Bimetallic DppfM(II) (M = Pt and Pd) dithiocarbamate complexes: Synthesis,characterization,and anticancer activity

Abstract

A series of bimetallic dppfM(II) (dppf = 1,1’-bis (diphenyphosphino) ferrocene; M = Pt and Pd) dithiocarbamate complexes is synthesized and characterized by spectroscopic methods and single-crystal X-ray diffraction. Their antitumor activities in vitro are investigated by MTT assays against four cancer cell lines. The anticancer studies indicate most of the complexes display good to excellent antitumor activity. Remarkably, the platinum complex with a pyrrolidinyl substituent (3b) was identified as the most promising candidate due to its high potency and broad spectrum of activity.

Keywords

bimetallic cytotoxic activity dithiocarbamates palladium(II) complexes platinum(II) complexes

The bimetallic dppfM(II) (dppf = 1,1’-bis(diphenyphosphino)ferrocene; M = Pt and Pd) dithiocarbamate complexes is prepared and display good to excellent antitumor activity.

Introduction

Following the discovery of cisplatin [cis-PtCl₂(NH₃)₂] as a DNA-modifying agent with high anticancer activity, the field of metallodrugs has become a major research area for medicinal inorganic chemists.^1,2 Despite the fact that cisplatin is a well-established metal-based antitumour agent, it has several drawbacks such as nausea and liver and kidney failure, being typical of heavy metal toxicity after continued treatment.^3–7 With the emergence of exciting antitumor activities of various other transition-metal complexes, the focus of research has gradually been expanding beyond platinum.⁸ Palladium(II) complexes are natural candidates to be considered as anticancer drugs due to the structural resemblance of palladium(II) complexes to those of platinum(II).⁹

Recently, several heterometallic complexes incorporating ferrocene and another metal such as Au(I),¹⁰ Pt(II),¹¹ Ru(II),¹² and Cu(I)¹³ have been reported. In most cases the antiproliferative properties of the resulting compounds improved with respect of that of the corresponding ferrocene-based ligand, which may be attributed to low toxicity, high lipophilicity, and unique electrochemical behavior.⁹ On the other hand, because of the diverse biological activities of dithiocarbamates, research on their synthesis and pharmacological activity has attracted considerable interest in the areas of organic chemistry and medicinal chemistry. In particular, their metal complexes in the treatment of cancer have been explored.^14–22 While the pharmacological fight against cancer has made significant progress in the last 10 years, novel molecules to fight this disease are still urgently needed. Stimulated by the promising earlier results of dithiocarbamate ruthenium(II) complexes,²³ it was decided to synthesize some novel mixed-ligand platinum(II) and palladium(II) complexes with dithiocarbamates and 1,1’-bis(diphenylphosphino)ferrocene (dppf) ligands. The anticancer activity evaluation results revealed that the heteronuclear dppfM(II) (M = Pt and Pd) dithiocarbamate complexes exhibited potent anticancer activity.

Results and discussion

Chemistry

The synthesis of heteronuclear dppfM(II) (M = Pt and Pd) dithiocarbamate complexes is shown in Scheme 1. The formation of the target dppfPt(II) dithiocarbamate complexes 3a–f was achieved by reacting salts 2a–f, K₂PtCl₄ and dppf in acetone, affording good yields of products 3. The Pd(II) analogues 5a–f were prepared by directly reacting dppfPdCl₂ with dithiocarbamates. The structures of all the target compounds were characterized by NMR and EI-MS spectroscopy, which are given in the Supporting Information. In addition, the crystal structure of 5b was determined by X-ray diffraction analysis.

Scheme 1.

Synthesis of binuclear dppfM(II) (M = Pd and Pt) dithiocarbamate complexes 3a–f and 5a–f.

X-ray diffraction studies

The single-crystal X-ray structure of complex 5b·CH₂Cl₂ is shown in Figure 1. The crystallographic details and selected bond distances and angles are presented in Supporting Information (Tables S1 and S2, respectively). The Pd-P bond and Pd-S distances are within the range of those reported for the precursor dppfPdX₂ complexes,²⁴ other Pd(II) dithiocarbamate complexes,^25–29 and a dppfPd complex with two thiolate ligands,³⁰ respectively. The S1-Pd-S2 bond angle from the bidentate ligand is 74.99(3)°, which is close to those of typical S1-Pd-S2 angles (75.29°–76.66°).^25–29 However, it is smaller than the S1-Pd-S2 angle (89.64°) of the dppfPd complex with two thiolate ligands.³⁰ The N(1)–C(35) bond length (1.303(4)) is significantly shorter than a normal C–N bond (1.47 Å) and longer than that of a C=N bond (1.28 Å).³¹

Figure 1.

Molecular structure of 5b·CH₂Cl₂ with displacement ellipsoids drawn at the 30% probability level.

Biological evaluations

The in vitro antiproliferative activities of complexes 3a–f and 5a–f were evaluated against four cancer (human ovarian cancer SKOV-3, human hepatoma carcinoma HepG-2, rat pheochromocytoma PC12 cell line, and human lung cancer A549) cell lines by using the classical MTT assay. Cisplatin (CDDP) was used as the reference drug. The IC₅₀ values of complexes 3a–f and 5a–f are listed in Table 1.

Table 1.

Antiproliferative activity of heteronuclear dppfMCl₂ (M = Pt and Pd) dithiocarbamate complexes against four cancer cell lines.

Complex	Antiproliferative activity (IC₅₀^a, µM)
Complex	SKOV-3	HepG-2	PC12	A549
3a	9.8 ± 0.97	9.9 ± 0.87	2.1 ± 0.11	5.1 ± 0.09
3b	7.7 ± 0.20	1.5 ± 0.04	1.6 ± 0.10	1.9 ± 0.31
3c	7.4 ± 0.44	4.2 ± 0.22	2.4 ± 0.06	10.0 ± 1.45
3d	7.2 ± 0.39	5.7 ± 0.32	2.2 ± 0.06	5.1 ± 0.28
3e	6.0 ± 0.74	2.8 ± 0.31	2.2 ± 0.15	2.5 ± 0.055
3f	8.6 ± 0.50	63.9 ± 9.71	1.6 ± 0.18	1.6 ± 0.02
5a	4.7 ± 0.34	17.3 ± 1.68	16.4 ± 1.07	5.6 ± 0.46
5b	4.4 ± 0.22	7.7 ± 0.51	57.0 ± 3.19	7.1 ± 0.06
5c	NA	48.0 ± 2.60	20.4 ± 1.8	11.0 ± 0.35
5d	NA	15.6 ± 0.42	8.6 ± 9.6	19.6 ± 1.27
5e	10.3 ± 0.76	3.0 ± 0.17	28.4 ± 0.71	5.6 ± 0.64
5f	7.0 ± 0.27	8.9 ± 0.58	14.1 ± 0.32	9.0 ± 0.50
CDDP	4.48 ± 0.41	9.83 ± 0.28	3.16 ± 2.91	1.26 ± 0.12

Antiproliferative activity was assayed by exposure of the cell lines for 24 h to complexes 3 and 5 and expressed as the concentration required to inhibit tumor cell proliferation by 50% (IC₅₀). Data are expressed as mean ± SD from triplicate determinations from three independent experiments.

For the Pt(II) series, this type of bimetallic dppfM(II) (M = Pt) dithiocarbamate complex 3a–f generally showed good to excellent antiproliferative activity against the four tumor cell lines. They exhibited moderate activity against SKOV-3 with IC₅₀ values ranging from 6.0 to 9.8 µM. Except for complex 3f, the complexes 3a–e exhibited promising antiproliferative activity against the HepG-2 cell line with the highest activity shown by compound 3b (IC₅₀ 1.5 µM), in which the level of activity was about 7 times higher than that of cisplatin. Complexes 3a–f also showed good antiproliferative activity against the PC12 cell line with IC₅₀ values below 3 µM. The cytotoxicity of complexes 3b and 3f was close to that of cisplatin in the A549 cell line, while other complexes 3 showed moderate activity toward A549. Remarkably, pyrrolidinyl-substituted complex 3b was found to display a broad spectrum of antitumor activities.

Compared with the control drug cisplatin, the Pd(II) analogues 5a and 5b exhibited almost the same antiproliferative activity against SKOV-3 cells. Complexes 5a–f showed good antiproliferation activity against HepG-2 cells, with IC₅₀ values ranging from 3.0 to 48.0 µM. Importantly, the level of activity of complex 5e substituted by methylpiperazine was 3 times higher than that of cisplatin. However, compared with the Pt(II) series, the antitumor activities of the Pd(II) analogues 5a–f were reduced significantly.

These studies indicated that the heteronuclear dppfPt(II)-dithiocarbamate complexes showed good to excellent antiproliferative activity, and represent excellent antitumor lead structures.

Conclusion

In conclusion, 12 new mixed-ligand Pt(II) and Pd(II) complexes have been synthesized and characterized. The anticancer activity of the synthesized metallodrugs was checked against four cancer cell line by MTT assays. Most of the compounds showed good to excellent antitumor activity and the Pt(II) complexes displayed higher antitumor activities compared with the corresponding Pd(II) derivatives. Importantly, complex 3b was identified as the most promising candidate due to its high potency and broad spectrum of activity. Notably, further investigations are required if complex 3b is to undergo trials as a new anticancer drug.

Experimental Analysis

General procedures

All manipulations were carried out at room temperature under a nitrogen atmosphere using standard Schlenk techniques, unless otherwise stated. All reagents were purchased from commercial sources and were used without further purification. ¹H, ¹³C, and ³¹P NMR spectra were collected on a Bruker 500 MHz magnetic resonance spectrometer. ¹H and ¹³C NMR chemical shifts are relative to TMS, and ³¹P NMR chemical shifts are relative to 85% H₃PO₄. Mass spectra were recorded with a Bruker (micrOTOF II). The reagents were commercially sourced and used as received unless mentioned otherwise. The starting materials dppfPdCl₂³² and sodium dithiocarbamates³³ were prepared by the methods reported in the literature.

General synthesis of complexes 3a–f

To suspension of sodium dithiocarbamate 2a–f (0.5 mmol) in CH₃OH (10 mL) was added a solution of K₂PtCl₄ (0.210 g, 0.50 mmol) in H₂O (10 mL). The reaction mixture was stirred for 30 min. Next, a solution of dppf (0.28 g, 0.50 mmol) in CH₂Cl₂ (10 mL) was slowly added to the above mixture and stirred for 24 h. KPF₆ (0.46 g, 2.5 mmol) was added and the mixture was stirred for another 8 h. The solvent was then evaporated, and dichloromethane was added to the residue and the mixture washed with water. The organic phases were dried over anhydrous Na₂SO₄. The crude product was purified by chromatography (eluent: CH₂Cl₂/CH₃OH, 50:1, v/v) to give complexes 3a–f.

3a: yellow solid, 0.30 g (Yield: 58%). ¹H NMR (500 MHz, CDCl₃): δ 7.64 (m, 7H, -PhH), 7.56 (t, J = 6.8 Hz, 5H, -PhH), 7.48 (t, J = 6.9 Hz, 8H, -PhH), 4.57 (s, 4H, -CpH), 4.38 (d, J = 1.7 Hz, 4H, -CpH), 3.54 (t, J = 7.2 Hz, 4H, -NCH₂-, -NCH₂-), 1.20 (t, J = 7.2 Hz, 6H, -CH₂CH₃, -CH₂CH₃). ¹³C NMR (125 MHz, CDCl₃): δ 133.94, 133.89, 133.85, 132.29, 129.48, 128.99, 128.94, 128.90, 76.18, 74.45, 44.67, 12.39. ³¹P NMR (200 MHz, CDCl₃): δ 15.94, -144.30 (m). ESI-MS(+): m/z found 843.1473 [M−Fe-PF₆]⁺, 897.0880 [M−PF₆]⁺, calcd for C₃₉H₃₈F₆FeNP₃PtS₂ 1042.0560.

3b: yellow solid, 0.29 g (Yield: 54%). ¹H NMR (500 MHz, CDCl₃): δ 7.65 (m, 8H, -PhH), 7.56 (t, J = 7.3 Hz, 4H, -PhH), 7.48 (t, J = 7.1 Hz, 8H, -PhH), 4.57 (s, 4H, -CpH), 4.38 (s, 4H, -CpH), 3.63 (d, J = 6.7 Hz, 4H, -NCH₂-, -NCH₂-), 2.05–1.99 (m, 4H, -CH₂CH₂-, -CH₂CH₂-). ¹³C NMR (125 MHz, CDCl₃): δ 134.07, 132.43, 132.29, 44.67, 12.39. ³¹P NMR (200 MHz, CDCl₃) δ 15.97, -144.32 (m). ESI-MS(+): m/z found 895.0790 [M−PF₆]⁺, calcd for C₃₉H₃₆F₆FeNP₃PtS₂ 1040.00403.

3c: yellow solid, 0.23 g (Yield: 43 %). ¹H NMR (500 MHz, CDCl₃): δ 7.63 (m, 8H, -PhH), 7.56 (t, J = 7.3 Hz, 4H, -PhH), 7.49 (t, J = 7.0 Hz, 8H, -PhH), 4.58 (s, 4H, -CpH), 4.39 (d, J = 1.5 Hz, 4H, -CpH), 3.72 (s, 8H, -NCH₂-, -NCH₂-, -OCH₂-, -OCH₂-). ¹³C NMR (125 MHz, CDCl₃): δ 133.93, 133.88, 133.83, 132.39, 129.06, 76.33, 74.60, 65.75, 47.35. ³¹P NMR (200 MHz, CDCl₃): δ 15.90, -144.29 (m). ESI-MS(+): m/z found 857.1558 [M−Fe−PF₆]⁺, 911.0760 [M−PF₆]⁺, calcd for C₃₉H₃₆F₆FeNOP₃PtS₂ 1056.0353.

3d: yellow solid, 0.22 g (Yield: 41%). ¹H NMR (500 MHz, CDCl₃): δ 7.64 (m, 8H, -PhH), 7.56 (t, J = 7.2 Hz, 4H, -PhH), 7.48 (t, J = 7.0 Hz, 8H, -PhH), 4.56 (s, 4H, -CpH), 4.42 (s, 2H, -NCH₂-), 4.38 (s, 4H, -CpH), 4.31 (s, 2H, -NCH₂-), 3.66–3.60 (m, 4H, -CH₂CH₂-, -CH₂CH₂-), 1.75 (d, J = 4.3 Hz, 2H -CH₂CH₂CH₂-). ¹³C NMR (125 MHz, CDCl₃): δ 133.98, 132.39, 129.09, 76.39, 74.69, 25.62. ³¹P NMR (200 MHz, CDCl₃): δ 15.93, -144.29 (m). ESI-MS(+): m/z found 857.1556 [M−Fe−PF₆]⁺, 897.0896 [M−N−PF₆]⁺, 911.0745 [M−PF₆]⁺, calcd for C₄₀H₃₈F₆FeNP₃PtS₂ 1054.0560.

3e: yellow solid, 0.20 g (Yield: 37%). ¹H NMR (500 MHz, CDCl₃): δ 7.66–7.61 (m, 8H, -PhH), 7.56 (t, J = 7.3 Hz, 4H, -PhH), 7.48 (t, J = 6.9 Hz, 8H, -PhH), 4.58 (s, 4H, -CpH), 4.39 (d, J = 1.6 Hz, 4H, -CpH), 3.72–3.68 (m, 4H, -NCH₂-, -NCH₂-), 2.49–2.45 (m, 4H, -NCH₂-, -NCH₂-), 2.31 (s, 3H, -NCH₃). ¹³C NMR (125 MHz, CDCl₃): δ 133.89, 133.86, 133.85, 133.80, 132.36, 132.35, 129.41, 128.96, 76.25, 74.55, 53.55, 46.95, 45.53. ³¹P NMR (200 MHz, CDCl₃): δ 15.89. ESI-MS(+): m/z found 870.1826 [M−Fe−PF₆]⁺, 924.1063 [M−PF₆]⁺, calcd for C₄₀H₃₈F₆FeN₂P₃PtS₂ 1069.0669.

3f: yellow solid, 0.34 g (Yield: 60%). ¹H NMR (500 MHz, CDCl₃): δ 7.68–7.61 (m, 8H, -PhH), 7.57 (t, J = 7.3 Hz, 4H, -PhH), 7.49 (t, J = 7.0 Hz, 8H, -PhH), 7.27 (d, J = 7.5 Hz, 1H, -PhH), 7.25 (d, J = 1.9 Hz, 1H, -PhH), 6.94–6.86 (m, 3H, -PhH), 4.58 (s, 4H, -CpH), 4.40 (d, J = 1.7 Hz, 4H, -CpH), 3.87–3.81 (m, 4H, -NCH₂-, -NCH₂-), 3.26–3.21 (m, 4H, -NCH₂-, -NCH₂-). ¹³C NMR (125 MHz, CDCl₃): δ 134.02, 132.38, 129.13, 76.74, 74.56. ³¹P NMR (200 MHz, CDCl₃): δ 24.24, 15.91, 7.60, -144.28 (m). ESI-MS(+): m/z found 896.0603 [M−CpFe−PF₆]⁺, 986.1199 [M−PF₆]⁺, calcd for C₄₅H₄₁F₆FeN₂P₃PtS₂ 1131.0825.

General synthesis of complexes 5a–f

Sodium dithiocarbamate 2a–f (0.66 mmol) and dppfPdCl₂ (0.3 mmol) were dissolved in acetone (30 mL) and the resulting solution was stirred for 20 h. Next, KPF₆ (0.46 g, 2.5 mmol) was added and the mixture stirred for another 8 h. The solvent was evaporated and dichloromethane was added to the residue and the mixture washed with water. The organic phases were dried with anhydrous Na₂SO₄. The crude product was purified by chromatography (eluent: / CH₂Cl₂CH₃OH, 50:1, v/v) to offer complexes 5a–5f.

5a: red solid, 0.17 g (Yield: 59%). ¹H NMR (500 MHz, CDCl₃): δ 7.66–7.60 (m, 8H, -PhH), 7.58 (t, J = 7.4 Hz, 4H, -PhH), 7.48 (t, J = 7.1 Hz, 8H, -PhH), 4.60 (s, 4H, -CpH), 4.38 (d, J = 1.6 Hz, 4H, -CpH), 3.63 (q, J = 7.2 Hz, 4H, -NCH₂-, -NCH₂-), 1.18 (t, J = 7.2 Hz, 6H, -CH₂CH₃, -CH₂CH₃). ¹³C NMR (125 MHz, CDCl₃): δ 134.88, 134.04, 131.12, 129.35, 127.94, 76.18, 44.72, 29.71, 13.04. ³¹P NMR (200 MHz, CDCl₃): δ 32.22, -144.30 (m). ESI-MS(+): m/z found 808.0335 [M−PF₆]⁺, calcd for C₃₉H₃₈F₆FeNP₃PdS₂ 952.9947.

5b: red solid, 0.15 g (Yield: 52%). ¹H NMR (500 MHz, CDCl₃): δ 7.63 (m, 8H, -PhH), 7.58 (t, J = 7.4 Hz, 4H, -PhH), 7.48 (t, J = 7.0 Hz, 8H, -PhH), 4.60 (s, 4H, -CpH), 4.38 (s, 4H, -CpH), 3.61 (t, J = 6.6 Hz, 4H, -NCH₂-, -NCH₂-), 2.01 (t, J = 6.7 Hz, 4H, -CH₂CH₂-, -CH₂CH₂-). ¹³C NMR (125 MHz, CDCl₃): δ 134.03, 132.35, 130.15, 129.95, 129.37, 75.01, 49.86, 31.40, 24.17. ³¹P NMR (200 MHz, CDCl₃): δ 32.52, -144.31 (m). ESI-MS(+): m/z found 806.0204 [M−PF₆]⁺, calcd for C₃₉H₃₆F₆FeNP₃PdS₂ 952.9947.

5c: red solid, 0.19 g (Yield: 66%). ¹H NMR (500 MHz, CDCl₃): δ 7.63–7.59 (m, 8H, -PhH), 7.58 (d, J = 7.4 Hz, 4H, -PhH), 7.49 (t, J = 7.1 Hz, 8H, -PhH), 4.62 (s, 4H, -CpH), 4.40 (d, J = 1.5 Hz, 4H, -CpH), 3.79 (d, J = 4.3 Hz, 4H, -OCH₂-, -OCH₂-), 3.72–3.69 (m, 4H, -NCH₂-, -NCH₂-). ¹³C NMR (125 MHz, CDCl₃): δ 133.84, 133.80, 133.75, 132.26, 130.02, 129.44, 129.25, 129.22, 129.18, 74.65, 69.52, 65.87, 53.78, 47.34, 31.75, 29.28. ³¹P NMR (200 MHz, CDCl₃): δ 32.77, -144.28. ESI-MS(+): m/z found 768.0941 [M−Fe−PF₆]⁺, 806.0205 [M−NH₂−PF₆]⁺, 822.0147 [M−PF₆]⁺, 853.9863 [M−CS₂N+Na]⁺, calcd for C₃₉H₃₆F₆FeNOP₃PdS₂ 966.9740.

5d: red solid, 0.15 g (Yield: 53%). ¹H NMR (500 MHz, CDCl₃): δ 7.64–7.59 (m, 8H, -PhH), 7.56 (dd, J = 14.7, 8.1 Hz, 8H, -PhH), 7.49 (d, J = 6.3 Hz, 4H, -PhH), 4.60 (s, 4H, -CpH), 4.38 (s, 4H, -CpH), 3.74–3.69 (m, 4H, -NCH₂-, -NCH₂-), 1.62 (s, 6H, -CH₂CH₂-, -CH₂CH₂CH₂-, -CH₂CH₂-). ¹³C NMR (125 MHz, CDCl₃): δ 133.89, 133.84, 133.80, 132.17, 129.20, 129.16, 129.11, 74.52, 48.29, 25.53, 24.22. ³¹P NMR (200 MHz, CDCl₃): δ 32.18. ESI-MS(+): m/z found 820.0329 [M−PF₆]⁺, calcd for C₄₀H₃₈F₆FeNP₃PdS₂ 964.9947.

5e: red solid, 0.14 g (Yield: 48%). ¹H NMR (500 MHz, CDCl₃): δ 7.64–7.56 (m, 12H, -PhH), 7.49 (t, J = 7.1 Hz, 8H, -PhH), 4.62 (d, J = 6.8 Hz, 4H, -CpH), 4.39 (d, J = 1.7 Hz, 4H, -CpH), 3.80–3.75 (m, 4H, -NCH₂-, -NCH₂-), 2.49–2.44 (m, 4H, -NCH₂-, -NCH₂-), 2.32 (s, 3H, -NCH₃). ¹³C NMR (125 MHz, CDCl₃): δ 134.17, 133.80, 132.23, 131.81, 129.31, 76.35, 74.28, 74.00, 51.65, 42.97. ³¹P NMR (200 MHz, CDCl₃): δ 32.67, -144.26. ESI-MS(+): m/z found 781.1247 [M−Fe−PF₆]⁺, 835.0447 [M−PF₆]⁺, calcd for C₄₀H₃₈F₆FeNP₃PtS₂ .980.0056

5f: red solid, 0.21 g (Yield: 68%). ¹H NMR (500 MHz, CDCl₃): δ 7.62 (s, 12H, -PhH), 7.51 (s, 8H, -PhH), 7.27 (s, 2H, -PhH), 6.90 (s, 3H, -PhH), 4.63 (s, 4H, -CpH), 4.39 (s, 4H, -CpH), 3.94 (s, 4H, -NCH₂-, -NCH₂-), 3.24 (s, 4H, -NCH₂-, -NCH₂-). ¹³C NMR (125 MHz, CDCl₃): δ 133.81, 132.24, 131.71, 131.27, 129.20, 128.32, 74.66, 74.63, 72.28, 71.78, 53.69, 46.77, 45.52. ³¹P NMR (200 MHz, CDCl₃): δ 32.93. ESI-MS(+): m/z found 820.0302 [M−CS₂−Fe−PF₆]⁺, 843.1364 [M−Fe−PF₆]⁺, 897.0582 [M−PF₆]⁺, calcd for C₄₅H₄₁F₆FeN₂P₃PdS₂ 1042.0212.

Crystal structure determination for 5b

Single crystals of complex 5b·CH₂Cl₂ suitable for X-ray analysis were obtained by slow diffusion of hexane into a solution of 5b in dichloromethane. Diffraction intensity data were collected on a Nonius Kappa CCD diffractometer with MoKα radiation (0.71073 Å). The structure was solved by direct methods (SHELXS-97) and refined by full matrix least squares on F² (SHELXL-97).^34,35 All non-H atoms were refined anisotropically. The hydrogen atoms were placed in geometric positions and refined using a riding model (X-H distances and Uiso were then listed relative to the parent atom).

Cytotoxicity assay in vitro

Cytotoxic activities were evaluated by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] method using SKOV-3 (a human ovarian cancer cell line), A549 (a human lung carcinoma cell line), PC12 (a rat pheochromocytoma cell line), and HepG-2 (a human hepatocellular carcinoma cell line) cells.³⁶ All cell lines were purchased from American Type Culture Collection (ATCC, Rockville, MD). Briefly, the cell suspensions (198 μL) were plated in 96-well microtiter plates at a density of 5 × 104 cells/mL and incubated for 12 h at 37 °C in a humidified incubator with 5% CO₂. The test compounds of different concentrations were dissolved in dimethyl sulfoxide (DMSO) and added to each well and further incubated for 24 h under the same conditions. Next, 20 μL of the MTT solution was added to each well and incubated for 4 h. The old medium (200 μL) containing MTT was then carefully replaced by DMSO and pipetted to dissolve any formazan crystals formed. The absorbance was then determined on a Spectra Max Plus plate reader at 570 nm. Dose-response curves were generated and the IC₅₀ values were determined. Cisplatin, a commonly approved agent for the treatment of many tumors, was used as the positive control.

Supplemental Material

Supporting_Information-Revised_0725 – Supplemental material for Bimetallic DppfM(II) (M = Pt and Pd) dithiocarbamate complexes: Synthesis, characterization, and anticancer activity

Supplemental material, Supporting_Information-Revised_0725 for Bimetallic DppfM(II) (M = Pt and Pd) dithiocarbamate complexes: Synthesis, characterization, and anticancer activity by Shou De Xu and Xiang Hua Wu in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors acknowledge financial support from National Natural Science Foundation of China (No. 21002086) and the Natural Science Foundation of Yunnan Province (No. 2010ZC071).

ORCID iD

Xiang Hua Wu

Supplemental material

CCDC 1865008 (complex 5b·CH₂Cl₂) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via .

References

Rosenberg

Van Camp

Krigas

Nature 1965; 205: 698–699.

Rosenberg

Van Camp

Trosko

et al. Nature 1969; 222: 385–386.

Torshizi

Moghaddam

Divsalar

et al. Bioorg Med Chem 2008; 16: 9616–9625.

Azam

Hussain

Warad

et al. Dalton Trans 2012; 41: 10854–10864.

Szucova

Travnicek

Zatloukal

et al. Bioorg Med Chem 2006; 14: 479–491.

Montana

Bernal

Lorenzo

et al. Bioorg Med Chem 2008; 16: 1721–1737.

Dorr

RT.

In: Platinum and other metal coordination compounds in cancer chemotherapy (eds HM Pinedo and JH Schornagel). New York: Plenum Press, 1996, p. 131.

Clarke

Zhu

Frasca

DR.

Chem Rev 1999; 99: 2511–2534.

Kapdi

Fairlamb

IJS

. Chem Soc Rev 2014; 43: 4751–4777.

10.

Fourie

Erasmus

Swarts

et al. Anticancer Res 2011; 31: 825–830.

11.

Nieto

Gonzalez-Vadillo

Bruna

et al. Dalton Trans 2012; 41: 432–441.

12.

Tauchman

Suss-Fink

Stepnicka

et al. J Organomet Chem 2013; 723: 233–238.

13.

Maity

Roy

Banik

et al. Organometallics 2010; 29: 3632–3641.

14.

Khan

Badshah

Murtaz

et al. Eur J Med Chem 2011; 46: 4071–4077.

15.

Ronconi

Marzano

Zanello

et al. J Med Chem 2006; 49: 1648–1657.

16.

Cristina

Luca

Federica

et al. Int J Cancer 2011; 12: 487–496.

17.

Zhang

Lok

et al. Chem Commun 2013; 49: 5153–5155.

18.

Ronconi

Giovagnini

Marzano

et al. Inorg Chem 2005; 44: 1867–1881.

19.

Keter

Guzei

Nell

et al. Inorg Chem 2014; 53: 2058–2067.

20.

Al-Jaroudi

Altaf

Seliman

et al. Inorg Chim Acta 2017; 464: 37–48.

21.

Altaf

Monim-ul-Mehboob

Kawde

et al. Oncotarget 2017; 8: 490–505.

22.

Altaf

Monim-ul-Mehboob

Seliman

AAA

et al. Eur J Med Chem 2015; 95: 464–472.

23.

Dou

Chen

et al. Phosphorus Sulfur Silicon Rel Elem 2017; 192: 1219–1223.

24.

Thomas

Raymundo

et al. J Organomet Chem 2001; 637-639: 691–697.

25.

Khan

Badshah

Murtaz

et al. Eur J Med Chem 2011; 46: 4071–4077.

26.

Ferreira

de Lima

Paniago

et al. Inorg Chim Acta 2014; 423: 443–449.

27.

Lee

Choi

K-Y

Kim

Y-J

et al. Polyhedron 2015; 85: 880–887.

28.

Khan

Badshah

Rehman

et al. Polyhedron 2012; 39: 1–8.

29.

Khan

Badshah

Said

et al. Appl Organomet Chem 2013; 27: 387–395.

30.

Al-Jiboria

Khaleel

Ahmed

SAO

et al. Polyhedron 2012; 41: 20–24.

31.

Allen

Kennard

Watson

et al. J Chem Soc, Perkin Trans 2 1987; S1–S19.

32.

Thomas

Raymundo

et al. J Organomet Chem 2001; 637–639: 691–697.

33.

Anastasiadis

Hogarth

Wilton-Ely

JDET

. Inorg Chim Acta 2010; 363: 3222–3228.

34.

Sheldrick

GM.

SHELXS-97, a program for crystal structure solution. Göttingen: University of Göttingen, 1997.

35.

Sheldrick

GM.

SHELXL-97, a program for crystal structure refinement. Göttingen: University of Göttingen, 1997.

36.

Mosmann

J Immunol Methods 1983; 65: 55–63.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

3.03 MB