Synthesis, X-ray crystal structures and anticancer studies of four Pd(II) dithiocarbamate complexes

2.1 Materials

All chemicals and solvents used were of analytical grades purchased from Merck and used as received with no further purification. All cell culture media and reagents were obtained from Lonza Biowhittaker (Walkersville, USA), and all sterile plastic ware from Corning Inc. (NY, USA). MCF-7 and HEK293 cells were originally sourced from the American Type Culture Collection (ATCC, Manassas, VA, USA).

2.2 Physical measurements

¹H and ¹³C NMR spectra of the ligands were recorded on a Bruker Biospin 600 MHz spectrometer and were referenced internally using residual solvent signals of D₂O (4.79 ppm for ¹H NMR) or (CD₃)₂CO (2.05 and 206.26 ppm for ¹H and ¹³C NMR) or (CD₃)₂SO (3.31 and 39.52 for ¹H and ¹³C NMR) at room temperature. Thermoscientific Flash 2000 elemental analyser was used to examine the elemental composition of each of the compounds. Melting points of the ligands and complexes were measured by Stuart SMP3 Digital Melting Point apparatus using melting point capillary tubes. The molar conductivity of the complexes was measured by an Electric Conductivity apparatus (Jenway 4510 Conductivity Meter) at room temperature. The ligands were dissolved in methanol while the complexes were dissolved in DMSO. The FTIR spectra were recorded on a PerkinElmer Spectrum 100 FTIR spectrometer in the 4000–650 cm⁻¹ range. Electronic spectra of the ligands were measured by a PerkinElmer Lambda 25 spectrometer from 200 to 700 nm in distilled water at room temperature. Mass spectra were recorded on Waters Micromass LCT Premier TOF-MS.

2.3 Synthesis of dithiocarbamate ligands

The ligands: sodium piperidinedithiocarbamate (Pipdtc-Na), sodium 1-phenylpiperazinedithiocarbamate (1-PhPzdtc-Na), ammonium phenyldithiocarbamate (Phdtc-NH₄) and sodium 4-benzylpiperidinedithiocarbamate (4-BenzPip-Na) were prepared as detailed in literature (Andrew and Ajibade, 2018; Andrew and Ajibade, 2019). In a typical synthesis, 0.05 mol of piperidine, 1-phenylpiperizine, aniline or 4-benzylpiperidine was added to a cold aqueous sodium hydroxide (0.05 mol) or concentrated aqueous ammonia (30 mL). The mixture was stirred rapidly for 30 min at 4 °C, and cold carbon disulphide (0.05 mol, 3.01 mL) was then added dropwise with constant stirring until a precipitate formed. The reaction was maintained for 4 h at 4 °C, after which, the precipitate was filtered, rinsed with diethyl ether, and desiccated.

Pipdtc-Na: White powder, yield (%): 94.23, m.p (°C): 289, Λ_m (μS): 215, Mw (g/mol): 160.03, ¹H NMR (D₂O, 400 MHz, ppm): 4.24–4.27 (d, 8H), 1.59–1.62 (d, 4H), 1.65–1.68 (t, 2H), ¹³C NMR (D₂O, 400 MHz, ppm): 53.7 (N-CH₂), 25.6, 23.8 (—C₅H₁₀), 205.16 (C—S). Selected FTIR (cm⁻¹): 1417 (N—C), 963 (C-S), 1216 (C⚌S). Molecular mass (m/z): Calc for C₆H₁₀NS₂ [M]⁺: 160.03, Found: 160.00. Ana. Calc. for C₆H₁₂NNaOS₂: C, 35.80; H, 6.01; N, 6.96. Found: C, 35.29; H, 6.43; N, 6.57.

1-PhPzdtc-Na: Cream solid, yield (%): 78.12, m.p (°C): 295, Λ_m (μS): 234, Mw (g/mol): 237.05, ¹H NMR (D₂O, 400 MHz, ppm): 3.23 (t, 4H), 4.51 (t, 4H), 7.04–7.42 (m, —C₆H₅), ¹³C NMR (D₂O, 400 MHz, ppm): 49.7–50.5 (N—CH₂), 118.0–150.34 (C₆H₅), 209.0 (C—S). Molecular mass (m/z): Calc for C₁₁H₁₃N₂S₂ [M]⁺: 237.05, Found: 237.00. Selected FTIR (cm⁻¹): 1416 (N—C), 995 (C-S), 1205 (C⚌S). Ana. Calc. for C₁₁H₁₇N₂NaO₂S₂: C, 44.58; H, 5.78; N, 9.45. Found: C, 44.37; H, 5.73; N, 9.40.

Phdtc-NH₄: White powder, yield (%): 58.96, m.p (°C): 109, Λ_m (μS): 146.1, Mw (g/mol): 168.00, ¹H NMR (D₂O, 400 MHz, ppm): 7.44–7.48(t, 2H), 7.20–7.23 (t, 1H), 7.14–7.12 (d, 2H), 4.27 (s, RN-H), ¹³C NMR (D₂O, 400 MHz, ppm): 126.1–140.7 (C₆H₅), 213.9 (C—S). Molecular mass (m/z): Calc for C₁₁H₁₃N₂S₂ [M]⁺: 167.99, Found: 168.00. Selected FTIR (cm⁻¹): 3078 (N—H), 1401 (N—C), 994 (C—S), 1280 (C⚌S). Ana. Calc. C₇H₁₀N₂S₂: C, 45.13; H, 5.41; N, 15.04. Found: C, 45.81; H, 5.40; N, 14.72.

BenzPip-Na: White powder, yield (%): 49.25. m.p (°C): 116, Λ_m (μS): 254, Mw (g/mol): 250.00, ¹H NMR (D₂O, 400 MHz, ppm): 1.36–1.35 (t, 4H), 1.96–2.01 (m, 1H), 2.64–2.66 (s, —CH₂—), 3.13–3.20 (t, 4H), 7.42–7.32 (C₆H₅), ¹³C NMR (D₂O, 400 MHz, ppm): 50.4 (N—CH₂), 29.9 (—CH₂—), 35.6 (—CH—), 40.0 (—CH₂—), 125.5–139.5 (C₆H₅), 204.0 (C-S). Molecular mass (m/z): Calc for C₁₃H₁₆NS₂ [M]⁺: 250.07, Found: 250.00. Selected FTIR (cm⁻¹): 1462 (N—C), 958 (C—S), 1164 (C⚌S). Ana. Calc. for C₁₃H₂₀NNaO₂S₂: C, 50.46; H, 6.51; N, 4.53. Found: C, 50.31; H, 6.51; N, 4.28.

2.4 Synthesis of bis(acetonitrile)dichloropalladium(II) precursor

Palladium(II) chloride (2.82 mmol, 0.5 g) dispersed in acetonitrile (10 mL) was refluxed for 1 h at 80 °C under nitrogen flow. The yellow residue was filtered, washed with acetonitrile, and dried under vacuum (Bego, et al, 2009, Dai et al., 2011).

Mw: 259.43 g/mol, Yield (%): 75.6. ¹H NMR (ppm): 2.30 (s, —CH₃), ¹³C NMR (ppm): 0.51 (—CH₃), 117.3 (—C≡N). Ana. Calc. for PdCl₂∙(CH₃CN)₂: C, 18.52; H, 2.33; N, 10.80. Found: C, 18.11; H, 2.31; N, 10.67.

2.5 Synthesis of the Pd(II) dithiocarbamate complexes

Complexes of palladium(II) dithiocarbamate (Fig. 1) were prepared using a method reported in literature (Marcheselli, et al., 1993, Mukherjee et al., 2012, Bobinihi et al., 2019) Bis(acetonitrile)dichloropalladium(II) (0.4 g, 1.56 mmol) dissolved in acetone (50 mL) was refluxed for 30 min at 60 °C. To this, dithiocarbamate ligand (3.12 mmol) dissolved in acetone (50 mL) was added. The reaction was carried out for 4 h at 60 °C and thereafter at room temperature overnight. The resultant yellow precipitate was filtered, washed, and dried under vacuum.

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Fig. 1

Structures of the prepared palladium(II) dithiocarbamate complexes.

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[Pd(Pipdtc)₂]: Yellow powder, yield (%): 61.32, m.p (°C): 299, Λ_m (μS): 3.67. ¹H NMR (ppm): 4.34–4.36 (t, 8H), 1.79–1.76 (m, 4H), 1.75–1.72 (m, 8H), ¹³C NMR (ppm): 54.6 (N—CH₂), 27.2, 25.4 (—C₅H₁₀), 206.9 (C—S). Selected FTIR (cm⁻¹): 1505 (N—C), 995 (C—S). Ana. Calc. for C₁₂H₂₄N₂O₂PdS₄: C, 31.13; H, 5.22; N, 6.05. Found: C, 31.21; H, 5.58; N, 5.72.

[Pd(1-PhPzdtc)₂]: Rusty-yellow solid, yield (%): 58.73, m.p (°C): 214. Λ_m (μS): 2.59. ¹H NMR (ppm): 2.51–2.52 (t, 8H), 3.34-0.32 (t, 8H), 6.84–7.29 (C₆H₅), ¹³C NMR (ppm): 52.7–53.5 (N—CH₂), 120.9–153.4 (C₆H₅), 212.03 (C—S). Molecular mass (m/z): Calc for C₂₂H₂₆N₄PdS₄ [M]⁺: 581.15, Found: 580.03. Selected FTIR (cm⁻¹): 1478 (N—C), 1009 (C—S). Ana. Calc. for C₂₂H₂₈N₄OPdS₄: C, 44.10; H, 4.71; N, 9.35. Found: C, 43.77; H, 4.36; N, 9.08.

[Pd(Phdtc)₂]: Dark brown powder, yield (%): 31.06, m.p (°C): 164. Λ_m (μS): 1.98. ¹H NMR (ppm): 7.52–7.54 (d, 4H), 7.45–7.47 (t, 4H), 7.33–7.37 (t, 2H), ¹³C NMR (ppm): 123.5–136.8 (C₆H₅), 210.8 (C—S). Molecular mass (m/z): Calc for C₁₄H₁₂N₂PdS₄ [M]⁺: 442.94, Found: 442.00. Selected FTIR (cm⁻¹): 3142 (N—H), 1507 (N—C), 974 (C—S). Ana. Calc. for C₁₄H₁₂N₂PdS₄: C, 39.96; H, 3.73; N, 6.32. Found: C, 39.53; H, 3.43; N, 6.34.

[Pd(BenzPipdtc)₂]: Orange powder, yield (%): 29.93. m.p (°C): 207 (decomposed). Λ_m (μS): 4.05. ¹H NMR (ppm): 1.14–1.24 (t, 4H), (m, 1H), 2.50–2.51 (s, —CH₂—), 3.13–3.20 (t, 4H), 7.18–7.30 (C₆H₅), ¹³C NMR (ppm): 54.5 (N-CH₂), 34.0 (—CH₂—), 39.7 (—CH—), 44.14 (—CH₂—), 128.6–143.7 (C₆H₅), 208.16 (C-S). Molecular mass (m/z): Calc for C₂₇H₃₆N₂OPdS₄ [M]⁺: 639.27, Found: 638.07. Selected FTIR (cm⁻¹): 1500 (N—C), 963 (C—S). Ana. Calc. for C₂₆H₃₆N₂O₂PdS₄: C, 48.55; H, 5.64; N, 4.35. Found: C, 48.33; H, 5.24; N, 4.37.

2.6 X-ray crystallography data collection

Single crystals of the four Pd(II) dithiocarbamate complexes were obtained by slow evaporation of the compound in dimethyl sulfoxide (DMSO) at room temperature. The crystals were isolated under oil and fixed on a MITIGEN crystal mounter. The data was gathered by a Bruker APEX-II CCD diffractometer fitted with an Oxford Cryostems low temperature instrument, running at T = 100(2) K. The structure was resolved by the She1XS-2013 software and refined using She1XL 2016/6 version (Sheldrick, 2015a, b).

2.7 Anticancer screening

The cytotoxic effect of the dithiocarbamate ligands and corresponding Pd(II) dithiocarbamate complexes on three human cell lines: Cervical cancer (HeLa), breast adenocarcinoma (MCF-7) and epithelial colorectal adenocarcinoma (Caco-2), were assessed by 3-[(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) assay (Ajibade et al., 2020b; Scudiero et al., 1988). Cells were seeded at a density of 2 × 10³ cells/well in 96-well microplates in growth medium (100 μL) and incubated for 24 h at 37 °C. Thereafter, the growth medium was removed and substituted with fresh medium containing the test compounds prepared in DMSO at four different concentrations (50, 30, 20 and 10 μg/ μL), and cells were incubated with the test compounds for 48 h at 37 °C. A cell control containing no test compounds was included. Following the incubation, growth medium (100 μL) containing 10 μL 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) salt solution (5 mg/mL in PBS) was added to each well and cells incubated for 4 h at 37 °C. The medium-MTT mixture was then removed and 100 μL of DMSO was added to each well to solubilize the formazan crystals produced. The absorbance of each well at was measured at 540 nm, and cell survival calculated using the equation (Moodley and Singh, 2019): $$\%Cellviabibility=\frac{\mathrm{A}\text{540}\mathrm{T}\mathrm{r}\mathrm{e}\mathrm{a}\mathrm{t}\mathrm{e}\mathrm{d}\mathrm{C}\mathrm{e}\mathrm{l}\mathrm{l}\mathrm{s}}{\mathrm{A}\text{540}\mathrm{c}\mathrm{o}\mathrm{n}\mathrm{t}\mathrm{r}\mathrm{o}\mathrm{l}\left(\mathrm{u}\mathrm{n}\mathrm{t}\mathrm{r}\mathrm{e}\mathrm{a}\mathrm{t}\mathrm{e}\mathrm{d}\right)cells\times 100\%}$$

Each experiment was done in triplicate and the IC₅₀ values were obtained using GraphPad Prism software.

3.1 Molecular structures of four palladium(II) dithiocarbamate complexes

Single crystals of [Pd(Pipdtc)₂], [Pd(1-PhPzdtc)₂], [Pd(Phdtc)₂] and [Pd(4-BenzPipdtc)₂] complexes were obtained by slow evaporation of DMSO solution of the compounds. Crystallographic and refinement information are given in Table 1. Selected bond lengths and angles are provided in Table 2. The molecular structures with the atom numbering schemes are illustrated in Fig. 2 and the unit cell packing diagrams are shown in Fig. 3. [Pd(Pipdtc)₂] formed a monoclinic crystal system with space group P2_1/c (Andrew and Ajibade, 2018), with molecules occupying the unit cell (Z = 2). We have found that the Pd-S bond lengths are slightly shorter compared to those of the same structure reported by Shaheen et. al (Shaheen et al. 2006).

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Fig. 2

Molecular structure of [Pd(Pipdtc)₂], [Pd(1-PhPzdtc)₂], [Pd(Phdtc)₂] and [Pd(4-BenzPipdtc)₂] showing 50 % probability displacement ellipsoid and atom labelling. The hydrogen atoms are excluded for clearness.

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Fig. 3

Unit cell packing diagram of [Pd(Pipdtc)₂], [Pd(1-PhPzdtc)₂], [Pd(Phdtc)₂] and [Pd(4-BenzPipdtc)₂].

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[Pd(1-PhPzdtc)₂] complex also formed a monoclinic crystal system with space group P2_1/c (Andrew and Ajibade, 2018; Paca and Ajibade, 2021), with four molecules in the unit cell (Z = 4). [Pd(Phdtc)₂] and [Pd(4-BenzPipdtc)₂] crystallized in a triclinic crystal system with space group P-1 with a Z value of 2. The [Pd(Phdtc)₂] complex is similar to those reported by Bobinihi et. al (Bobinihi, et al., 2019) which crystallized in an orthorhombic crystal system which might be due to the solvent and method used for crystallization.

In all the complexes, the Pd(II) ion is coordinated to four sulphur atoms from two bidentate dithiocarbamato anions. The Pd(II) ion lies within the center of symmetry, hence each asymmetric unit consist of half distinct molecule. The palladium(II) ion is coordinated to four sulphur atoms to form a distorted square planar geometry. Though the equatorial PdS₄ fraction is planar, distortion is a result of the small bite angle of S(1)-Pd-(S2) of 75.41 (4), 75.458 (18), 75.66 (33) and 75.369 (17) for [Pd(Pipdtc)₂], [Pd(1-PhPzdtc)₂], [Pd(Phdtc)₂] and [Pd(4-BenzPipdtc)₂], respectively which are approximately 75° and therefore hindering the formation of a perfect square planar geometry (Ehsan, et al., 2014, Gupta et al. 2014). The S1-Pd-S2 bond angles are 180(4), 104.59(4) and 75.41(18)° for [Pd(Pipdtc)₂], 180, 104.542(18) and 75.458(18)° for [Pd(1-Phpzdtc)₂], 180, 104.34(3) and 75.66(4)° for [Pd(Phdtc)₂] and 180.00(3), 104.64300(17) and 75.369(17)° and 180.00(2), 104.736(17) and 75.736(17)°. These bond angles are comparable to those of previously reported related compounds (Mukherjee et al., 2012, Poirier et al., 2018) [43, 44]. The Pd-S bond lengths in all the complexes are almost equidistance and are similar to related complexes retrieved from the CSD (Bonamico et al., 1977, Eslami et al. 2016, Ferreira et al., 2014, Konarev et al., 2005, Phadnis et al., 2005, Poirier et al. 2014). Even though the four dithiocarbamate ligands are all coordinated to Pd(II) ion, the bond lengths and bond angles are not exactly the same. This might be ascribed to the nature of the dithiocarbamato anions, and their electronic influence on the stereochemistry of the Pd(II) dithiocarbamate complexes which resulted in the variations observed in the Pd-S bond lengths. It was observed that the bulkier the dithiocarbamate ligand, the longer the bond distance.

The C—S bond lengths are intermediate between the C—S and C⚌S bond lengths suggesting a partial double bond character because of delocalization of the CS₂ electron density in the dithiocarmate moiety. The thioureide N(1)-C(1) bond lengths are 1.471(6), 1.327(3), 1.328(5) and 1.321(2) Å for [Pd(Pipdtc)₂], [Pd(1-PhPzdtc)₂], [Pd(Phdtc)₂] and [Pd(4-BenzPipdtc)₂], respectively. These values suggested a partial (N ≅ C) double-bond because of the higher electronic density expected on coordination of the dithiocarbamato anions to the Pd(II) ions which indicate sp² hybridization and delocalization of the electron density in the CS₂ group (Ferreira et al., 2014).

3.2 FTIR spectra studies

The FTIR spectra of the dithiocarbamate ligands and corresponding Pd(II) dithiocarbamate complexes were assigned after careful comparisons. Dithiocarbamates have three mains characteristic FTIR bands that can be used to determine the mode of coordination between the dithiocarbamato anions and the metal ions. The FTIR spectra of the ligands showed ʋ(C—N) stretching bands at 1417, 1416, 1401 and 1462 cm⁻¹ for Pipdtc-Na, 1-PhPzdtc-Na, Phdtc-NH₄ and BenzPipdtc-Na, respectively. These bands were observed in the complexes at 1505, 1478, 1507 and 1500 cm⁻¹ for [Pd(Pipdtc)₂], [Pd(1-PhPzdtc)₂], [Pd(Phdtc)₂] and [Pd(BenzPipdtc)₂], respectively. The shifts to higher frequencies observed in the spectra of the Pd(II) complexes are ascribed to the coordination of the dithiocarbamato anions and the Pd(II) ions that causes delocalization of the thioureide electrons within the dithiocarbamate moiety (Ajibade et al., 2020a,c, Oluwalana and Ajibade, 2020). This was confirmed by the single crystal X-ray crystal structure bond lengths in the complexes. The binding mode of the dithiocarbamate ligand to the metal center was established based on the Bonati-Ugo method (Mbese and Ajibade, 2017; Bonati and Ugo, 1967). Two bands in the region 940–1060 cm⁻¹ in the FTIR spectra of the dithiocarbamate ligands are assigned to the v(C⚌S) stretching vibrations. In the spectra of the Pd(II) complexes, only one peak was observed that signifies the symmetrical bidentate coordination of the dithiocarbamate ligand to the Pd(II) ion (Sathiyaraj et al., 2015). The v(M—S) band normally appears in the far-IR region but could not be detected by the FTIR instrument used in this study.

3.3 Electronic spectra studies

Relevant electronic spectra data of the dithiocarbamate ligands and their corresponding Pd(II)complexes are summarized in Table 3. Three absorptions bands were observed for each ligand as shown in Fig. 4. The first band observed around 264, 258, 257 and 254 nm for Pipdtc-Na, 1-PhPzdtc-Na, Phdtc-NH₄ and 4-BenzPipdtc-Na, respectively are assigned to the π-π* transition of N—C⚌S fragment (Ajibade et al., 2020; Al-Hasani and Al-Taie, 2015). The second absorption band at 282 nm for pipdtc-Na, 286 nm for 1-phpzdtc-Na, 295 nm for Phdtc-NH₄ and 301 nm for 4-BenzPipdtc-Na are due to the π-π* transitions of the S—C⚌S system (Mbese and Ajibade, 2014). The band at about 443 nm in the spectrum of (Pipdtc-Na), 430 nm in (1-PhPzdtc-Na), 429 nm in (Phdtc-NH₄) and 435 nm in (4-BenzPipdtc-Na) are due to the n-π* transition of the lone pair of electrons found on the dithiocarbamate sulphur atoms.

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Fig. 4

Electronic spectra of the dithiocarbamate ligands.

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The electronic spectrum of [Pd(Pipdtc)₂] exhibited three absorption bands around 283, 305 and 340 nm. The bands observed at 283 and 305 nm are due to the inter-ligand π-π* transitions of the dithiocarbamate moiety. The broad band at about 340 nm could be due to the charge transfer transitions. The spectrum of [Pd(1-PhPzdtc)₂] complex exhibited two absorption peaks at 262 and 308 nm which are ascribed to the π-π* transitions. The electronic spectra of [Pd(Phdtc)₂] and [Pd(4-BenzPipdtc)₂] exhibited two absorption bands. The first set of bands ascribed to the inter-ligand transitions due to the dithiocarbamate moiety. The second bands are attributed to the metal–ligand-charge-transfer (MLCT) transitions, a consequence of the coordination of the dithiocarbamate ligands to the Pd(II) ion. The stability of the Pd(II) complexes were investigated under physiological conditions in dimethyl sulfoxide (DMSO). Absorption spectrum for each complex was recorded at different intervals as shown in Fig. 5. The results indicate that all the Pd(II) complexes were stable in DMSO for 48 h.

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Fig. 5

Electronic spectra of palladium(II) dithiocarbamate complexes in DMSO over time.

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3.4 ¹H and ¹³C NMR of the ligands

The ¹H and ¹³C NMR spectra of the dithiocarbamate ligands corresponded with the suggested formulation of the compounds. Pipdtc-Na ligand showed an overlapped triplet-like doublet of doublet at 4.24–4.27 ppm for the –CH₂N protons due to the germinal proton attached to the same carbon atom. These protons were deshielded due to the existence of the electron withdrawing cloud towards the nitrogen atom. The other –CH₂ protons shifted upfield in the region 1.29–1.68 ppm and appeared a triplet-like multiplet. In the ¹³C NMR, C-S bond was observed at 205.16 ppm for the free dithiocarbamate ligands. The spectrum of 1-PhPzdtc-Na showed protons of the piperazine group at 4.51 and 3.23 ppm as doublet of doublet of doublets (Andrew and Ajibade, 2018). The protons of the phenyl ring appeared at 7.04–7.42 ppm. Upon coordination to the palladium(II) ion, the protons shifted upfield. For the Phdtc-NH₄ ligand, the protons due to the phenyl ring appeared at 7.48–7.14 ppm. The proton of the RNH group appeared at 4.27 ppm. Once coordinated to the Pd(II) ion, a downfield shift was observed for the phenyl ring but the C-S bond shifted from 213.92 to 210.77 ppm. In the spectrum of 4-BenzPip-Na, the –CH₂ protons of the piperidine ring appeared at 1.34–1.188 and 2.91–3.01 ppm for the protons near the nitrogen atom and methyl group, respectively. The methyl protons appeared at 2.54 ppm and the benzyl ring appeared at 7.27–7.40 ppm. In the spectrum of [Pd(4-BenzPipdtc)₂], a shift was observed on the proton and carbon NMR spectra confirming the formation of the palladium(II) dithiocarbamate complex.

3.5 Cytotoxicity studies

In vitro cytotoxic activities of the dithiocarbamate ligands and their corresponding Pd(II) complexes were evaluated against cervical cancer (HeLa), breast adenocarcinoma (MCF-7), and epithelial colorectal adenocarcinoma (Caco-2) cell lines and their IC₅₀ values presented in Table 4. The tested compounds showed highly potent cytotoxic activity against MCF-7 cells with cytotoxic activity in the sequence [Pd(1-PhPzdtc)₂] > [Pd(Phdtc)₂] > [Pd(4-BenzPipdtc)₂] > [Pd(Pipdtc)₂] with IC₅₀ values of 8.09, 0.151, 0.11, and 0.032 μM, respectively. The cytotoxic activities of the Pd(II) complexes are higher than that of the dithiocarbamate ligands. This proved that the coordination of the dithiocarbamate ligands to the Pd(II) enhances the activity of the compounds in MCF-7 cells. Andrew and Ajibade, 2018 prepared Cu(II), Zn(II) and Pt(II) complexes of 1-phenylpiperazine dithiocarbamate (1-PhPzdtc) and assessed their activity against MCF-7 cell line. Their results showed that the [Pt(1-PhPzdtc)₂] complex is only active at concentration higher than 100 μM. The IC₅₀ values of 17.52 and 8.42 μM were obtained for the [Cu(1-PhPzdtc)₂] and [Zn₂(μ-1-PhPzdtc)₂(1-PhPzdtc)₂] complexes, respectively. Comparing their results with what we obtained for the [Pd(1-PhPzdtc)₂] against MCF-7 cell line, one can deduce that palladium(II) complexes have better cytotoxicity compared to Cu(II), Zn(II) and Pt(II). Three of the Pd(II) complexes are highly potent against the MCF-7 cancer cell line and their potency is more than that of cis-platin against the same cancer cell line. When these four compounds were screened against HeLa cell, only [Pd(Pipdtc)₂] and [Pd(Phdtc)₂] complexes showed higher potency than their corresponding dithiocarbamate ligands. The potency of [Pd(Pipdtc)₂] against the cell line is higher than that of cis-platin while the potency of [Pd(Phdtc)₂] is comparable to that of cis-platin against the cancer cell line. [Pd(Phdtc)₂] and the ligand showed excellent cytotoxicity against Caco-2 cells but that of the Pd(II) is better than that of the free ligand which indicate that the coordination of the Pd(II) to the dithiocarbamate ligand enhances the potency of the complex. While this is the case in most instances, but in others, the potency of the Pd(II) complexes are lower than that of the free ligands. It was deduced that the presence of the Pd(II) ion does not have much significant cytotoxicity in HeLa and Caco-2 cells. However, the four Pd(II) dithiocarbamate compounds exhibited potent anticancer activity against the breast cancer cells (MCF-7), with lower activity when compared to their respective free ligands. This cancer cell specificity in vitro is encouraging and interesting, warranting their further optimization and screening in additional cells lines to confirm their potential as future anticancer agents. After optimization, it will also be necessary to carry out structure activity relationship studies on the active compound for further derivatization.