>O)<sub>2</sub>]. (Hydrogen—white, carbon—gray, nitrogen—blue, oxygen—red, sulfur—yellow, nickel—light blue).</p> "> Figure 5
<p>The EPR spectra of the (<b>a</b>) DEPMPO-HO<sup>•</sup> adduct and (<b>b</b>) ascorbyl radical in the absence (black line) and presence of different concentrations of [Ni(PLSC)(SO<sub>4</sub>)(H<sub>2</sub>O)<sub>2</sub>].</p> "> Figure 6
<p>The fluorescence emission spectra of HSA for the titration with various concentrations of [Ni(PLSC)(SO<sub>4</sub>)(H<sub>2</sub>O)<sub>2</sub>] at (<b>a</b>) 27°, (<b>b</b>) 32°, and (<b>c</b>) 37 °C, and (<b>d</b>) the van ’t Hoff plot for the binding process.</p> "> Figure 7
<p>HSA molecule (PDB ID: 1AO6) with bound ligands: [Ni(PLSC)(H<sub>2</sub>O)<sub>2</sub>(SO<sub>4</sub>)] complex and HPO<sub>4</sub><sup>2−</sup> anion, occupying FA9 and FA8 binding sites, respectively. Ligands and tryptophane are depicted using ball representation; each is colored distinctly. HPO<sub>4</sub><sup>2−</sup> ion from buffer solution is colored by element, Ni(II) complex is shown in light green, and Trp213 is represented in dark grey.</p> "> Figure 8
<p>A 3D representation of the supramolecular interactions of [Ni(PLSC)(H<sub>2</sub>O)<sub>2</sub>(SO<sub>4</sub>)] located in the FA8 binding site. Only the interacting parts of the amino acids are shown, with colors corresponding to their respective regions of the HSA molecule: yellow for subdomain IB, green for subdomain IIA, interdomain region between subdomains IIA and IIB is light grey, and subdomain IA is violet. For the representation of nickel(II), complex sticks colored by the element were used. Supramolecular interactions are represented by dashed lines colored according to the type of interaction denoted in the figure’s legend.</p> "> Figure 9
<p>Fluorescence emission spectra of [Ni(PLSC)(H<sub>2</sub>O)<sub>2</sub>(SO<sub>4</sub>)] for the titration with various concentrations of CT-DNA at (<b>a</b>) 27°, (<b>b</b>) 32°, and (<b>c</b>) 37 °C, and (<b>d</b>) the van ’t Hoff plot for the binding process.</p> "> Figure 10
<p>Fluorescence emission spectra of [Ni(PLSC)(H<sub>2</sub>O)<sub>2</sub>(SO<sub>4</sub>)] without CT-DNA (<b>a</b>) and with CT-DNA (<b>b</b>) in the presence of different concentrations of KI, and (<b>c</b>) the Stern–Volmer plots for the complex fluorescence quenching by KI.</p> "> Figure 11
<p>(<b>a</b>) Fluorescence emission spectra of CT-DNA-EB for the titration with the complex at 27 °C and (<b>b</b>) the double-log Stern–Volmer dependency of intensity on the concentration of [Ni(PLSC)(H<sub>2</sub>O)<sub>2</sub>(SO<sub>4</sub>)].</p> "> Figure 12
<p>Binding of square planar Ni(II) complex with PLSC ligand at two distinct sites: intercalation site (depicted in dark green, ball-and-stick representation) and minor groove (shown in pink, ball-and-stick representation). DNA molecule is colored yellow. Experimentally determined binding energy (ΔG<sub>exp</sub>), best-calculated binding energy (ΔG1), and fifth calculated binding energy value (ΔG<sub>5</sub>) are also indicated.</p> "> Figure 13
<p>The supramolecular interactions of the square planar Ni(II) complex in (<b>a</b>) the intercalation site and (<b>b</b>) the major groove. Only the interacting parts of the nucleobases are shown colored in yellow. For the representation of the square planar Ni(II) complex, sticks colored by element were used. Supramolecular interactions are represented by dashed lines colored according to the type of interaction denoted in the figure’s legend. The experimentally determined binding energy (ΔG<sub>exp</sub>) and the calculated binding energy values are also indicated.</p> ">
Versions Notes

Abstract

:
The pyridoxal-semicarbazone (PLSC) ligand and its transition metal complexes have shown significant biological activity. In this contribution, a novel nickel(II)-PLSC complex, [Ni(PLSC)(SO4)(H2O)2], was obtained, and its structure was determined by X-ray crystallographic analysis, FTIR, and UV-VIS spectroscopy. The sulfate ion is directly coordinated to the central metal ion. The intermolecular stabilization interactions were examined using Hirshfeld surface analysis. The crystal structure was optimized by a B3LYP functional using two pseudopotentials for nickel(II) (LanL2DZ and def2-TZVP) together with a 6-311++G(d,p) basis set for non-metallic atoms. The experimental and theoretical bond lengths and angles were compared, and the appropriate level of theory was determined. The stabilization interactions within the coordination sphere were investigated by the Quantum Theory of Atoms in Molecules (QTAIM). The antioxidant activity towards hydroxyl and ascorbyl radicals was measured by EPR spectroscopy. The interactions between Human Serum Albumin (HSA) and the complex were examined by spectrofluorimetric titration and a molecular docking study. The mechanism of binding to DNA was analyzed by complex fluorescence quenching, potassium iodide quenching, and ethidium bromide displacement studies in conjunction with molecular docking simulations.

1. Introduction

Pyridoxal-semicarbazone (PLSC) is a tridentate ligand formed in the reaction between pyridoxal and semicarbazone [1,2]. The donor atoms of PLSC include phenolic oxygen, hydrazone nitrogen, and carbonyl oxygen. Because pyridoxal moiety is a part of the vitamin B6 structure, this ligand resembles many active biomolecules [3]. Due to the presence of several protonation sites, PLSC can exist in three forms: neutral (H2L), monoanionic (HL−), and dianionic (L2−) (Figure 1). When in neutral form, pyridine and hydrazone nitrogen atoms are protonated, while the hydroxyl group attached to the aromatic ring is deprotonated. The monoanionic form is obtained by removing hydrogen atoms from protonated hydrazone nitrogen. When both protons from the mentioned nitrogen atoms are removed, the ligand is dianionic. The presence of several donor atoms in the structure leads to the formation of many transition metal complexes. The overall geometry of complexes depends on the chosen metal and pH of the solution (when pH is above 7, the mono- and dianionic forms are predominantly present).
The first complex compounds incorporating the PLSC ligand were those with copper and platinum, [Pt(PLSC-H)Cl3], and [CuBr2(PLSC)] [4]. Vojinović-Ješić and coworkers described several chromium(III)-PLSC complexes with mer-octahedral structure [5]. To the present date, only several complexes between nickel(II) and PLSC ligands have been described in the literature. Complex compounds containing PLSC and nickel(II) described in the literature include Ni(PLSC)Cl2∙3.5H2O, [Ni(PLSC)(H2O)3](NO3)2, Ni(PLSC-2H)(NCS)2∙4H2O, and [Ni(PLSC-2H)NH3]∙1.5H2O [6]. The first three compounds were paramagnetic with an octahedral structure, while the fourth was diamagnetic with a square planar structure. Two complexes were formed between nickel(II) nitrate and PLSC in the presence of NaN3: binuclear octahedral complex [Ni2(PLSC)2(μ1,1-N3)2]∙2H2O and octahedral [Ni(PLSC-H)2]∙2H2O [7]. An unusual complexation mode of PLSC was examined in the paper by Leovac and coworkers in which an elementary cell consisted of two monomeric complex cations [Ni(PLSC)(H2O)3]2+, one centrosymmetric dimeric cation [Ni2(PLSC)2(H2O)4]4+, eight Cl− anions, and four molecules of crystal water [8]. In the paper by Jevtovic and coworkers, the crystal structure and antibacterial activity of [Ni(PLSC-H)2]∙H2O are presented [9]. Aduri and coworkers published an article describing the synthesis, characterization, DNA binding, and antibacterial studies of [Ni(PLSC-H)Cl(H2O)2] and [Cu(PLSC-H)2]∙2H2O [10].
Nickel is an important transition metal, and its complex compounds can be used for S-C bond formation [11], hydrogen production [12,13], and control of the polyethylene microstructure [14]. The effects of nickel(II) compounds on SARS-CoV-2 enzymes have been examined theoretically [15] and experimentally [16]. Bhandarkar and coworkers reported moderate inhibitory effects of nickel(II) complexes towards the COVID-19 and hepatitis viruses [17]. Nickel complexes also show anticancer potential towards human prostate cancer cells [18], primary lung cancer cells [19], mammary gland breast carcinoma, humane prostate carcinoma, colorectal carcinoma [20], and chronic myeloid leukemia [21]. Perontsis and coworkers presented results on the significant radical-scavenging activity of nickel(II) complexes with the anti-inflammatory drug diflunisal towards diphenyl-picrylhydrazyl (DPPH•), 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) and hydroxyl radicals [22]. The radical-scavenging activity of nickel(II)-rutin complex towards DPPH• was higher than the respective activity of free rutin in reference [23]. The antibacterial activity of the nickel(II) complex with N and the O donor Schiff base towards Gram-positive and Gram-negative bacteria is explained by Overtone’s concept and Tweedy’s chelation theory [24].
This paper presents results on the synthesis and structural analysis of a novel nickel(II)-PLSC complex with a coordinated sulfate anion and two molecules of water, [Ni(PLSC)(SO4)(H2O)2]. The crystallographic structure was obtained by X-ray analysis. The most important stabilization interactions within the experimental structure were determined by Hirshfeld surface analysis. The structure optimization was performed by quantum chemical methods, and donor interactions within the coordination sphere were examined by the Quantum Theory of Atoms in Molecules (QTAIM). The antioxidant activity towards hydroxyl (HO•) and ascorbyl (•Asc) radicals was determined by EPR spectroscopy. The binding mechanisms towards the transport protein (HSA) and DNA were investigated by spectrofluorometric titration and molecular docking simulations.

2. Results and Discussion

2.1. Structural Analysis

Complex [Ni(PLSC)(SO4)(H2O)2] was obtained from the mixture of nickel(II) sulfate and the PLSC ligand in water. The crystal structure of the Ni(II)-PLSC included the PLSC ligand in neutral form, as verified by the presence of hydrogen atoms on pyridine and hydrazone nitrogen atoms (Figure 2a). This ligand contained phenolic hydroxyl oxygen, hydrazone nitrogen, and phenol oxygen as coordination sites. The experimental bond lengths and angles are presented in Tables S1 and S2. The geometry of the complex is a distorted octahedron with two water molecules and a sulfate group in coordination (Figure 2a). The position of the ligands around the central metal ion is influenced by the rigidity of the PLSC ligand and the relative flexibility of water molecules, along with the hydrogen bond between the water molecule and sulfate anion. The Ni-Owater bond lengths are 2.0411 and 2.0751 Å, while the distance between the sulfate oxygen atom and nickel(II) is 2.0555 Å. The shortest distance is found between the nitrogen atom and the central metal ion (2.0230 Å, Table S1).
This compound crystallizes in the monoclinic space group P2(1)/n. Additional details on the crystal structure are presented in the Methodology Section. Several hydrogen bonds are formed within unit cells. These interactions are listed in Table 1 and presented in Figure 2b and Figure 3. Two intermolecular hydrogen bonds are formed between protonated nitrogen atoms in the aliphatic chain of the first unit and the sulfate anion of another (2.819(2) and 2.987(2) Å, Table 1). Due to steric hindrance, these bonds deviate from linearity (169 and 145°). Water molecules interact with the hydroxymethyl group with a bond distance of 2.662(2) Å and an angle of 165°. These interactions prove that co-crystalized solvent molecules are important for stabilizing crystal structure. Protonated hydrazine nitrogen forms hydrogen bonds with the sulfate anion (2.791 Å). Additionally, intramolecular interaction between the water molecule and sulfate anion stabilizes each unit. This interaction is characterized by the angle of 164°, which is limited by the overall geometry of the complex. The chains are propagating along the crystallographic b axes (Figure 3). Non-classical interactions in crystal structure are examined by the Hirshfeld surface analysis in the following section.

2.2. Characterization

The FTIR spectra of the PLSC ligand and complex are presented in Figures S1 and S2. The FTIR spectrum of the PLSC ligand contains a sharp peak at 3461 cm−1 assigned to the O-H stretching vibration. This peak is absent from the spectrum of the ligand due to deprotonation. An intense band between 2800 and 3500 cm−1 contains vibrations of N-H and O-H in the ligand structure, and the formation of hydrogen bonds induces additional widening of the group [25,26]. The same band was found in the FTIR spectrum of the complex. The bands between 2950 and 2800 cm−1 are also assigned to the stretching vibration of the +N-H group of the pyridine ring [1]. In the complex, the PLSC ligand is present in zwitterion form, as the migration of hydrogen atoms of the OH group to pyridine nitrogen occurred [27]. Another notable band in the FTIR spectrum of the ligand at 1680 cm−1 is assigned to C=O vibration, which coincides with the results presented in [1]. This band is absent from the FTIR spectrum of the complex. This supports the assumption that coordination occurred from this group to nickel(II) ion in imidazole form. The C=N vibration is located at 1570 cm−1 in the spectrum of the ligand. This band is shifted towards higher wavenumbers (1630 cm−1) as this group is included in coordination with the central metal ion through the azomethine nitrogen atom [1,27]. The phenolic C-O group vibration is positioned at 1151 cm−1 in the ligand spectrum, as suggested in [9]. The position of this group is shifted to 1130 cm−1 due to the coordination of central metal ions. A weak band at 620 cm−1 is attributed to the sulfate ion vibration [9].
The UV-VIS spectrum of the complex was prepared in water, and it is depicted in Figure S3. The experimental spectrum contains two wide bands centered around 300 and 400 nm. Their structure is complex, suggesting that they are composed of two close position bands, which coincide well with the previously described spectrum of Ni(PLSC)Cl2∙3.5H2O [6]. As explained in the previous reference, the band at 300 nm includes two types of transitions, the n→π* imine and n→π of both the imine and pyridine ring. These transitions can be seen in the spectrum of the PLSC ligand [28]. The other band at 400 nm is assigned to the LMCT transition between the central metal ion and azomethine nitrogen. Low-intensity d→d bands are usually located in this region, although the CT transitions probably mask them. The authors have also discussed that the octahedral geometry of the complex could be suggested from the position of this band [7], which, in the present case, was confirmed by X-ray crystallography.
The obtained value of the molar conductivity for the complex solution was 111 S cm2, which falls within the typical range for 1:1 electrolytes (100–140 S cm2) [29]. This could be explained by the partial replacement of the sulfate group by the solvent molecules, as discussed for similar complexes in [6]. The obtained value is much lower than that of PLSC complexes with Ni(II) and chloride/nitrate ions [6]. This exchange has significant implications, as the sulfate ion can be removed from the structure in the solution, changing the possible interactions with biomolecules, as presented in the following sections.

2.3. Hirshfeld Surface Analysis

Stabilization interactions are a crucial part of crystal structures, influencing the spatial distribution of units. In this contribution, Hirshfeld surface analysis was used for their identification and quantification. The fingerprint plots of the most important contacts are given in Figure S4.
The most important stabilization interactions were formed between oxygen and hydrogen atoms, denoted as O∙∙∙H, which amounts to 52.9% of all contacts. The presence of a sulfate ion greatly increases the amount of these interactions within crystal structures compared to similar compounds [30,31]. The sulfate ion oxygen atoms act as hydrogen atom acceptors. On the other side, oxygen atoms of water molecules and the hydroxymethyl group are hydrogen atom donors in these interactions. Another important type of contact can be marked as H∙∙∙H (29.7%). The abundance of hydrogen atoms in the structure of ligands and water molecules is responsible for compound stability through these interactions. Protonated pyridine, hydrazone, and amino nitrogen atoms are part of N∙∙∙H contacts (4.5%). The interactions between carbon and hydrogen atoms amount to 11.8%. The PLSC core includes the aromatic ring and aliphatic chain, and the abundance of hydrogen atoms contributes to these interactions. Additionally, interactions between positively charged hydrogen atoms attached to electronegative atoms and negatively charged π aromatic cloud contribute to the mentioned contacts [32].
The interactions between electronegative atoms are characterized by much lower percentages, namely 0.6 (O∙∙∙O) and 1.1% (O∙∙∙N). Interaction, including carbon atoms and oxygen/nitrogen atoms, has a similar contribution to the total number of contacts, around 1.1%. It is important to emphasize that the central metal ion is not included in the contacts due to the octahedral geometry and bulkiness of the ligands. The same applies to the sulfur atom surrounded by four oxygen atoms.

2.4. Theoretical Structural Analysis

The crystallographic structure of the complex was further used for structural optimization by DFT methods and the B3LYP functional. For nonmetallic atoms, a 6-311++G(d,p) basis set was employed, while for the nickel(II) ion, two basis sets were checked, namely LanL2DZ and def2-TZVP, to determine the appropriate level of theory. These functional/basis set combinations were previously used for other nickel(II) complex compounds [33,34,35]. The comparison between experimental and theoretical structures included the calculation of the correlation coefficient (R) and the mean absolute error (MAE). The latter parameter determines the average value of the absolute difference between two data sets. The experimental and theoretical bond lengths and angles and R and MAE parameters are presented in Tables S1 and S2. The optimized structure at the B3LYP/6-311++G(d,p)(H,C,N,O,S)/LanL2DZ(Ni) level of theory is shown in Figure 4.
The correlation coefficients for the bond lengths are 0.988 (LanL2DZ) and 0.984 (def2-TZVP), with MAE values of 0.036 and 0.039 Å, respectively. These differences are comparable to the experimental error, showing that both levels of theory are applicable for examining the system. During the optimization, specific differences in bond lengths were observed. Where bonds including a central metal ion are concerned, the MAE values are 0.086 (LanL2DZ) and 0.098 Å (def2-TZVP). It is important to mention that an additional hydrogen bond was found between the sulfate ion and water molecule, leading to a slight change in Ni-O bond lengths with the water molecule and anion. Also, the differences in values of sulfate ion S-O bonds due to the interaction with water molecules were much more pronounced in the optimized structure, which disrupted the local symmetry of this anion.
Bond angles are much more prone to change during optimization, mainly if new interactions are formed between ligands. The correlation coefficients are still very high, 0.97 in both cases, although the MAE values are 3.45 (LanL2DZ) and 3.33° (def2-TZVP). The difference between the experimental and optimized structures in angle O4-Ni-O3 is around 10° for both theoretical structures, which is a direct consequence of the slight incline of the sulfate ion towards the water molecule. The angle that includes the water molecule (O1-Ni-O8) is also larger by 11° (94.03 vs. 105.41/104.88°). The strength of the formed hydrogen bond is responsible for the elongation of the O8-H bond to 1.515 Å, which is 0.6 Å more extended than the other O-H bond. These interactions are examined in more detail in the QTAIM analysis section. The octahedral geometry around the central metal ion is distorted, leading to the lower O1-Ni1-O3 value in the optimized structure. This value is 167.5° in the experimental and 150.8/151.7° in the theoretical structure. These changes result from the optimization of the isolated complexes in a vacuum, while other intramolecular interactions influence the stability of the crystal structure, as explained in the previous section. The angles within the PLSC ligand are not influenced by the optimization procedure, as this ligand contains extended delocalization and rigidity that prevents any conformational change. Therefore, the selected level of theory for the optimization and further structural analysis of the obtained complex was B3LYP/6-311++G(d,p)(H,C,N,O,S)/LanL2DZ(Ni), as the relative differences between the correlation coefficients/MAE values between two structures were in favor of this effective core potential. Similar results were found for other Ni(II) and Cu(II) complexes with PLSC ligands [9].
The stabilization interactions within the structure of [Ni(PLSC)(SO4)(H2O)2] were examined by the QTAIM approach. Particular emphasis was put on the interactions between donor atoms and the central metal ion, which were quantified through parameters of Bond Critical Points (BCPs), such as the electron density (ρ(r)), Laplacian (∇2ρ(r)), Lagrangian kinetic electron density (G(r)), potential electron density (V(r)), density of total electron energy (H(r) = G(r) + V(r)), and interatomic bond energy (Ebond = V(r)/2) [36]. Bader and Essen proposed a classification of interactions based on the values of electron density and the Laplacian. Shared (covalent) interactions have an electron density higher than 0.1 a.u., while closed-shell interactions (hydrogen bonds, ionic bonds, and van der Waals interactions) have a much lower electron density (usually around 0.01 a.u.) [37]. The mentioned parameters are shown in Table S3, along with the positions of BCPs in the structure of the obtained complex in Figure S5.
The Laplacian values of the bonds between donor atoms and the central metal ion are positive, between 0.150 and 0.320 a.u. The kinetic and potential energy values are included in Bianchi and coworkers’ more detailed classification of interactions [38]. The shared shell region of covalent bonds has a –G(r)/V(r) ratio lower than 1; the intermediate region of dative and ionic bonds with a weak covalent degree has a ratio between 1 and 2, and closed-shell interactions (ionic bonds and van der Walls interactions) are characterized by a ratio higher than 2. The highest electron density values were obtained for the interactions between the central metal ion and sulfur oxygen and water oxygen atoms (0.068 and 0.075 a.u., Table S3). These interactions have –G(r)/V(r) values equal to 1, classifying them as ionic bonds with the highest interatomic bond energy of −142.3 and −156.3 kJ mol−1. The second water molecule interacts with nickel(II) through a bond with a weak covalent character (–G(r)/V(r) = 1.1) and interatomic bond energy of −66.6 kJ mol−1. Among the three donor atoms of PLSC, the highest electron density was found for interactions with a phenyl oxygen atom (0.54 a.u.). These interatomic bond energies were −92.2 (N2), −104.1 (O1), and −74.1 kJ mol−1 (O3). An aromatic ring and other electronegative atoms influence the interaction energy. These values follow results obtained for various nickel(II) complexes with similar ligands [39].
It is important to observe that electron densities and interatomic bond energies are significantly different for two molecules of water that interact with a central metal ion. The reason is additional interactions between ligand molecules. As presented in Table S4, there is a weak interaction between one of the oxygen atoms of the sulfate anion and the methyl group of PLSC, with an electron density of 0.017 a.u. and interatomic bond energy of −16.5 kJ mol−1. This is a classic example of a weak hydrogen bond. Another hydrogen bond is found between the sulfate anion and the hydrogen atom attached to the O9 atom. This is a stronger bond with an interaction energy of −26.2 kJ mol−1. A weak covalent character is proven by a –G(r)/V(r) equal to 1.1. In the crystallographic structure, one of the hydrogen bonds was particularly important for stabilization (O7∙∙∙H-O8). This interaction was present in the optimized structure, and it has a high value of electron density (0.280 a.u.) and interatomic bond energy of −656.2 kJ mol−1 proving the formation of a covalent bond (–G(r)/V(r) = 0.2). The negative H(r) value of −1312.4 kJ mol−1 is additional proof of the covalent character. This result is expected due to the high electronegativity of the sulfate anion. As previously discussed, the deprotonation of water molecules leads to a much stronger interaction between O8 and nickel(II) ions. It should be emphasized that interactions between the central metal ion and water molecules are probably influenced by the optimization in a vacuum and that significant changes in strength and bond length can be expected in the solution.

2.5. Antioxidant Activity Determination

The antioxidant activity of the complex towards two biologically relevant radicals, •Asc and HO•, was examined by EPR spectroscopy. The first radical is a long-living species that can be directly monitored by EPR spectroscopy. On the other hand, for HO•, a spin trap was used. The hydroxyl radical was generated in the Fenton system, as described in the methodology section. Figure 5 presents the DPMPO-HO• spectra without and with different amounts of complex. The low-field signals were used to determine antioxidant activity (Equation (1)), and the results are expressed as the amount of radical scavenged by the complex. It is important to outline that additional peaks were present in the spectra upon adding a complex, probably due to the use of DMSO as a solvent. The amount of reduced HO• was 82.5, 87.0, 88.8, and 90.4% for the final concentration of the complex between 0.3 and 2 μM. The reduction process was controlled by the concentration of the complex. Similar activity (86.2%) for the 0.5 μM solution of {RuCl(η6-p-cymene)}2(μ-Cl)(μ-1-N,N′-naphthyl)]Cl was determined by the same methodology [40], which was comparable to the standard antioxidant, ascorbic acid. As the obtained complex does not contain any hydrogen-donating groups, it can be postulated that radical adduct formation is a dominant reduction mechanism [41]. The •Asc species has a much simpler spectrum, as shown in Figure 5. For this analysis, a nickel(II)-PLSC complex concentration range was taken between 0.5 and 2 μM. The reduction of radical was 53.0 (0.5 μM), 69.0 (1 μM), and 86.9 (2 μM). Again, the reduction process was concentration-dependent. These results show that the obtained complex acts as a radical scavenger and could be included in protecting cells from oxidative stress or influencing processes in cancer cells that occur through free radicals. Other nickel(II) complexes have also shown considerable radical-scavenging activity towards hydroxyl radicals and other reactive oxygen species [42,43,44].

2.6. Experimental and Theoretical Protein-Binding Affinity

The distribution of compounds in the bloodstream usually occurs through their interactions with transport proteins such as HSA. Spectrofluorimetric titration was employed to examine the thermodynamics of the binding process. The HSA solution was irradiated by 280 nm, and the emission spectra were obtained between 300 and 500 nm, as shown in Figure 6. The fluorescence emission spectra were recorded upon adding the complex in equimolar amounts. The emission maxima value was dependent on the concentration of a quencher. The measurements were repeated at three temperatures in a range mimicking physiological conditions. The obtained fluorescence values were corrected because of the absorption of the complex at the excitation and emission wavelengths, as shown in Equation (2).
Upon the addition of the complex, the fluorescence intensity decreased. From this dependency, the Stern–Volmer constants of the process were calculated (Equation (3)). These constants and their dependency on temperature were further used to determine the fluorescence quenching mechanism. If static quenching occurs, a complex is formed between the fluorophore and quencher, and KSV values decrease with temperature. On the other side, dynamic quenching includes the collision between the excited molecule and the quencher, increasing KSV with temperature. The calculated KSV values are presented in Table 2. It should be noted that the intercept in these calculations was set to 1. As found, these values were in the narrow range between 1.95 × 104 (27 °C) and 1.84 × 104 M−1 (37 °C) (Figure S6). These values lead to the conclusion that strong interactions were formed by the complex and HSA molecules [25], and the quenching mechanism was denoted as static. Other nickel(II) complexes showed the same quenching mechanism towards HSA [45,46]. If the fluorophore lifetime was taken as 4.43 ns, as proposed by Hu and coworkers, the quenching constant is of the order of 1013 M−1 s−1. This value is much higher than the collisional quenching constant of 2 × 1010 M−1 s−1 [47]. The double-log Stern–Volmer equation (Equation (4)) was used to determine the binding constant and the number of binding positions within the HSA molecule. These values are also given in Table 2.
The change in the fluorescence intensity linearly decreased with the increase in the quencher concentration. The number of binding positions was between 1.08 and 1.28, which proved that one complex molecule was bound to one HSA molecule. The binding constants were 3.87 × 104 (27 °C), 1.08 × 105 (32 °C), and 3.51 × 105 (37 °C) (Figure S6). The binding constants were of the same order of magnitude as previously determined for similar nickel complexes with similar ligands [31,45]. The thermodynamic parameters of binding were calculated through Equation (4). The entropy and binding enthalpy changes were 170.5 kJ mol−1 and 655.9 J mol−1 K−1. The positive values of these parameters are characteristic of the formation of non-specific interactions, mainly van der Waals and hydrogen bonds [48]. The changes in Gibbs free energy of binding were between −26.3 and −32.8 kJ mol−1, proving that the binding was spontaneous in the examined range. The spontaneity of the process is entropy-driven, as the entropic term (TΔSb) is higher than the enthalpic. The binding mechanism was further investigated through molecular docking simulations. The negative value of the change in enthalpy (−11.026 kJ mol−1) and positive value of the change in entropy (46.396 J mol−1 K−1) were obtained for the octahedral nickel(II) complex with the N,N0-dibenzylethane-1,2-diamine ligand in [49]. Much lower changes in Gibbs free energy of binding (between −24.9 and −25.5 kJ mol−1) compared to the obtained complex result from the lower number of reactive groups in the ligand structure. A similar range in ΔGb values (between −28.30 and −34.97 kJ mol−1) was determined for the binding of the octahedral nickel(II) complex with 2-(2-nitrophenyl)imidazo [4,5-f]1,10-phenanthroline) in reference [50]. The electrostatic interactions between prepared nickel(II) complexes with nalidixic acid, 2,2′-bipyridine, and the 1,10-phenanthroline ligands and HSA were determined as the most appropriate based on the negative change in enthalpy and positive change in the entropy of binding, while the changes in Gibbs free energy were around −30 kJ mol−1 [51].
Several starting positions were examined for the binding of the nickel(II) complex to HSA. The best binding configuration at the FA9 binding site had a change in Gibbs free energy of −26.4 kJ mol−1, comparable to the experimentally obtained value of −26.3 kJ mol−1. The possible influence of hydrogen phosphate (HPO42−) and dihydrogen phosphate (H2PO4−) anions from the buffer solution on the binding affinity was examined in subsequent simulations. Separate investigations were undertaken to determine the interactions of each species (HPO42− and H2PO4−) with the target molecule. Two anions had slightly lower binding affinities compared to the nickel(II) complex, namely −25.9 (HPO42−) and −20.5 kJ mol−1 (H2PO4−). The FA9 binding sight is the preferred location for all three ligands. The presence of the nickel(II) complex did not affect the anions’ binding position or energy. However, both anions directed the complex towards the FA8 binding site. The presence of H2PO4− slightly decreased the binding energy of the Ni(II) complex (−25.8 kJ mol−1), while HPO42− had virtually no effect on its binding energy (−26.5 kJ mol−1), although the binding site of the complex was changed to FA8. This is a significant result, as the FA8 binding site is near the fluorescent amino acid Trp213 (Figure 7). Therefore, it can be expected that the interactions of the complex with surrounding amino acids change the chemical environment of Trp213, leading to a decrease in fluorescence emission, as experimentally observed. Also, the presence of additional charged species significantly influences the binding position.
Although bound to the FA8 binding site in the IIA subdomain, the nickel(II) complex interacts with amino acids from three subdomains and one interdomain region surrounding this binding site. These include the IB subdomain (Lys195), the IIA subdomain (Arg218, Arg222, and Asn295), the interdomain region between subdomains IIA and IIB (Val293 and Asn295), and the IIIA subdomain (Pro447 and Cys448) (Figure 8).
Figure 8 presents the most stable configuration. The obtained complex, rich in electronegative oxygen and nitrogen atoms, requires a specific environment for proper stabilization. This complex is bound near the polar (Lys195, Asn295, Pro447, and Cys 448) and positively charged amino acids (Arg218 and Arg222) (Figure 8). As a result, favorable intermolecular interactions include classic hydrogen bonds formed between the polar NH and OH groups of the complex and the polar (-NH2 and -C=O) or charged (-C(NH2)+ and -NH3+) groups of nearby amino acids. Additionally, the charged group of amino acids participates in favorable electrostatic interactions with the SO42− group. However, due to the bulkiness of the amino acid residues, the positively charged -C(NH2)2+ group is located in the vicinity of the Ni2+ ion, leading to electrostatic repulsion or steric clashes between coordinated H2O molecule and the -NH3+ group. Classic hydrogen bonds dominate over carbon–hydrogen bonds in this environment. Hydrophobic interactions are not observed, as the coordinated SO42− anion and two water molecules shield aromatic rings of the coordinated PLSC ligand from hydrophobic amino acid residues. Instead, the sulfate group forms two carbon–hydrogen bonds with the C-H group of Lys195 and Arg218. A third carbon–hydrogen bond is formed between the C=O group of Asn195 and the aromatic CH2 group of the octahedral Ni(II) complex.

2.7. Experimental and Theoretical DNA Binding Affinity

2.7.1. Spectrofluorimetric Titration of [Ni(PLSC)(H2O)2(SO4)] by CT-DNA

The interactions between DNA and complexes are often examined as the first part of the biological assessment that leads to anticancer activity [52,53]. The complex showed relatively stable fluorescence upon irradiation at 280 nm. The emission spectra of the complex were recorded between 300 and 500 nm (Figure 9) upon the addition of CT-DNA, as explained in reference [54]. The intensity of fluorescence emission was low, although measurable with 10 nm slits. The measurements were repeated at three temperatures, as explained previously for HSA binding experiments. The KSV values, binding constants, number of binding positions, and thermodynamic parameters of binding are presented in Table 3.
The KSV binding constants for the additions of CT-DNA to the solution of the complex are in a very narrow range, between 1.71 and 1.89 × 104 M−1. The trend is reversed from the previous discussion, and the KSV values increase with temperature, which characterizes the dynamic quenching of fluorescence [54]. The collision of particles leads to the nonradioactive relaxation of the complex. When the modified Stern–Volmer equation is applied, the binding constants are 8.23 × 102 (27 °C), 2.64 × 103 (32 °C), and 2.74 × 104 (32 °C). These changes in binding constants are additional proof that temperature significantly affects the interactions between CT-DNA and the complex. The number of binding positions is around one, showing that one complex molecule interacts with one CT-DNA. The changes in enthalpy and entropy of the process are both positive—270.4 kJ mol−1 and 955.5 J mol−1 K−1, respectively. The formation of non-specific interactions, such as hydrophobic interactions, dominates the process, as explained in [54]. These values of thermodynamic parameters lead to a wide range of changes in Gibbs free energy of the process, between −16.2 and −25.8 kJ mol−1. The binding process is spontaneous at all three temperatures, although the actual value of this parameter increases by more than 9 kJ mol−1. Again, the entropic term is dominant, and the interactions between two species lead to the increase in order. Shahabadi and coworkers examined water-soluble nickel(II) complex with 2,20-bipyridine and 1,10-phenanthroline-5,6-dione ligands in a much wider temperature range (between 293 and 318 K) and the change in Gibbs free energy of binding changed between −29.11 and −21.01 kJ mol−1 [55]. The stability and voluminosity of ligands in the mentioned case were crucial for the interactions with CT-DNA. Positive changes in the enthalpy (63.75 kJ mol−1) and entropy (271.04 J mol−1 K−1) of binding were obtained for nickel(II) complexes with the drug mesalamine in [56], indicating that hydrophobic forces are dominant for the process, similar to the results for the nickel(II)-PLSC complex.
The possible binding mechanism was further investigated by the potassium iodide quenching experiments. This ion is a potent quencher of the intrinsic fluorescence of compounds, but it is repelled by the negatively charged DNA phosphate backbone. When the complex is intercalated into or positioned within a minor groove of the CT-DNA structure, the quenching constant should decrease compared to the measurements without CT-DNA. On the other hand, if the KSV values are similar, external binding is more probable [57]. The fluorescence emission spectra of the complex in the absence and presence of CT-DNA and varying concentrations of KI are shown in Figure 10. As presented, adding KI led to a decrease in fluorescence emission intensity dependent on the amount of KI. The reduction in fluorescence was much faster in the presence of CT-DNA. The values of KSV were 62.5 and 38.0 M−1 when CT-DNA was absent and present, respectively. This decrease in the KSV value is characteristic of intercalation/minor groove binding of complexes, as previously shown for planar copper(II) complexes [58]. This is an interesting result, as octahedral complexes are usually too voluminous for this type of binding. This experimental result is further examined through molecular docking simulations to verify the obtained mode of interaction with DNA.

2.7.2. Ethidium Bromide Displacement Studies

Ethidium bromide (EB) displacement studies examine the binding mechanism of different compounds to DNA [59]. This method is based on removing EB and comparing the interaction strength. The intercalation of EB in the DNA structure, as a result, has a formation of a highly fluorescent species CT-DNA-EB with an excitation wavelength of 520 nm and emission maximum at 600 nm [60]. Upon the addition of the complex, the structure of CT-DNA-EB is decomposed, which is observed as the fluorescence emission intensity decreases. The unbound EB is easily quenched by the present species in the solution.
The emission spectra of CT-DNA-EB in the presence of various concentrations of the complex at 27 °C are shown in Figure 11. As expected, the emission maxima lowers as the concentration of the complex increases. The Stern–Volmer constant for this process is 1.14 × 104 M−1. Previously investigated nickel(II) complexes with 3-amino-5-(4-fluorophenyl) isoxazole derivatives showed KSV values that were an order of magnitude lower than the one obtained in this experiment, which is a result of ligand stability through delocalization of the structure [61]. The KSV value in the case of the nickel(II) complex with the Schiff base derived from 3–ethoxy salicylaldehyde and o–phenylenediamine was 6.01 × 104 M−1 [62], which is comparable to the obtained results in this study due to the existence of electronegative groups in the ligand structure. The binding constant obtained through the double log equation is 6.73 × 103 M−1, with the value of n equal to 0.95 (Figure 11). These values show that one molecule of EB is replaced by one complex molecule. The binding affinity, calculated from the binding constant, is −22.0 kJ mol−1.

2.7.3. Molecular Docking Simulations of the Binding Mechanism to DNA

The binding mechanism of the title complex to DNA was elucidated through molecular docking simulations. After numerous attempts, the obtained binding energies of the octahedral complex were significantly higher than the experimental ones, and the binding position was not in line with the experimental data. Considering that the experimentally obtained binding mode included intercalation and minor groove binding, it was assumed that specific changes in the octahedral geometry might happen. Intercalation of the Ni(II) complex was only possible after the dissociation of two coordinated water molecules, resulting in the transformation from the octahedral geometry to the square planar Ni(II) complex, [Ni(PLSC)(SO4)]. A similar change in geometry explained the minor groove binding of the Cr(III) complex with the (Z)-2-((pyridine-2-ylimino)methyl)phenol ligand through removal of two chlorine and one water ligand [63]. Upon binding to the DNA molecule, the square planar Ni(II) complex favored intercalation (ΔG1 = −25.6 kJ mol−1) over minor groove binding (ΔG5 = −17.4 kJ mol−1). The first four binding positions are located in the intercalation region, while the fifth binding position is in the minor groove (Figure 12). No binding to the major groove was observed. In spectrofluorometric experiments involving the replacement of ethidium bromide, the binding energy (−22.0 kJ mol−1) was comparable to the calculated value (−22.5 kJ mol−1). The binding energy from spectrofluorimetric measurement of DNA (ΔGexp = −16.2 kJ mol−1) closely matches the estimated value for minor groove binding (ΔGcal = −17.4 kJ mol−1).
Following the dissociation of coordinated water molecules from the octahedral Ni(II) complex, the π systems of nucleobases become available to the SO4 group and hydrogen atoms bound to electronegative or aromatic carbon atoms (Figure 13). This enables the square planar arrangement of the obtained complex to engage in additional interactions involving π electronic systems, such as π-sigma, π-sulfur, and π-alkyl interactions. The SO42− group forms the majority of these interactions, both in number and type, which is expected due to its prominent position and negative charge.
In the minor groove, the supramolecular interactions are limited to hydrogen bonds, as depicted in Figure 13. In this binding position, the SO4 group of the square planar Ni(II) complex is not involved. Instead, the interactions primarily involve hydrogen atoms bound to electronegative or carbon atoms. These results verify the experimental findings and assumption that certain changes in the geometry are possible in solution.

3. Materials and Methods

3.1. Chemicals

All of the chemicals were obtained from Merck (Darmstadt, Germany) and used without further purification.

3.2. Synthesis of PLSC

PLSC ligand was synthesized according to the previous procedure [64]. The obtained ligand was further examined by FTIR spectroscopy and elemental analysis. Anal. Calcd. for PLSC∙2H2O (C9H16N4O5, 260.25): C, 41.53; H, 6.19; N, 20.52. Found: C, 42.02; H, 6.82; N, 20.52. FTIR: 3461 (υ(O-H) stretching), 1570 (υ(C=N)), 1500 (υ(C-N)), 2956 cm−1 (υ(+NH)); broad band above 3000 cm−1 is attributed to hydrogen bonded groups. These positions match those of the PLSC ligand in reference [1].

3.3. Synthesis of [Ni(PLSC)(SO4)(H2O)2]

A measured amount of 0.5 mmol (0.78 g) NiSO4 and 0.5 mmol (0.13 g) of PLSC∙2H2O ligand were dissolved in 15 cm3 of water without additional substances. The molar ratio of nickel salt and ligand was 1:1. With the addition of water, a gentle dissolution began. The dissolution was intensified upon heating at 100 °C. After ten minutes of boiling, the solid compounds were completely dissolved, leading to a clear solution of intense dark green color. The solution was left to crystalize at room temperature. After seven days, dark green crystals were separated. The obtained crystals were washed with cold water as the crystals were not highly soluble. This helped remove water-soluble impurities without dissolving the product. Yield: 0.120 g (76%) Anal. Calcd. for [Ni(PLSC)(SO4)(H2O)2] (C9H16NiNO9S, 415.03): C, 26.04; H, 3.86; N, 3.38; S, 7.72. Found: C, 26.14; H, 3.55; N, 3.42; S, 7.60.

3.4. Characterization

Ligand and complex FTIR spectra were recorded on a Thermo Nicolet-Avatar 370 FTIR spectrometer (Thermo Fisher Scientific, Waltham, MA, USA) between 4000 and 600 cm−1. The KBr pellet technique was used to obtain spectra with a mass ratio of 3:150 mg (compound: KBr). The UV-VIS spectrum was prepared between 250 and 800 nm on a Thermo Scientific UV-VIS Spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA) with a resolution of 1 nm and integration time of 0.20 s. The UV-VIS spectrum was obtained for the 1.3 × 10−4 M solution of complex in water. The elemental analysis of air-dried samples was conducted on an Elementar Vario El III (Elementar Analysesysteme GmbH, Langenselbold, Germany). The mass percentages were calculated based on the intensity corresponding to different oxides. Molar conductivity of freshly prepared 1.3 × 10−4 M solution complex in water was recorded on WTW inoLab Cond 720 Conductometer (Thermo Fisher Scientific, Waltham, MA, USA).

3.5. X-Ray Crystallographic Analysis

A representative pale green plate-like crystal with dimensions 0.122 × 0.083 × 0.021 mm was selected and mounted on a nylon cryoloop. Diffraction data were collected at 123 K using CuKα radiation (λ = 1.54184 Å) on a Rigaku Synergy S diffractometer fitted with a HYPIX 6000 hybrid photon counting detector. Data were collected and processed, including an empirical (multi-scan) absorption correction, with CrysAlisPro software [65]. The structure was solved and refined by standard methods using the SHELX software suite in conjunction with the Olex2 graphical interface [66,67]. Non-hydrogen atoms were refined with anisotropic displacement ellipsoids, and hydrogen atoms attached to carbon were placed in calculated positions using a riding model. The positions of hydrogen atoms attached to oxygen and nitrogen were apparent in the difference Fourier map and were refined with restrained geometry (DFIX/DANG); d(N-H) = 0.91(2) or d(O-H) = 0.88(2) Å.
Crystallographic data were deposited in the Cambridge Crystallographic Data Centre (CCDC, 12 Union Road, Cambridge CB2 IEZ, UK; e-mail: [email protected]) with the CCDC number 2348551 for [Ni(PLSC)(SO4)(H2O)2]. The crystal data and structure refinement details are listed in Table 4.

3.6. Hirshfeld Surface Analysis

The stabilization interactions in the crystallographic structures were examined in the CrystalExplorer [68] program through Hirshfeld surface analysis. These interactions are depicted through a graph characterized by two distances, one between the two nearest nuclei (de) and the other connecting nuclei with the external surface (di) [30,69,70]. If distances are shorter, equal, or longer than van der Waals separations between nuclei, they are colored red, white, and blue. The normalized distances are between −0.7224 (red) and 1.2925 (blue). The percentages of specific contacts are determined from the fingerprint plots shown in the Supplementary Information.

3.7. Quantum Chemical Analysis

The crystallographic structure of the title compound was optimized in the Gaussian 09 program package (Gaussian 09, revision C 01) [71] using B3LYP functional [72] in conjunction with 6-311++G(d,p) [73] basis set for H, C, N, O, and S atoms and LanL2DZ/def2-TZVP basis sets [74,75,76] for nickel atoms. The optimization was performed without any geometrical constraints, and the absence of imaginary frequencies was used as proof that the minimum on the potential energy surface was obtained. The stabilization interactions were quantified by the Quantum Theory of Atoms in Molecules (QTAIM), an approach proposed by Bader [77,78]. Particular emphasis was put on the donor atoms–central metal interactions. Electron density, Laplacian, and other parameters were determined in the Bond Critical Points (BCPs) [79]. The AIMAll program package [80] was used for these calculations, starting from the .wfx files from the Gaussian 09.

3.8. Antioxidant Activity

To investigate the scavenging activity of the samples towards HO• radicals, a solution containing the samples and a Fenton reaction with the DEPMPO (5-diethoxyphosphoryl-5-methyl-1-pyrroline-N-oxide) spin-trap was used [81]. The reaction mixture, with a total volume of 29 µL, consisted of 2 µL H2O2 (final concentration 0.35 mM), 1 µL DEPMPO (final concentration 3.5 mM), and 1/2/3/6 µL of 10 µM sample solution (dissolved in water/DMSO mixture; final concentration 0.3/0.6/1/2 µM) and the rest was deionized water. Following this, 1 µL FeSO4 (final concentration 0.15 mM) was added to the mixture and transferred to a gas-permeable Teflon tube, which was then placed in the EPR resonator (Bruker ELEXSYS-II E540 (Bruker, Billerica, MA, USA). The EPR signal of the DEPMPO/OH spin adduct was recorded after 2 min, using the following parameters: microwave power 10 mW, 9.85 GHz microwave frequency, 100 kHz modulation frequency, and 1 G modulation amplitude. Control measurements were conducted by replacing the sample with an equivalent volume of solvent. The antioxidant activity of the sorghum extracts (AA) was calculated using the formula
A A = 100 · I c − I a I c   ( % )
where Ic and Ia refer to the average intensity of the two most intense signals in the low field in the control spectrum and spectrum with added complex.
To evaluate the samples’ activity against ascorbyl radicals, the EPR signal of •Asc in a DMSO solution was measured following a previously established method [82]. Briefly, 10 µL of EDTA (final concentration 250 µM) and 1 µL of FeCl3 (final concentration 8 µM) were combined to form the Fe(III)-EDTA complex in 74 µL of DMSO. Subsequently, 5/10/20 µL of the sample (dissolved in water/DMSO mixture; final concentration 0.5/10/20 µM) was added. The •Asc radical was then generated by adding 10 µL of ascorbic acid (final concentration 250 µM) to the mixture, and 30 µL of it was transferred to a gas-permeable Teflon tube. The X-band EPR spectra of the •Asc radical were recorded 2 min later, under the following parameters: 10 mW microwave power, 9.85 GHz microwave frequency, 100 kHz modulation frequency, and 2 G modulation amplitude. Control measurements were performed by replacing the sample with solvent. The antiradical activity of the samples was calculated as described previously.

3.9. Spectrofluorimetric Determination of HSA Binding Affinity

The protein and DNA binding affinities of the obtained complex were examined by spectrofluorimetric titration on a Cary Eclipse MY2048CH03 spectrophotometer (Agilent Technologies, Santa Clara, CA, USA). The scan rate was set to 600 nm min−1 with both slits of 5 nm. The HSA fluorescence was excited at 280 nm, sufficient for activating tryptophan residues. The protein concentration was constant at 5 × 10−6 M in phosphate buffer saline at pH = 7.4 (concentrations of NaCl and KCl were 137 and 2.7 mM). The number concentration of complex changed between 1 and 10 μM. The fluorescence spectra were recorded between 300 and 500 nm two minutes after adding the quencher. The emission spectra maximum was located around 340 nm. The emission intensity was corrected for absorption of excitation wavelength and re-emission of emitted light by the following equation [83,84]:
F c = F m e A 1 + A 2 2
In this equation, Fc and Fm are the corrected and measured fluorescence emissions, while A1 and A2 are the absorbances of the complex at the excitation and emission wavelengths. Throughout the manuscript, only the corrected fluorescence intensities are presented.
The quenching mechanism was determined by the Stern–Volmer equation through the dependence of the Stern–Volmer constant (KSV) and temperature [85,86]. KSV values were obtained in the following equation, in which F0 and F denote the fluorescence intensity of pure compounds (HSA or complex) and compounds with added quenchers ([Q]).
F 0 F = 1 + K S V c o m p l e x = 1 + τ 0 k q [ Q ]
The double-log Stern–Volmer equation was employed to further examine the mechanism [87]. In this equation, F0 and F have the same meaning, as previously discussed, while Kb is the binding constant and n is the cooperativity number [88].
log ⁡ F 0 − F F = log ⁡ K b + n log ⁡ [ c o m p l e x ]
The thermodynamic parameters of binding were calculated through the dependency of the binding constant on temperature. The change in enthalpy and entropy were obtained from the slope and intercept, respectively:
ln ⁡ K b = − ∆ H b R T + ∆ S b R

3.10. Spectrofluorimetric Determination of DNA Binding Affinity

The DNA binding studies were followed through complex fluorescence quenching by CT-DNA. For these experiments, calf thymus DNA was chosen. The concentration of CT-DNA solution was determined from the absorbance value at 260 nm (molar extinction coefficient 6600 dm3 mol−1 cm). The absorbance ratio (A260/A280) was approximately 1.9, indicating that CT-DNA was sufficiently free from proteins [46]. These experiments were conducted using a Thermo Scientific Evolution 220 spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA). The concentration of the complex was kept constant at 10−5 M. The excitation wavelength (280 nm) was selected as it gave a measurable fluorescence. The emission spectra were recorded between 300 and 500 nm, with both slits set to 10 nm. The standard solution of CT-DNA (2.3 × 10−4 M) in phosphate buffer saline was added stepwise, and fluorescence spectra were recorded two minutes after the addition.
The iodide quenching experiment was performed by keeping the concentrations of complex and DNA constant at 10 and 20 μM. The concentration of KI ranged between 0 and 9 mM, with a step of 1 mM. The excitation wavelength was determined from the absorption spectra of the complex (280 nm), while the emission spectra were recorded between 300 and 500 nm.
The spectrofluorimetric titration was also used for the ethidium bromide (EB) displacement studies in the presence of the obtained complex. The concentrations of CT-DNA and EB were held constant at 50 and 5 μM in phosphate buffer saline pH = 7.4 (concentrations of NaCl and KCl were 137 and 2.7 mM). The concentration of the complex was changed from 0 to 9 μM in steps of 1 μM. The excitation wavelength for CT-DNA-EB was set to 520 nm, and the emission spectra were recorded between 540 and 650 nm. Both slits were set to 10 nm. The thermodynamic parameters of the displacement were determined from the binding constant [89].

3.11. Molecular Docking

The synthesized octahedral Ni(II) complex, [Ni(PLSC)(H2O)2(SO4)], contains an abundance of electronegative atoms, enabling a variety of potential interactions. However, the bulkiness of the complex introduces steric hindrance. Molecular docking calculations were employed to investigate the binding process to target molecules (BSA and DNA) at the molecular level. The crystal structure of the HSA molecule without any bound ligands (PDB ID: 1AO6 [90]) was selected as one target. Another target was the crystal structure of DNA with PDB ID:1XRW [91], which is suitable for comparison with spectrofluorimetric measurements, including ethidium bromide displacement e and Ni(II) complex binding to free DNA. The original crystal structures from the PDB were cleaned from water and ligand molecules before docking studies. Density Functional Theoretical (DFT) calculations using GAUSSIAN09 were performed at the B3LYP/6-311++G(d,p)(H,C,N,O,S)/LanL2DZ(Ni) level to optimize the crystal structure of the synthesized [Ni(PLSC)(H2O)2(SO4)] complex. All molecular docking calculations were conducted at ambient temperature (25 °C) and physiological pH (7.4) using AutoDock 4.2.6 within the AMDock program, version 1.5.2 [92].

4. Conclusions

The obtained complex [Ni(PLSC)(SO4)(H2O)2] contains a PLSC ligand in neutral form, a sulfate ion directly coordinated with the central metal ion, and two molecules of water. The compound crystallized in the monoclinic space group P2(1)/n. The crystal structure was stabilized by several hydrogen bonds, of which the hydrogen bond between the sulfate ion and molecules of water directly affected the pseudo-octahedral geometry. The most numerous contacts were formed between oxygen and hydrogen atoms (52.9%) due to their high abundance, as determined by the Hirshfeld surface analysis. The interactions between hydrogen atoms accounted for 29.7% of all contacts. Other interactions between hydrogen and nitrogen/carbon atoms were present to a lesser extent. Optimization of a structure employing two pseudopotentials for nickel(II) ions led to structures very similar to the experimental one. Based on the comparison between bond lengths and angles, the B3LYP/6-311++G(d,p)(H,C,N,O,S)/LanL2DZ(Ni) level of theory was chosen for further theoretical analysis. The QTAIM parameters of the interactions between the donor atoms and nickel(II) ion showed the effects of the intramolecular hydrogen bond between the sulfate ion and water molecule. Additional stabilization interactions were identified within the structure of the obtained complex. The EPR measurements showed that the amount of reduced HO• was 82.5, 87.0, 88.8, and 90.4% for the final concentration of complex between 0.3 and 2 μM, while in the case of the ascorbyl radical, the reduction percentages were 53.0 (0.5 μM), 69.0 (1 μM), and 86.9 (2 μM). The binding of the complex to HSA was spontaneous in the temperature range between 27 and 37 °C. The changes in Gibbs free energy of binding were between −26.9 and −32.8 kJ mol−1. The quenching of the HSA fluorescence was marked as static. The molecular docking results verified that the binding occurs at the FA8 binding site near the fluorescent amino acid Trp213 with the change in Gibbs free energy of −26.5 kJ mol−1. The binding to DNA was also spontaneous in the same range, although dynamic. The potassium iodide experiments proved that minor groove/intercalation was the probable quenching mechanism. The binding affinities predicted by the molecular docking studies showed that the geometry of the complex in solution was changed to square planar through the removal of water molecules. The experimental binding energies were well reproduced. Further experimental studies on the cytotoxicity of the compound are advised.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/inorganics12110280/s1, Table S1: Experimental and theoretical (functionals for Ni given below in conjunction with B3LYP/6-311++G(d,p)(H,C,N,O,S) level of theory) bond lengths of [Ni(PLSC)(SO4)(H2O)2] (in Å); Table S2: Experimental and theoretical (functionals for Ni given below in conjunction with B3LYP/6-311++G(d,p)(H,C,N,O,S) level of theory) bond lengths (in °) of [Ni(PLSC)(SO4)(H2O)2]; Figure S1: FTIR spectrum of PLSC ligand; Figure S2: FTIR spectrum of [Ni(PLSC)(SO4)(H2O)2]; Figure S3: UV-VIS spectrum of [Ni(PLSC)(SO4)(H2O)2]; Figure S4: Fingerprint plots of the most numerous contacts within crystallographic structure of [Ni(PLSC)(SO4)(H2O)2]; Table S3: The calculated Bond Critical Point (BCP) properties at the DFT/B3LYP-D3BJ/6-311+G(d,p)/LanL2DZ level of theory: the electron density (ρ(r)) and its Laplacian (∇2ρ(r)); the Lagrangian kinetic electron density (G(r)) and the potential electron density (V(r)); the density of the total energy of electrons (H(r))—Cremer–Kraka electronic energy density; the interatomic bond energy, Ebond; Figure S5: Bond Critical Points within structure of Ni(PLSC)(SO4)(H2O)2]; Figure S6: Stern-Volmer and double-log Stern-Volmer plots for the binding of [Ni(PLSC)(SO4)(H2O)2] to HSA.

Author Contributions

Conceptualization, V.J., D.D., J.D.M. and A.R. (Aleksandra Rakić); methodology, L.G., O.A.O.A. and M.S.A.; software, T.Y.A.A., A.R. (Aleksandra Radulović) and A.R. (Aleksandra Rakić); validation, Đ.N., J.D.M., L.G. and O.A.O.A.; formal analysis, M.S.A., T.Y.A.A. and A.R. (Aleksandra Radulović); investigation, L.G., O.A.O.A., M.S.A. and T.Y.A.A.; resources, A.R. (Aleksandra Radulović), Đ.N. and A.R. (Aleksandra Rakić); data curation, L.G., O.A.O.A. and M.S.A.; writing—original draft preparation, T.Y.A.A., A.R. (Aleksandra Radulović), Đ.N. and A.R. (Aleksandra Rakić); writing—review and editing, D.D., J.D.M. and V.J.; visualization, D.D.; supervision, J.D.M., D.D. and V.J.; project administration, V.J.; funding acquisition, V.J. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Scientific Research Deanship at the University of Ha’il, Kingdom of Saudi Arabia, grant number RG-23080.

Data Availability Statement

Data are contained in this article. Further inquiries can be directed to the corresponding author.

Acknowledgments

The authors are thankful to the University of Ha’il, Kingdom of Saudi Arabia. This research was funded by the Scientific Research Deanship at the University of Ha’il, Kingdom of Saudi Arabia, through Project Number RG-23080.

Conflicts of Interest

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

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Inorganics 12 00280 g001
Figure 1. Different binding modes of PLSC ligand.
Figure 1. Different binding modes of PLSC ligand.
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Figure 2. (a) Molecular diagram of [Ni(PLSC)(SO4)(H2O)2], with non-hydrogen atoms represented by 50% displacement ellipsoids and hydrogen atoms as spheres of arbitrary size. (b) The ball and stick representation shows part of the hydrogen bonding between the molecules. (Hydrogen-white, carbon-gray, nitrogen-blue, oxygen-red, sulfur-lilac, nickel-light blue).
Figure 2. (a) Molecular diagram of [Ni(PLSC)(SO4)(H2O)2], with non-hydrogen atoms represented by 50% displacement ellipsoids and hydrogen atoms as spheres of arbitrary size. (b) The ball and stick representation shows part of the hydrogen bonding between the molecules. (Hydrogen-white, carbon-gray, nitrogen-blue, oxygen-red, sulfur-lilac, nickel-light blue).
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Figure 3. Cell packing is viewed down the b-axis, and the 3D hydrogen-bonded network is shown as comprising parallel layers of the Ni(PLSC) structural units.
Figure 3. Cell packing is viewed down the b-axis, and the 3D hydrogen-bonded network is shown as comprising parallel layers of the Ni(PLSC) structural units.
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Figure 4. (a) Hirshfeld surface and (b) optimized structure (hydrogen atoms are omitted for clarity) at the B3LYP/6-311++G(d,p)(H,C,N,O,S)/LanL2DZ(Ni) level of theory of [Ni(PLSC)(SO4)(H2O)2]. (Hydrogen—white, carbon—gray, nitrogen—blue, oxygen—red, sulfur—yellow, nickel—light blue).
Figure 4. (a) Hirshfeld surface and (b) optimized structure (hydrogen atoms are omitted for clarity) at the B3LYP/6-311++G(d,p)(H,C,N,O,S)/LanL2DZ(Ni) level of theory of [Ni(PLSC)(SO4)(H2O)2]. (Hydrogen—white, carbon—gray, nitrogen—blue, oxygen—red, sulfur—yellow, nickel—light blue).
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Figure 5. The EPR spectra of the (a) DEPMPO-HO• adduct and (b) ascorbyl radical in the absence (black line) and presence of different concentrations of [Ni(PLSC)(SO4)(H2O)2].
Figure 5. The EPR spectra of the (a) DEPMPO-HO• adduct and (b) ascorbyl radical in the absence (black line) and presence of different concentrations of [Ni(PLSC)(SO4)(H2O)2].
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Figure 6. The fluorescence emission spectra of HSA for the titration with various concentrations of [Ni(PLSC)(SO4)(H2O)2] at (a) 27°, (b) 32°, and (c) 37 °C, and (d) the van ’t Hoff plot for the binding process.
Figure 6. The fluorescence emission spectra of HSA for the titration with various concentrations of [Ni(PLSC)(SO4)(H2O)2] at (a) 27°, (b) 32°, and (c) 37 °C, and (d) the van ’t Hoff plot for the binding process.
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Figure 7. HSA molecule (PDB ID: 1AO6) with bound ligands: [Ni(PLSC)(H2O)2(SO4)] complex and HPO42− anion, occupying FA9 and FA8 binding sites, respectively. Ligands and tryptophane are depicted using ball representation; each is colored distinctly. HPO42− ion from buffer solution is colored by element, Ni(II) complex is shown in light green, and Trp213 is represented in dark grey.
Figure 7. HSA molecule (PDB ID: 1AO6) with bound ligands: [Ni(PLSC)(H2O)2(SO4)] complex and HPO42− anion, occupying FA9 and FA8 binding sites, respectively. Ligands and tryptophane are depicted using ball representation; each is colored distinctly. HPO42− ion from buffer solution is colored by element, Ni(II) complex is shown in light green, and Trp213 is represented in dark grey.
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Figure 8. A 3D representation of the supramolecular interactions of [Ni(PLSC)(H2O)2(SO4)] located in the FA8 binding site. Only the interacting parts of the amino acids are shown, with colors corresponding to their respective regions of the HSA molecule: yellow for subdomain IB, green for subdomain IIA, interdomain region between subdomains IIA and IIB is light grey, and subdomain IA is violet. For the representation of nickel(II), complex sticks colored by the element were used. Supramolecular interactions are represented by dashed lines colored according to the type of interaction denoted in the figure’s legend.
Figure 8. A 3D representation of the supramolecular interactions of [Ni(PLSC)(H2O)2(SO4)] located in the FA8 binding site. Only the interacting parts of the amino acids are shown, with colors corresponding to their respective regions of the HSA molecule: yellow for subdomain IB, green for subdomain IIA, interdomain region between subdomains IIA and IIB is light grey, and subdomain IA is violet. For the representation of nickel(II), complex sticks colored by the element were used. Supramolecular interactions are represented by dashed lines colored according to the type of interaction denoted in the figure’s legend.
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Figure 9. Fluorescence emission spectra of [Ni(PLSC)(H2O)2(SO4)] for the titration with various concentrations of CT-DNA at (a) 27°, (b) 32°, and (c) 37 °C, and (d) the van ’t Hoff plot for the binding process.
Figure 9. Fluorescence emission spectra of [Ni(PLSC)(H2O)2(SO4)] for the titration with various concentrations of CT-DNA at (a) 27°, (b) 32°, and (c) 37 °C, and (d) the van ’t Hoff plot for the binding process.
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Figure 10. Fluorescence emission spectra of [Ni(PLSC)(H2O)2(SO4)] without CT-DNA (a) and with CT-DNA (b) in the presence of different concentrations of KI, and (c) the Stern–Volmer plots for the complex fluorescence quenching by KI.
Figure 10. Fluorescence emission spectra of [Ni(PLSC)(H2O)2(SO4)] without CT-DNA (a) and with CT-DNA (b) in the presence of different concentrations of KI, and (c) the Stern–Volmer plots for the complex fluorescence quenching by KI.
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Figure 11. (a) Fluorescence emission spectra of CT-DNA-EB for the titration with the complex at 27 °C and (b) the double-log Stern–Volmer dependency of intensity on the concentration of [Ni(PLSC)(H2O)2(SO4)].
Figure 11. (a) Fluorescence emission spectra of CT-DNA-EB for the titration with the complex at 27 °C and (b) the double-log Stern–Volmer dependency of intensity on the concentration of [Ni(PLSC)(H2O)2(SO4)].
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Figure 12. Binding of square planar Ni(II) complex with PLSC ligand at two distinct sites: intercalation site (depicted in dark green, ball-and-stick representation) and minor groove (shown in pink, ball-and-stick representation). DNA molecule is colored yellow. Experimentally determined binding energy (ΔGexp), best-calculated binding energy (ΔG1), and fifth calculated binding energy value (ΔG5) are also indicated.
Figure 12. Binding of square planar Ni(II) complex with PLSC ligand at two distinct sites: intercalation site (depicted in dark green, ball-and-stick representation) and minor groove (shown in pink, ball-and-stick representation). DNA molecule is colored yellow. Experimentally determined binding energy (ΔGexp), best-calculated binding energy (ΔG1), and fifth calculated binding energy value (ΔG5) are also indicated.
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Figure 13. The supramolecular interactions of the square planar Ni(II) complex in (a) the intercalation site and (b) the major groove. Only the interacting parts of the nucleobases are shown colored in yellow. For the representation of the square planar Ni(II) complex, sticks colored by element were used. Supramolecular interactions are represented by dashed lines colored according to the type of interaction denoted in the figure’s legend. The experimentally determined binding energy (ΔGexp) and the calculated binding energy values are also indicated.
Figure 13. The supramolecular interactions of the square planar Ni(II) complex in (a) the intercalation site and (b) the major groove. Only the interacting parts of the nucleobases are shown colored in yellow. For the representation of the square planar Ni(II) complex, sticks colored by element were used. Supramolecular interactions are represented by dashed lines colored according to the type of interaction denoted in the figure’s legend. The experimentally determined binding energy (ΔGexp) and the calculated binding energy values are also indicated.
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Table 1. Hydrogen bonds for [Ni(PLSC)(SO4)(H2O)2 [Å and °].
Table 1. Hydrogen bonds for [Ni(PLSC)(SO4)(H2O)2 [Å and °].
D-H...Ad(D-H)d(H...A)d(D...A)<(DHA)
O(2)-H(2)...O(6)#10.893(18)1.772(18)2.662(2)174(3)
N(1)-H(1N)...O(7)#20.899(18)1.912(19)2.791(2)165(3)
N(3)-H(3N)...O(5)#30.870(18)1.961(19)2.819(2)169(3)
N(4)-H(4N)...O(6)#30.895(18)2.21(2)2.987(2)145(2)
N(4)-H(5N)...O(4)#40.879(18)2.24(2)3.062(2)155(3)
O(8)-H(8D)...O(7)0.863(18)1.85(2)2.695(2)164(3)
O(8)-H(8E)...O(2)#50.855(18)1.925(19)2.771(2)170(3)
O(9)-H(9D)...O(5)#60.858(18)1.84(2)2.671(2)162(4)
O(9)-H(9E)...O(1)#60.851(19)2.00(2)2.813(2)160(4)
Symmetry transformations used to generate equivalent atoms: #1 x − 1/2, −y + 3/2, z − 1/2; #2 −x, −y + 1, −z + 1; #3 x, y + 1, z; #4 −x + 3/2, y + 1/2, −z + 3/2; #5 −x, −y + 2, −z + 1; #6 −x + 1, −y + 1, −z + 1.
Table 2. The Stern–Volmer constant (KSV), binding constant (Kb), Hill coefficient (n), and thermodynamic parameters of [Ni(PLSC)(SO4)(H2O)2] binding to HSA.
Table 2. The Stern–Volmer constant (KSV), binding constant (Kb), Hill coefficient (n), and thermodynamic parameters of [Ni(PLSC)(SO4)(H2O)2] binding to HSA.
CompoundT [K]KSV [M−1]Kb [M−1]nΔHb [kJ mol−1]ΔSb [J mol−1 K−1]ΔGb [kJ mol−1]
13001.95 × 1043.87 × 1041.08170.5655.9−26.3
3051.87 × 1041.08 × 1051.18−29.5
3101.84 × 1043.51 × 1051.28−32.8
Table 3. The Stern–Volmer constant (KSV), binding constant (Kb), Hill coefficient (n), and thermodynamic parameters of [Ni(PLSC)(SO4)(H2O)2] binding to DNA.
Table 3. The Stern–Volmer constant (KSV), binding constant (Kb), Hill coefficient (n), and thermodynamic parameters of [Ni(PLSC)(SO4)(H2O)2] binding to DNA.
CompoundT [K]KSV [M−1]Kb [M−1]nΔHb [kJ mol−1]ΔSb [J mol−1 K−1]ΔGb [kJ mol−1]
13001.71 × 1048.23 × 1020.77270.4955.5−16.2
3051.86 × 1042.64 × 1030.83−21.0
3101.89 × 1042.74 × 1041.03−25.8
Table 4. Crystal data of the newly obtained complex.
Table 4. Crystal data of the newly obtained complex.
Empirical Formula[Ni(PLSC)(SO4)(H2O)2]
C9H16NiNO9S
Formula weight415.03
Temperature (K)123 (2)
Crystal systemmonoclinic
Space groupP21/n
Radiation/Wavelength [Å]CuKα/1.54184 Å
Volume (Å3)1442.02(3)
Unit cell dimension (Å/°)a = 8.96650(10)
b = 9.28740(10)
c = 17.6603(3)
β = 101.327(2)
Z4
Volume1442.02(3) Å3
Calculated density1.912 g cm−3
Goodness-of-fit on F2856
h, k, lmax11, 11, 22
Nref3087
Bond precision: C-C 0.0030 Å
Data Completeness0.978
Θ max [°]80.075
R1 [I > 2s(I)], R1 (all)0.0350
wR2 [I > 2s(I)], wR2 (all)0.1009
CCDC no. 2348551
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Jevtovic, V.; Golubović, L.; Alshammari, O.A.O.; Alhar, M.S.; Alanazi, T.Y.A.; Radulović, A.; Nakarada, Đ.; Dimitrić Marković, J.; Rakić, A.; Dimić, D. Structural, Antioxidant, and Protein/DNA-Binding Properties of Sulfate-Coordinated Ni(II) Complex with Pyridoxal-Semicarbazone (PLSC) Ligand. Inorganics 2024, 12, 280. https://doi.org/10.3390/inorganics12110280

AMA Style

Jevtovic V, Golubović L, Alshammari OAO, Alhar MS, Alanazi TYA, Radulović A, Nakarada Đ, Dimitrić Marković J, Rakić A, Dimić D. Structural, Antioxidant, and Protein/DNA-Binding Properties of Sulfate-Coordinated Ni(II) Complex with Pyridoxal-Semicarbazone (PLSC) Ligand. Inorganics. 2024; 12(11):280. https://doi.org/10.3390/inorganics12110280

Chicago/Turabian Style

Jevtovic, Violeta, Luka Golubović, Odeh A. O. Alshammari, Munirah Sulaiman Alhar, Tahani Y. A. Alanazi, Aleksandra Radulović, Đura Nakarada, Jasmina Dimitrić Marković, Aleksandra Rakić, and Dušan Dimić. 2024. "Structural, Antioxidant, and Protein/DNA-Binding Properties of Sulfate-Coordinated Ni(II) Complex with Pyridoxal-Semicarbazone (PLSC) Ligand" Inorganics 12, no. 11: 280. https://doi.org/10.3390/inorganics12110280

APA Style

Jevtovic, V., Golubović, L., Alshammari, O. A. O., Alhar, M. S., Alanazi, T. Y. A., Radulović, A., Nakarada, Đ., Dimitrić Marković, J., Rakić, A., & Dimić, D. (2024). Structural, Antioxidant, and Protein/DNA-Binding Properties of Sulfate-Coordinated Ni(II) Complex with Pyridoxal-Semicarbazone (PLSC) Ligand. Inorganics, 12(11), 280. https://doi.org/10.3390/inorganics12110280

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