Synthesis, characterization, theoretical and cytotoxicity studies of Pd(II) and Pt(II) complexes with new bidentate carbon donor ligand

Polyhedron 161 (2019) 179–188

Contents lists available at ScienceDirect

Polyhedron journal homepage: www.elsevier.com/locate/poly

Synthesis, characterization, theoretical and cytotoxicity studies of Pd(II) and Pt(II) complexes with new bidentate carbon donor ligand Mohsen Sayadi a, Seyyed Javad Sabounchei a,⇑, Asieh Sedghi a, Mehdi Bayat a, Leila Hosseinzadeh b, Robert W. Gable c a b c

Faculty of Chemistry, Bu-Ali Sina University, Hamedan 65174, Iran Pharmaceutical Sciences Research Center, School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran School of Chemistry, University of Melbourne, Victoria 3010, Australia

a r t i c l e

i n f o

Article history: Received 2 December 2018 Accepted 7 January 2019 Available online 14 January 2019 Keywords: C,C-chelating phosphorus ylide Pd(II) and Pt(II) complexes Cytotoxic activity X-ray structure DFT study

a b s t r a c t The new phosphonium salt, the C,C-chelating phosphorus ylide ligand, (MeOC6H5C(O) CH@PPh2(CH2)2PPh2@CHC(O)C6H5OMe), and its Pd(II) and Pt(II) complexes have been synthesized and the cytotoxic activity of the synthesized complexes against three human cancer cell lines, including HeLa (Human cervix cancer cell line), KB (human oral cancer cell line) and U87 MG (human glioblastoma cell line) were evaluated using an MTT assay. The new compounds were identified and characterized using multinuclear (1H, 13C and 31P) NMR, infrared (IR) spectroscopy, elemental analysis, and through UV absorption and fluorescence emission spectra. Also, the crystal structure of the phosphorus ylide ligand was determined by single-crystal X-ray diffraction analysis. According to the obtained results from the MTT assay, the Pd(II) and Pt(II) complexes demonstrated a higher cytotoxic activity against KB human oral cancer cells in comparison with other cell lines, rendering these compounds into suitable candidates for further anti-oral cancer studies. Furthermore, a theoretical study on structure and nature of the MAC bonding between the Y ligand (ylide) and MCl2 fragment in the [YMCl2] (M = Pd, Pt and Y = (MeOC6H5C(O)CH@PPh2(CH2)2PPh2@CHC(O)C6H5OMe)) complexes have been reported via NBO and energy-decomposition analysis (EDA). Ó 2019 Elsevier Ltd. All rights reserved.

1. Introduction In recent years, the coordination and organometallic chemistry of a-ketostabilized phosphorus ylides have undergone substantial development and have found widespread applications in synthetic organic chemistry, especially in the synthesis of naturally occurring products with biological and pharmacological activities [1–4]. C,C-chelating phosphorus ylides, derived from bisphosphines, viz., RC(O)CH@PPh2(CH2)2PPh2@CHC(O)R (R = alkyl or aryl groups) [5,6] show interesting properties such as a high stability, which allows them to be easily handled in air, and an ambidentate ligand character, due to the C-coordination (Fig. 1). Although the preparation and characterization of transition metal complexes, containing a-ketostabilized phosphorus ylides, have been known since the last century [7–9], interest in these compounds has increased significantly in recent years. This interest has been driven primarily by the necessity to develop new reagents for chemical synthesis that exhibit enhanced properties ⇑ Corresponding author. E-mail address: [email protected] (S.J. Sabounchei). https://doi.org/10.1016/j.poly.2019.01.016 0277-5387/Ó 2019 Elsevier Ltd. All rights reserved.

[10,11]. However, the synthesis of C,C-chelating phosphorus ylides, and the study of their complexation to transition metals, is a less documented field and only very few examples have been reported in the literature [12–14], in spite of their practical importance [15,16]. Synthesis of transition metal complexes, derived from C, C-chelating phosphorus ylides has started in 2000 by Spannenberg et al. [5]. In 2014, we reported the synthesis of Pd(II) complexes containing such C,C-chelating phosphorus ylides [6]. As part of our interest in transition metal chemistry of C,Cchelating phosphorus ylides, we now focus on the synthesis, electronic and geometric properties of new transition metal complexes with the aim of studying their biological activities. The modern use of transition metal complexes as chemotherapeutic agents dates back returns to the discovery of cisplatin by Rosenberg and coworkers, followed by one of the most impressive drug success stories ever and a significant improvement of cancer therapy [17–22]. In general, cisplatin and other platinum-based compounds such as carboplatin and oxaliplatin are considered as cytotoxic drugs ultimately leading to programmed cell death by damaging DNA, inhibiting tumor cell division, and inducing apoptosis. Nevertheless, because of serious side effects associated with

180

M. Sayadi et al. / Polyhedron 161 (2019) 179–188

2.3. Computational details

Fig. 1. Coordination behavior of a C,C-chelating phosphorus ylide a towards transition metal (M).

cisplatin prevent the effectiveness of this compound and significant attempts have been made to replace cisplatin and its derivatives, by more efficient cytotoxic complexes with other transition metals and new ligands. Pd(II) and Pt(II) complexes containing phosphorus ylides are square-planar d8, isoelectronic and isostructural, and therefore appear to be very good candidates for anticancer investigations [23]. In some systems, Pd(II) complexes have greater activity than Pt(II) analogues [24–28]. However, studies on the cytotoxic properties of Pd(II) and Pt(II) complexes containing C,C-chelating phosphorus ylides, have not yet been reported. Herein we report the synthesis and characterization of a new C,C-chelating phosphorus ylide ligand and its Pd(II) and Pt (II) complexes. Also, the cytotoxic potential of these C,C-chelating phosphorus ylide Pd(II)/Pt(II) complexes were evaluated against three human cancer cell lines including HeLa, KB and U87 MG by an MTT assay.

2. Experimental 2.1. General In this study, starting materials and solvents were purchased from Aldrich or Merck and used without further purification. All the reactions were carried out under an atmosphere of dry nitrogen. Infrared spectra were recorded on a Shimadzu 435-U-04 spectrophotometer in the spectral range of 4000–400 cm
1 using the KBr pellets technique. Melting points were measured on a SMPI apparatus and are reported without correction. UV–vis spectra were recorded on a Perkin voyager DE-PRO spectrometer in the region of 200–800 nm and the fluorescence emission spectra were performed on a Varian Cary spectrofluorometer. Elemental analysis was performed on a Perkin–Elmer 2400 apparatus. NMR spectra were measured on a 90 MHz Jeol spectrometer and 250 MHz Bruker spectrometer using standard pulse sequences at 25 °C. The splitting of proton resonances in the 1H and 31P NMR spectra are shown as: s = singlet, d = doublet, t = triplet and m = multiplet. 2.2. X-ray data collection and structure determination A suitable single crystal of 2 was grown by vapor diffusion of diethyl ether into a chloroform solution. Data collection was performed on an Oxford Diffraction SuperNova diffractometer using mirror monochromated Cu Ka radiation (k = 1.54018 Å) at 130 K. Using OLEX2 [29], the structure was solved with the SHELXS [30] structure solution program using direct methods and refined with the SHELXL [31] refinement package using Least Squares minimization. All non-hydrogen atoms were refined with anisotropic displacement parameters; H-atoms were constrained to geometrical estimates, with an isotropic displacement parameter of 1.5 times (Me) or 1.2 times (other) of the parent carbon atom.

The geometries of the C,C-chelating phosphorus ylide complexes of palladium (II) and platinum (II) [YMCl2] (M = Pd, Pt and Y = (MeOC6H5C(O)CH@PPh2(CH2)2PPh2@CHC(O)C6H5OMe)) have been optimized at the BP86 [32,33]/def2-SVP [34] level of theory. As shown in former studies, the BP86 is considered a suitable level for the calculation of the bonding properties in such and this complexes [35–42]. All calculations were performed using the Gaussian 09 set of programs [43]. NBO analyses [44] were also carried out with the internal model of GAUSSIAN 09. For bonding analyses, the terms of EDA analysis were carried out at the BP86/TZ2P (ZORA)//BP86/def2-SVP with level C1 symmetry. The basis sets for all elements have triple-f quality augmented by one set of polarization functions (ADF basis set TZ2P (ZORA)) within the program package ADF2009.01.

2.4. Synthesis of the ligands and the metal complexes 2.4.1. Synthesis of [MeOC6H5C(O)CH2PPh2(CH2)2PPh2CH2C(O) C6H5OMe]Br2 (1) To a stirred solution of diphosphine Ph2PCH2CH2PPh2 (0.32 g, 0.8 mmol) in acetone (10 ml) at room temperature for 24 h, a solution of BrCH2C(O)C6H5OMe (0.46 g, 1.6 mmol) was added. The resulting precipitate was filtered off, washed with diethyl ether and dried. Yield: 0.69 g, 81%. Mp: 263–265 °C. Anal. Calc. for C44H42Br2O4P2: C, 61.70; H, 4.94. Found: C, 61.85; H, 4.80%. IR (KBr disk, cm
1) m: 1668 (CO). 31P NMR (DMSO-d6) dP: (ppm): 26.91 (s, PPh2). 1H NMR (DMSO-d6) dH: 3.70 (br, 4H, CH2); 3.89 (s, 6H, OCH3); 6.12 (br, 4H, PCH2CO); 7.40–8.03 (m, 28H, Ph). 13C NMR (CDCl3) dC: 17.91 (t, CH2, 1JPC = 51.57); 36.52 (t, PCH2CO, 1 JPC = 59.12); 55.98 (s, OCH3); 112.74–159.88 (Ph); 192.01 (s, CO). 2.4.2. Synthesis of MeOC6H5C(O)CH@PPh2(CH2)2PPh2@CHC(O) C6H5OMe (2) To a suspension of the phosphonium salt 1 in toluene (15 mL), sodium bis(trimethylsilyl) amide (1.0 mL) was added. The resulting mixture was stirred for 30 min at room temperature, then filtered of to remove NaBr, concentrated under vacuum to ca. 5 ml and treated with petroleum ether. The white solid obtained was filtered, washed with petroleum ether and dried under vacuum. Yield: 0.31 g, 87%. Mp: 220–222 °C. Anal. Calc. for C44H40O4P2: C, 76.07; H, 5.80. Found: C, 76.21; H, 5.67%. IR (KBr disk, cm
1) m: 1599 (CO). 31P NMR (DMSO-d6) dP: (ppm): 18.01 (s, PPh2). 1H NMR (DMSO-d6) dH: 3.04 (br, 4H, CH2); 3.77 (s, 6H, OCH3); 4.35 (m, 2H, CH); 6.92–7.73 (m, 28H, Ph). 13C NMR (CDCl3) dC: 21.75 (m, CH2); 47.91 (d, PCH, 1JPC = 113.51); 55.36 (s, OCH3); 111.19– 159.52 (Ph), 185.02 (s, CO). 2.4.3. Synthesis of Pd{r2(C,C)-MeOC6H5C(O) CH@PPh2(CH2)2PPh2@CHC(O)C6H5OMe}Cl2 (3) [PdCl2COD] (0.085 g, 0.3 mmol) in 10 mL of CH2Cl2 was added dropwise to phosphorus ylide 2 (0.2 g, 0.3 mmol) in 10 mL of CH2Cl2. After it was stirred for 2 hat room temperature, the solution was filtered, concentrated to ca. 2 mL in volume and layered with cool n-hexane to afford the products, which were collected and dried under vacuum. Yield: 0.313 g, 72%. Mp: 168–170 °C. Anal. Calc. for C44H40Cl2O4P2Pd: C, 60.60; H, 4.62. Found: C, 60.47; H, 4.50%. IR (KBr disk, cm
1) m: 1627, 1667 (CO). 31P NMR (CDCl3) dP: (ppm): 27.31 (d, P1, 3JP-P = 4.71 Hz); 30.81 (d, P2, 3 JP-P = 3.99 Hz). 1H NMR (DMSO-d6) dH: 2.93 (m, 4H, CH2); 3.78 (s, 6H, OCH3); 5.56 (br, 2H, CH); 6.96–8.03 (m, 28H, Ph). 13C NMR (CDCl3) dC: 19.18 (m, CH2); 27.95 (m, PCH); 55.53 (s, OCH3); 56.06 (s, OCH3); 111.70–159.93 (Ph); 189.43 (s, CO); 190.13 (s, CO).

M. Sayadi et al. / Polyhedron 161 (2019) 179–188

2.4.4. Synthesis of Pt{r2(C,C)-MeOC6H5C(O)CH@PPh2(CH2)2PPh2@CHC (O)C6H5OMe}Cl2 (4) This product was similarly synthetized as described for the complex 3. Yield: 0.18 g, 64%. Mp: 177–179 °C. Anal. Calc. for C44H40Cl2O4P2Pt: C, 55.01; H, 4.20. Found: C, 54.87; H, 4.07%. IR (KBr disk, cm
1) m: 1628, 1671 (CO). 31P NMR (CDCl3) dP: (ppm): 17.41 (d, P1, 2JP-Pt = 38.80 Hz, 3JP-P = 7.97 Hz); 29.29 (d, P2, 2 JP-Pt = 36.62 Hz, 3JP-P = 7.97 Hz). 1H NMR (CDCl3) dH: 3.28 (m, 4H, CH2); 3.78 (s, 6H, OCH3); 5.60 (td, 2H, CH, 2JH-Pt = 68.09 Hz); 6.94–7.82 (m, 28H, Ph). 13C NMR (CDCl3) dC: 19.16 (m, CH2); 30.89 (s, PCH); 55.89 (s, OCH3); 55.41 (s, OCH3); 111.47–160.14 (Ph); 185.10 (s, CO); 185.51 (s, CO).

181

uptake, KB cells were plated in 6-well cell culture plates at a cell density of 7  105 cells per well. After overnight cells was treated with the most potent compounds at a concentration of 18 mM and then the plates transferred to a 37 °C incubator for 4 h. After treatment, cells were washed twice with ice-cold PBS and the fluorescence images immediately was measured using a fluorescence microscope (Model: Micros AUSTR1A) with imaging system at 100 magnifications. For cells without any treatment were taken as a staining control. 3. Results and discussion 3.1. Synthesis and spectroscopic characterization

2.5. Cytotoxic activity 2.5.1. MTT assay KB, U87 MG and HeLa cell lines were kindly provided by the Pasteur Institute of Iran (Tehran, Iran). The cell cultures were obtained using DMEM-F12 culture medium supplemented with 10% fetal bovine serum, and incubation at 37 °C with 5% CO2. At about 65% confluence, different concentrations (0–150 mM) of the synthetized compounds were added to the cells. An MTT assay was used to check the cytotoxicity of the compounds after 24 h of incubation. In this assay the medium was replenished with 0.5 mg/mL MTT solution and plates were further incubated for 3 h at 37 °C. After the incubation period, and to solubilize the formazan crystals, 100 mL DMSO was added to each well. The optical density at 570 nm (OD570) was detected using an Eliza (micro plate) reader (Biotek Instruments, USA). The cell viability percentage was determined by dividing the optical density of the treatment group to that of the control group at 570 nm, multiplied by a factor of 100. The IC50 value was obtained considering the concentration in which 50% of the cells were killed. All the MTT assays were conducted in triplicate in this study. For evaluation cellular

In the present research, the reaction of the diphosphine Ph2P (CH2)2PPh2 with 2 equiv of the 3-methoxyacetophenone for 24 h in acetone gave the corresponding phosphonium salt 1 in good yield. Further treatment with [(CH3)3Si]2NNa led to two-fold elimination of 2 mol HBr, giving the phosphorus ylide 2. The reactions of [MCl2(COD)] (M = Pd and Pt) with phosphorus ylide 2 in a 1:1 molar ratio yielded the C,C-chelated complexes 3 and 4 (Scheme 1). IR spectral data of the synthesized phosphonium salt and the phosphorus ylide (1 and 2) and the palladium (II) and platinum (II) complexes (3 and 4) are presented in the experimental section. In the IR spectra of the phosphonium salt, a strong stretching absorption (1668 cm
1) due to carbonyl groups can be observed, which confirms the symmetrical formation of salt 1. The m(CO) band in the IR spectrum of the phosphorus ylide 2 is observed in the 1599 cm
1 and it is shifted to higher frequencies (1627– 1671 cm
1) in the complexation, showing the coordination of the carbon atoms (ylidic carbon) to the metal center [45]. The two carbonyl groups of these complexes (3 and 4) are non-equivalent and discriminable in IR spectra (see Section 2).

Scheme 1. Synthesis of compounds 1–4.

182

M. Sayadi et al. / Polyhedron 161 (2019) 179–188

Among the spectroscopic methods, the 31P resonances are usually broad and sensitive to even relatively small variations in the chemical environment around the phosphorus atoms of these compounds (see Supplementary data). The phosphonium salt 1 exhibits a singlet (around 27 ppm) due to the PPh2 groups in the 31P {H} NMR spectrum, which indicates that the two phosphorus atoms are equivalent. The 31P{H} NMR spectrum of phosphorus ylide 2 shows a singlet peak, which correspond to the PPh2 group. This peak is shifted to around 18 ppm and show upfield shifts compared to that of parent phosphonium salt (see Supplementary file), suggesting some electron density increase in the PAC bonds [46]. The 31P{1H} NMR spectrum of the palladium(II) complex 3 features two doublets at 27.29 and 30.34 ppm, shifted significant downfield to that of the phosphorus ylide (around 18 ppm), due to the coordination of the ylide to palladium through the carbon atoms (ylidic carbon) [47], which was reported for similar palladium(II) complexes (see Supplementary file) [5,6]. Also, the 31P{1H} NMR spectrum of the platinum(II) complex 4 shows the presence of two sets of doublets, the first centred at 17.41 ppm, with a coupling constants 2JP–Pt of 38.80 Hz and a 3JP–P of 7.97 Hz. The second set appears at 29.29 ppm with a coupling constant 2JP–Pt of 36.62 Hz and a 3JP–P of 7.97 Hz due to the P1 and P2 atoms, respectively (see Supplementary file). The 1H NMR spectra of the phosphonium salt and phosphorus ylide (1 and 2) and complexes (3 and 4) have been obtained in DMSO-d6 and chloroform solvents (as illustrated in the Supplementary file). The resultant physicochemical data of the synthesized compounds are summarized in the experimental section. The 1H NMR spectrum of the phosphonium salt 1 in DMSO exhibits one broad peak due to one P-bound CH group at 6.12 ppm and it is shifted to higher frequencies (around 4.35 ppm) in the phosphorus ylide, indicating that synthesis of the phosphorus ylide 2 has occurred. Furthermore, strong deshielding and broadening in resonance values were observed for the ylidic proton after complexation (around 5.56–5.60 ppm), which is in agreement with the C, C-coordination character of the ylidesin these complexes [6]. The presence of the carbonyl group in the C,C-chelated phosphorus ylide is also confirmed by 13C{1H} NMR spectroscopy displaying signals at 185.02 ppm, compared to 192.01 ppm for the same carbon in the parent phosphonium salt, indicating a higher shielding of the carbon of the CO group in this phosphorus ylide. Chemical shift values (CO, PCH) in the 13C NMR spectra of complexes 3 and 4 showed significant shift in comparison to the parent phosphorus ylide (see Supplementary data). This observation also confirmed that coordination of phosphorus ylide 2 occurred through the C-coordination site.

Fig. 2. Electronic absorption spectra of compounds 1–4.

Fig. 3. Fluorescence emission spectra of (a) 1 and 2 (b) 3 and 4.

3.2. Electronic absorption and fluorescence emission spectroscopy

3.3. X-ray crystallography

The electronic absorption spectra of compounds 1 and 2 in DMSO are dominated by intense absorption bands in the region of 293–330 nm (Fig. 2). These intense absorption bands are due to intra-ligand transitions (p ? p*/n ? p*). Electronic absorption spectra of complexes 3 and 4 shows absorption peaks at ca. 280– 292 and 320–322 nm. The bands appearing in the range of 280– 292 nm are assigned to ILCT (intraligand charge transfer) and p ? p* transition and the 320–322 nm absorptions to the MLCT (metal to ligand charge transfer) bands. The fluorescence emission of all compounds was investigated at room temperature in DMSO solution with a concentration 1  10
5 M. Compounds show intense emission bands in the 350–600 nm region with kmax at 398 to 532 nm upon an excitation at kex = 200 nm. As shown in Fig. 3(a and b), the emission bands are attributed to the transitions from the excited state of the ligands (p*) to their ground state (p) (LLCT) and transition from the excited state of the ligands (p*) to the ground state of the metal (d) orbital (LMCT).

Colorless crystals of 2 were obtained by vapor diffusion of diethyl ether into a chloroform solution. Relevant parameters concerning data collection and refinement for 2 are given in Table 1. Selected bond distances and angles for the two independent but chemically identical molecules found in the unit cell of 2 are displayed in Table 2. The crystal structure of this compound is shown in Fig. 4. The molecule lies on a center of symmetry. The methoxy substituent is coplanar with the aromatic ring, while the dihedral angle between the keto group and the aromatic ring is 21.17 (12)°. Within each molecule there are two CAH  O interactions (C18AH18  O1i and C18iAH18i  O1), linking the two halves of the molecules across the center of symmetry, while further weak intermolecular CAH  O interaction links the molecules together along the c-axis. In addition there p  p interactions are observed, involving one of the phenyl rings from two adjacent molecules. While the two rings are parallel, with a vertical separation of

M. Sayadi et al. / Polyhedron 161 (2019) 179–188

183

Table 1 Crystal data and structure refinement for 2. Empirical formula

C44H40O4P2

Formula weight T (K) Crystal system Space group

694.70 130.00(10) triclinic

a (Å) b (Å) c (Å) a (°) b (°) c (°) V (Å3) Z qcalc g/cm3 l (mm
1) F(0 0 0) Crystal size (mm) 2h range (°) Index ranges Reflections collected Independent reflections (Rint) Data/restraints/parameter Goodness-of-fit (GOF) on F2 R1/wR2[I > 2r(I)]




P1 8.8380(5) 9.8974(4) 11.0797(6) 75.808(4) 79.541(4) 76.563(4) 905.86(8) 1 1.273 1.430 366.0 0.1761  0.146  0.106 8.304–153.976
11  h  11,
11  k  12,
13  l  12 8093 3760 [Rint = 0.0240] 3760/0/307 1.071 0.0327/0.0865

Fig. 4. ORTEP view of the X-ray crystal structure of 2. H atoms are omitted for clarity.

(R = 4 isopropylphenyl) [51,35]. This bond distance suggests resonance delocalization in these molecules [48]. 3.4. Theoretical studies

Table 2 Selected bond lengths [Å] and bond angles [°] for 2. Bond distances P1AC1 P1AC10 P1AC11 P1AC17 C1AC2 O1AC2 O2AC5 C2AC3 C3AC4

1.7232(13) 1.8212(13) 1.8066(13) 1.8023(13) 1.4001(18) 1.2602(16) 1.3650(17) 1.5088(17) 1.3996(18)

Bond angles C1AP1AC10 C1AP1AC11 C1AP1AC17 C11AP1AC10 C17AP1AC10 C17AP1AC11 C5AO2AC9 C2AC1AP1 O1AC2AC1 O1AC2AC3

113.42(6) 116.24(6) 106.36(6) 104.07(6) 108.70(6) 107.79(6) 117.56(12) 118.09(10) 122.76(12) 118.39(11)

2.979(10) Å, the interactions involve only C20 and the symmetry equivalent atom, which are almost superimposed [C20  C20iii 3.194(3) Å; C17  C20  C20iii 104.94(7)°; symmetry code: iii 1
x, 2
y,
z]. These interactions link the molecules into a 2D network lying in the bc plane. The P(1)AC(1) (1.723 Å) and C(1)A C(2) (1.400 Å) bond lengths are shorter than the (P+AC (sp3) (1.800) Å) and (CAC (sp3) (1.511) Å) normal values [48], respectively. This is due to the ylidic resonance and the values are intermediate between the common values for single (PAC = 1.80 Å) and double (P@C = 1.66 Å) bonds. The PAC(H) and C(1)AC(2) bond lengths in this ligand are close to the corresponding distances PAC(H) and CAC found in similar phosphorus ylides, such as [Ph2PCH2PPh2C(H)C(O)Ph] and Ph3P@C(H)C(O)R (R = 2,4-dichlorophenyl) [49,50]. Also, the CO bond in this ligand is longer (1.260 (3) Å) than the normal value (1.210 Å) and similar to the bond length in [Ph2P(CH2)2PPh2C(H)C(O)PhOMe] and Ph3P@C(H)C(O)R

A Theoretical study on the structure and nature of Y ? M bonds in [YMCl2] (M = Pd, Pt and Y = (MeOC6H5C(O)CH@PPh2(CH2)2 PPh2@CHC(O)C6H5OMe)) have been reported at BP86/def2-SVP level of theory. Recently Spannenberg [5] and Sabounchei [6] report the formation of seven-membered rings with a square planar geometry around the metal center which have similar skeleton to the complexes reported in this study. Thus the observed geometry of the synthesized compound was used as a basis for the DFT calculations of both palladium(II) and platinum(II) complexes (see Scheme 1). The optimized structure of the [YMCl2] (M = Pd, Pt) complexes are shown in Fig. 5. The result showed that changing the M atom from Pd to Pt has an insignificant effect on values of C ? M bond lengths and CAMAC bond angel. The calculated C ? M bond lengths in these complexes are in ranges of 2.10 Å and 2.12 respectively. Natural bond orbital (NBO) analysis was used to studying of Y ? M interactions. In this regard, the partial charge amounts of the C(ylide) and M atoms of C ? M bonds in the [YMCl2] (M = Pd, Pt) complexes and also the total charge amounts of the MCl2 fragment are shown in Table 3. As can be seen, the C(ylide) atom and MCl2 fragment carry negative charge. These data show that there is a charge transfer from phosphorus ylide ligand to MCl2 fragment in the complexes. Also, the results confirm that by changing M atom from Pd to Pt the value of charge transfer is significantly increased. In continuation, the value of Wiberg bond index (WBIs) is also studied. Result is in good agreement with the value of charge transfer showed that by changing the M atoms from Pd to Pt, the values of WBIs of C ? M bonds in the complexes are increased. The energy decomposition analysis (EDA) is a powerful method for a quantitative interpretation of chemical bonds. This method has the ability to provide a bridge between quantum chemical calculations and heuristic bonding models of traditional chemistry. The results of EDA analyses for [YMCl2] (M = Pd, Pt) complexes are given in Table 4. In the EDA, the bonding formation of interacting fragments would affect 4 main components as following;

DEint ¼ DEelstat þ DEpauli þ DEorb þ DEdisp

184

M. Sayadi et al. / Polyhedron 161 (2019) 179–188

Fig. 5. Optimized structures of [YMCl2] (M = Pd, Pt) at the BPB6/def2-SVP level of theory. Bond lengths are given in Å, and bond angles are in degrees.

Table 3 Wiberg bond indices (WBI) of the CAM bond and natural charges of the C(ylide) atom and total charge of MCl2 fragment at the BPB6/def2-SVP level of theory. Name of complex

WBI

M

C

MCl2

[YPdCl2] [YPtCl2]

0.46(0.47) 0.56(0.48)

0.05
0.04


0.82
0.82


0.70
0.92

Table 4 EDA analysis (BP86-D3/TZ2P(ZORA)//BP86/def2-SVP) of [YMCl2] (M = Pd, Pt) complexes. [YPdCl2]

[YPtCl2]

Parameter

Value

Parameter

Value

DEint DEpauli DEelstat DEorb DEdisp DEorb, rd DEorb, rd DEorb, rd DEorb,p \ DEorb, p\ DEorb, pk DEorb, pk DEorb, rest


131.04 254.70
218(56.61)
143.83(37.35)
23.26(6.04)
77.29(53.73)
20.02(13.91)
6.41(4.45)
7.39(5.13)
5.47(3.80)
4.89(3.65)
4.81(3.34)
13.44

DEint DEpauli DEelstat DEorb DEdisp DEorb, rd DEorb, rd DEorb, rd DEorb,p \ DEorb, p\ DEorb, pk DEorb, pk DEorb, rest


161.45 333.54
284.45(57.47)
182.92(36.95)
27.59(5.57)
88.81(48.55)
38.05(20.88)
7.98(4.36)
9.60(5.24)
7.00(3.82)
6.73(3.67)
5.66(3.10)
15.6

where DEelstat is electrostatic interaction, DEpauli is Pauli repulsion, DEorbis orbital interaction, and DEdisp is dispersion energy between two fragments. Changing the M atom from Pd to Pt led to significantly increases (From 131 kcal mol
1 to 165 kcal mol
1) in the value of DEint. These data are in good agreement with the values of charge transfer and WBIs which reported in Table 3 and our recent study showed that PtCl2 compared to PdCl2 forms stronger bonds with Y ligand [52]. Also according to Table 4 the main portions of DEint, about 56.5– 57.5% is related to DEelstat. Thus it can be concluded that the nature of bond between Y ligand and MCl2 fragments in the complexes is more electrostatic. The EDA-NOCV method makes it possible to calculate the individual portions of pair-wise interactions between two investigated fragments. The visualization of the NOCV pairs (Dq) between the donor orbitals of Ylide (Y) and the acceptor orbitals of MCl2 fragment are shown in Fig. 6. As can be seen, the dominant term of DEorb for all of the aforementioned complexes arises from r-orbi-

tal interactions (Dq1, Dq2) and r-back donation orbital interactions (Dq3). The calculated data show that the r-orbital interactions (donation and back donation) account for 72.09
73.79% of the DEorb term for studied complexes. Also, the shapes of the orbital pairs of Dq4–Dq7 refer to p back-donations which are out of plain and the in plain and accounts for about 15.83
15.90% of DEorb term (see Table 4 and Fig. 6). 3.5. Anti-proliferative effect of the compounds Cytotoxic effects of the different concentration of Pd(II) and Pt (II) complexes on HeLa, KB and U87 MG human carcinoma cells were assessed by an MTT assay. The results are graphically presented in Fig. 7. A glance at the figure indicates that both compounds exhibit strong cytotoxic activity with IC50 values of 18.2 and 19.1 mM against human oral cancer KB cell line. These values are below 20 mM, which indicates that these compounds potentially present an interesting cytotoxic activity towards human oral carcinoma cell line [53]. This type of cancer is a major health problem in the developing countries; generally, the overall survival rate of patients with oral cancer is only about 50%, partly due to the resistance to the presently used therapy [54]. The Pd(II) complex also possesses a good inhibitory effect (IC50 value 37.5 lM) against U87 MG whilst the other Pt(II) complex has no significant effect on the U87 MG viability up to a concentration of 150 mM. Moreover, the Pd(II) and Pt(II) complexes exhibit weak inhibitory effects on the growth of HeLa cells. Based on this information, it can be concluded that these compound have potent cytotoxic effects against KB cells predicating their therapeutic potential in treatment of human oral cancer. In the current study fluorescence microscopy images after 4 h incubation with these compounds, for example compound 3, showed almost every cell was stained red with clear cell borders, indicating a very effective uptake of this compound (Fig. 8). Taken together our results demonstrated that compound 3 shows the high tumor-specific cytotoxicity against human epidermoid carcinoma of oral cavity cell line indicating new drug candidates for cancer chemotherapy. A comparison between the cytotoxic effects against the KB cell line for Pd/Pt complexes (3 and 4) and some of other Pd/Pt-based complexes reported in the literature was carried out [55–62]. The results revealed that these complexes exhibited similar and even higher cytotoxic activity than that of the other palladium and platinum complexes (Table 5, entries 7–12). Also, the Cisplatin was found to have the highest cytotoxic effects against the KB cell line among the studied compounds (Table 5, entry 1). Overall, based on the results of cytotoxic experiments and comparative study, it can

185

M. Sayadi et al. / Polyhedron 161 (2019) 179–188

[YPdCl2] (3)

[YPtCl2] (4)

1: ΔE= -77.29, ν= 1.21, Contour=0.001

1: ΔE= -88.81, ν= 1.15, Contour=0.001

2: ΔE= -20.02, ν= 0.42, Contour=0.0005

2: ΔE= -38.05, ν= 0.58, Contour=0.0005

3: ΔE= -6.41, ν= 0.3, Contour=0.0005

3: ΔE= -7.98, ν= 0.38, Contour=0.0005

4: ΔE= -7.39, ν= 0.27, Contour=0.0005

4: ΔE= -9.60, ν= 0.30, Contour=0.0005

5: ΔE= -5.47, ν= 0.22, Contour=0.0003

5: ΔE= -7.0, ν= 0.26, Contour=0.0005

6: ΔE= -4.84, ν= 0.20, Contour=0.0003

6: ΔE= -6.73, ν= 0.3, Contour=0.0003

7: ΔE= -4.81, ν= 0.19, Contour=0.0003 ΔErest= -13.44

7: ΔE= -5.66, ν= 0.23, Contour=0.0003 ΔErest= -15.60

Fig. 6. Deformation densities associated with the most important orbital interactions for [YMCl2] (M = Pd, Pt) complexes.

186

M. Sayadi et al. / Polyhedron 161 (2019) 179–188

Fig. 7. Cell viability of (a) HeLa, (b) KB and (c) U87 MG cell lines after treatment with different concentrations of compounds 3 and 4. Cell viability measured by MTT assay. Data are expressed as the mean ± S.E.M of three separate experiments (n = 3).

Fig. 8. Fluorescence microscope images demonstrating the intracellular compound 3 distribution in KB cell line. (A) Control cells incubated without compound and (B) Cells exposed to IC50 concentration of compound 3 for 4 h.

be concluded that the metal ions have important effect on anticancer activity and also primary ligands can exert additional effects on the cytotoxicity [59]. Therefore, coordination of symmetrical phosphorus ylides as primary ligands to metal center resulted in high cytotoxic effect and low IC50 value, which makes the examined samples as new drug candidate for further development in cancer chemotherapy. 4. Conclusion Herein, the synthesis and characterization of a new C,C-chelating phosphorus ylide ligand and its palladium(II) and platinum(II)

complexes are reported. The structures of the phosphonium salt and the phosphorus ylide ligand were confirmed by single crystal X-ray diffraction analysis. On the basis of the physicochemical and spectroscopic data, we propose that the ligand herein exhibits a chelating CAC coordination behavior to the metal center, affording a seven-membered chelate ring. Likewise, in vitro cytotoxic activity of the test compounds 3 and 4 shows that these compounds have a high tumor-specific cytotoxicity against KB, a human epidermoid carcinoma of oral cavity cell line. It can be concluded that, these compounds can be considered as a promising lead in cancer drug discovery and development. Also, theoretical studies have been done on the structures and nature of Y ? M

M. Sayadi et al. / Polyhedron 161 (2019) 179–188 Table 5 Comparison of cytotoxic effects against KB cell line between the Pd/Pt complexes (3 and 4) and other Pd/Pt-based complexes reported in literature. Entry

Compound

IC50 (lM)

Refs.

1 2 3 4

2.6 1.5 2.8 6.7

[55] [56] [56] [57]

7.6

[57]

4.6

[58]

7 8 9 10 12

Cisplatin [PtCl2(L)2]H2O (L = 1,3-benzothiazol-2-amine) [PdCl2(L)2]H2O (L = 1,3-benzothiazol-2-amine) [PtCl(L)]Cl (L = 40 -(4-hydroxyphenyl)-2,20 ,60 ,200 terpyridine) [PdCl(L)]Cl (L = 40 -(4-Carboxymethylphenyl)2,20 ,60 ,200 -terpyridine) [PdCl2(L)]0.2(DMSO) (L = (2,3-f)pyrazino(1,10) phenanthroline-2,3-dicarboxylic acid) Pd(dap)(L)] (L = 4-toluenesulfonyl-L-alanine)a K[PtCl(L)] (L = 2-(2-hydroxybenzylamino)acetoxyl) [Pt(bpy)(L)]H2O (L = 4-toluenesulfonyl-L-serine)b [Pt(bpy)(L)]H2O (L = benzoyl-L-leucine)b Complex Pd(II) (3)

19.7 26.0 22.4 20.0 18.2

12

Complex Pt(II) (4)

[59] [60] [61] [62] This work This work

5 6

a b

19.1

dap = 1,3-diaminopropane. bpy = 2,20 -bipyridine.

bonds in [YMCl2] (M = Pd, Pt) complexes via NBO, EDA and EDA NOCV analysis. The results show that PtCl2 compared to PdCl2 forms stronger bonds with Y ligands in the complexes. The result of EDA analysis confirms that the main portions of DEint, about 56.5–57.5% in the complexes are allocated to DEelstat and confirmed that that the nature of bond between Y ligand and MCl2 fragments in the complexes is more electrostatic Also the NOCV pairs (Dq) between the donor orbitals of phosphorus ylides (L) and the acceptor orbitals of MCl2 fragment are showed that the dominant term of DEorb for all of the aforementioned complexes arises from r-orbital interactions (about 72.09
73.79%). Acknowledgements Funding of our research from the Bu-Ali Sina University is gratefully acknowledged. Appendix A. Supplementary data CCDC 1431942 contains the supplementary crystallographic data for compound 2. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-mail: [email protected]. Supplementary data to this article can be found online at https://doi.org/10.1016/j.poly.2019.01.016. References [1] A.K. Mishra, N.K. Kaushik, Eur. J. Med. Chem. 42 (2007) 1239. [2] M. Juribašic´, K. Molcˇanov, B. Kojic´-Prodic´, L. Bellotto, M. Kralj, F. Zani, L. TušekBozˇic´, J. Inorg. Biochem. 105 (2011) 867. [3] S.J. Sabounchei, M. Ahmadi, Z. Nasri, E. Shams, S. Salehzadeh, Y. Gholiee, R. Karamian, M. Asadbegy, S. Samiee, C. R. Chim. 16 (2013) 159. [4] S.J. Sabounchei, A. Hashemi, A. Yousefi, P. Gohari Derakhshandeh, R. Karamian, M. Asadbegy, K. Van Hecke, Polyhedron 135 (2017) 1. [5] A. Spannenberg, W. Baumann, U. Rosenthal, Organometallics 19 (2000) 3991. [6] S.J. Sabounchei, M. Panahimehr, M. Ahmadi, F. Akhlaghi, C. Boscovi, C. R. Chim. 17 (2014) 81. [7] J. Vicente, M.T. Chicote, J. Femandez-Baeza, J. Organomet. Chem. 364 (1989) 407. [8] U. Belluco, R.A. Michelin, M. Mozzon, R. Bertani, G. Facchin, L. Zanotto, L. Pandolfo, J. Organomet. Chem. 557 (1998) 37. [9] (a) L.R. Falvello, S. Fernandez, R. Navarro, A. Rueda, E.P. Urriolabeitia, Inorg. Chem. 37 (1998) 6007; (b) L.R. Falvello, S. Fernandez, R. Navarro, A. Rueda, E.P. Urriolabeitia, Organometallics 17 (1998) 5887.

187

[10] M. Taillefer, H.J. Cristau, Top. Curr. Chem. 229 (2003) 41. [11] S.J. Sabounchei, F. Akhlagh Bagherjeri, C. Boskovic, R.W. Gable, R. Karamian, M. Asadbegy, J. Mol. Struct. 1034 (2013) 265. [12] H. Schmidbaur, T. Costa, B.M. Mahrla, F.H. Kohler, Y.H. Tsay, C. Kruger, J. Abart, F.E. Wagner, Organometallics 1 (1982) 1266. [13] E. Fluck, K. Bieger, G. Heckmann, B. Neumuller, J. Organomet. Chem. 459 (1993) 73. [14] H. Schmidbaur, C. Paschalidis, O. Steigelmann, G. Muller, Angew. Chem., Int. Ed. 29 (1990) 516. [15] K. Dimroth, Acc. Chem. Res. 15 (1982) 58. [16] G. Maerkl, P. Kreitmeier, Elsevier, Oxford, 1996. [17] B. Rosenberg, L. Vancamp, T. Krigas, Nature 205 (1965) 698. [18] M.J. Cleare, J.D. Hoeschele, Bioinorg. Chem. 2 (1973) 187. [19] B. Rosenberg, Interdiscipl. Sci. Rev. 3 (1978) 134. [20] B. Rosenberg, L. Vancamp, J.E. Trosko, V.H. Mansour, Nature 222 (1969) 385. [21] C.G. Hartinger, P.J. Dyson, Chem. Soc. Rev. 38 (2009) 391. [22] G. Gasser, I. Ott, N. Metzler-Nolte, J. Med. Chem. 54 (2011) 3. [23] S.J. Sabounchei, M. Hosseinzadeh, S. Salehzadeh, F. Maleki, R.W. Gable, Inorg. Chem. Front. 4 (2017) 2107. [24] L. Tusek-Bozic, M. Juribasic, P. Traldi, V. Scarcia, A. Furlani, Polyhedron 27 (2008) 1317. [25] F. Shaheen, A. Badshah, M. Gielen, C. Gieck, M. Jamil, D. de Vos, J. Organomet. Chem. 693 (2008) 1117. [26] A. Garoufis, S.K. Hadjikakou, N. Hadjiliadis, Hadjikakou, N. Hadjiliadis, Coord. Chem. Rev. 253 (2009) 1384. [27] K.S. Prasad, L.S. Kumar, S. Chandan, R.M.N. Kumar, H.D. Revanasiddappa, Spectrochim. Acta, Part A 107 (2013) 108. [28] F. Ari, E. Ulukaya, M. Sarimahmut, V.T. Yilmaz, Bioorg. Med. Chem. 21 (2013) 3016. [29] O.V. Dolomanov, L.J. Bourhis, R.J. Gildea, J.A.K. Howard, H. Puschmann, J. Appl. Crystallogr. 42 (2009) 339. [30] G.M. Sheldrick, Acta Crystallogr., Part A 71 (2015) 3. [31] G.M. Sheldrick, Acta Crystallogr., Sect. A 64 (2008) 112. [32] A.D. Becke, Phys. Rev. A 38 (1988) 3098. [33] J.P. Perdew, Phys. Rev. B 33 (1986) 8822. [34] A. Schäfer, C. Huber, R. Ahlrichs, J. Chem. Phys. 100 (1994) 2571. [35] S.J. Sabounchei, M. Sarlakifar, S. Salehzadeh, M. Bayat, M. Pourshahbaz, H.R. Khavasi, Polyhedron 38 (2012) 131. [36] S.J. Sabounchei, H. Nemattalab, S. Salehzadeh, S. Khani, M. Bayat, H.R. Khavasi, Polyhedron 27 (2008) 2015. [37] M. Bayat, M. von Hopffgarten, S. Salehzadeh, G. Frenking, J. Organomet. Chem. 696 (2011) 2976. [38] M. Bayat, S. Salehzadeh, G. Frenking, J. Organomet. Chem. 697 (2012) 74. [39] M. Bayat, N. Ahmadian, Polyhedron 96 (2015) 95. [40] M. Bayat, N. Ahmadian, J. Iran. Chem. Soc. 13 (2016) 397. [41] S.J. Sabounchei, M. Ahmadianpoor, A. Yousefi, A. Hashemi, M. Bayat, A. Sedghi, F. Akhlaghi Bagherjeri, R.W. Gable, RSC Adv. 6 (2016) 28308. [42] S.J. Sabounchei, A. Yousefi, M. Ahmadianpoor, A. Hashemi, M. Bayat, A. Sedghi, F.A. Bagherjeri, R.W. Gable, Polyhedron 117 (2016) 273. [43] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, G. Scalman, V. Barone, B. Mennucci, G.A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H.P. Hratchian, A.F. Izmaylov, J. Bloino, G. Zheng, J.L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J.A. Montgomery Jr., J.E. Peralta, F. Ogliaro, M. Bearpark, J.J. Heyd, E. Brothers, K.N. Kudin, V.N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J.C. Burant, S.S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J.M. Millam, M. Klene, J.E. Knox, J.B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, R.L. Martin, K. Morokuma, V.G. Zakrzewski, G.A. Voth, P. Salvador, J.J. Dannenberg, S. Dapprich, A.D. Daniels, Ö. Farkas, J.B. Foresman, J.V. Ortiz, J. Cioslowski, D.J. Fox, Gaussian 09, Revision A.02, Gaussian, Inc., Wallingford, CT, 2009. [44] E.D. Gladdening, A.E. Reed, J.A. Carpenter, F. Weinhold, NBO Version 3.1. [45] S.J. Sabounchei, H. Nemattalab, S. Salehzadeh, S. Khani, M. Bayat, H. Adams, M. D. Ward, Inorg. Chim. Acta 362 (2009) 105. [46] J. Vicente, M.T. Chicote, M.C. Lagunas, P.G. Jones, J. Chem. Soc., Dalton Trans. (1991) 2579. [47] S.J. Sabounchei, S. Samiee, D. Nematollahi, A. Naghipour, D.M. Morales, Inorg. Chim. Acta 363 (2010) 3973. [48] S.J. Sabounchei, H. Nemattalab, H.R. Khavasi, X-ray Struct. Anal. Online 26 (2010) 35. [49] M.M. Ebrahima, K. Panchanatheswaran, A. Neels, H. Stoeckli-Evans, J. Organomet. Chem. 694 (2009) 643. [50] S.J. Sabounchei, M. Sarlakifar, M. Pourshahbaz, S. Salehzadeh, M. Bayat, H.R. Khavasi, F. Akhlaghi Bagherjeri, C. Boscovic, J. Inorg. Organomet. Polym. 23 (2013) 401. [51] S.J. Sabounchei, A. Hashemi, M. Sayadi, M. Bayat, A. Sedghi, R. Karamian, S.H. Moazzami Farida, R.W. Gable, J. Mol. Struct. 1165 (2018) 142. [52] S.J. Sabounchei, M. Sayadi, M. Bayat, A. Sedghi, R.W. Gable, J. Coord. Chem. 70 (2017) 3727. [53] F.P. Ruphin, R. Baholy, R. Emmanuel, R. Amelie, M.T. Martin, N. Koto-Te-Nyiwa, Asian Pac. J. Trop. Biomed. 4 (2014) 169. [54] T. Chuprajob, C. Changtam, R. Chokchaisiri, W. Chunglok, N. Sornkaew, Bioorg. Med. Chem. Lett. 24 (2014) 2839. [55] L.-W. Wang, S.-Y. Liu, J.-J. Wang, W. Peng, S.-H. Li, G.-Q. Zhou, X.-Y. Qin, S.-X. Wang, J.-C. Zhang, Synth. React. Inorg. Met.-Org. Chem. 45 (2015) 1049.

188

M. Sayadi et al. / Polyhedron 161 (2019) 179–188

[56] E.J. Gao, L. Liu, M.C. Zhu, Y. Huang, F. Guan, X.N. Gao, M. Zhang, L. Wang, W.Z. Zhang, Y.G. Sun, Inorg. Chem. 50 (2011) 4732. [57] S. Wang, W. Chu, Y. Wang, S. Liu, J. Zhang, S. Li, H. Wei, G. Zhou, X. Qin, Appl. Organomet. Chem. 27 (2013) 373. [58] Y.-G. Sun, Y.-N. Sun, L.-X. You, Y.-N. Liu, F. Ding, B.-Y. Ren, G. Xiong, V. Dragutan, I. Dragutan, J. Inorg. Biochem. 164 (2016) 129.

[59] J. Zhang, L. Ma, H. Lu, Y. Wang, S. Li, S. Wang, G. Zhou, Eur. J. Med. Chem. 58 (2012) 281. [60] L.-J. Li, C. Wang, C. Tian, X.-Y. Yang, X.-X. Hua, J.-L. Du, Res. Chem. Intermed. 39 (2013) 733. [61] J.C. Zhang, L. Li, L. Ma, F. Zhang, S. Wang, J. Coord. Chem 64 (2011) 1695–1706. [62] J. Zhang, F. Zhang, L. Wang, J. Du, S. Wang, S. Li, J. Coord. Chem. 65 (2012) 2159.