New palladium(II) formamidine complexes: Preparation, characterization, theoretical calculations and cytotoxic activity

Accepted Manuscript New palladium(II) formamidine complexes: preparation, characterization, theoretical calculations and cytotoxic activity

Ahmed A. Soliman, Amany. M. Sayed, Othman I. Alajrawy, Wolfgang Linert PII:

S0022-2860(17)30221-1

DOI:

10.1016/j.molstruc.2017.02.062

Reference:

MOLSTR 23456

To appear in:

Journal of Molecular Structure

Received Date:

05 January 2017

Revised Date:

14 February 2017

Accepted Date:

15 February 2017

Please cite this article as: Ahmed A. Soliman, Amany. M. Sayed, Othman I. Alajrawy, Wolfgang Linert, New palladium(II) formamidine complexes: preparation, characterization, theoretical calculations and cytotoxic activity, Journal of Molecular Structure (2017), doi: 10.1016/j.molstruc. 2017.02.062

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ACCEPTED MANUSCRIPT Graphical Abstract Binary Pd(II) formamidine complexes formulated as [Pd(L1-4)Cl2] where L=formamidine ligands, were synthesized and characterized. The complexes are diamagnetic and the electronic spectral data showed the peaks due to square planar Pd(II) complexes. The structures are geometrically optimized and the energy parameters are calculated. The complexes have noticeable cytotoxicity.

Complex (1) Molecular electronic potential (MEP) of complex (1) (isocontour value=0.02). Hydrogen atoms are omitted for simplicity.

ACCEPTED MANUSCRIPT

Research Highlights Binary Pd(II) complexes were synthesized and characterized. The structures are geometrically optimized. The computed vibrations and transition are compared with the experimental.  The HOMO and LUMO energies were computed and interpreted.  The cytotoxicity of complexes was tested with promising IC50 values.   

ACCEPTED MANUSCRIPT New palladium(II) formamidine complexes: preparation, characterization, theoretical calculations and cytotoxic activity Ahmed A. Soliman1,2*, Amany. M. Sayed1,3, Othman I. Alajrawy1,4, and Wolfgang Linert5 1Department

of Chemistry, Faculty of Science, Cairo University, 12613 Giza, Egypt. President Office, University of Dammam, Dammam 31441, KSA. 3 Hazard Waste Management Division, Ministry of Environmental Affairs, Cairo, Egypt 4Department of General Sciences, Faculty of Veterinary Medicine, Al-Fallujah University, Fallujah, Iraq. 5Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9163-AC, A-1060 Vienna, Austria. 2Vice

Abstract Binary Pd(II) formamidine complexes formulated as [Pd(L1-4)Cl2] where L=formamidine ligands, were synthesized and characterized using different tools, such as; elemental analyses, mass, infrared spectroscopy, magnetic susceptibility, thermal analysis and DFT calculations. The complexes are diamagnetic and the electronic spectral data showed the peaks due to square planar Pd(II) complexes. The optimized structures of complexes (1-4) indicate a distorted square planar geometry with Cl-Pd-Cl and N-Pd-N bond angles in the range 83.89º-94.27º. The electronic energies (a.u.) (-553.79 to -763.92) and the highest occupied molecular orbital (-0.223 to -0.250) and lowest unoccupied molecular orbital energies (-0.091 to -0.127) of the complexes were negative in their values indicated the stability of the complexes. The complexes are polarized as indicated from dipole moment values (6.50-15.71 Debye). All complexes are neutral, stable and nonhygroscopic. The complexes have noticeable cytotoxicity with IC50 (M): 0.0740 (MCF-7), 0.0074-0.0082 (HEP-2), and 0.0119-0.0144 (HepG-2). Keywords: Pd(II) complexes, formamidine, cytotoxic activity, theoretical calculations.

*Correspondent

author: Prof. Dr. Ahmed A Soliman, e-mail: [email protected], Tel: 002 01110121379, Fax: 002 02 35676556.

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1. INTRODUCTION Platinum complexes are clinically tested as drugs for treating of various types of tumors [1-2]. There are many drawback of using such drugs such as side effects, drug resistance, adverse toxicity, and selectivity [3]. For these reasons, many research groups are actively tried other transition metal complexes other than platinum as antitumor candidates [4-9]. Considerable attention of palladium(II) complexes have been made due to their pharmacological properties. Especially palladium complexes with aromatic N-containing ligands, e.g., 1,10-phenanthroline, pyridine, quinolone, and pyrazole, have shown very promising antitumor activities [5, 10-13]. For this purpose, palladium complexes have been investigated and have been found as better candidates due to their stability, low toxicity and high selectivity for tumor cells. Recently, we published the synthesis and cytotoxicity of a series of formamidine and their complexes with Pd(II) and Pt(II) [14-16]. Following our research work in the area of antitumor complexes, we report in this article the synthesis, characterization and cytotoxicity of new Pd(II) formamidine complexes. The structures of formamidine ligands are given in Scheme 1.

2. 2.1.

Experimental Section Materials

The chemicals used are highly pure. Sodium tetrachloropalladate(II) (Na2[PdCl4]) was supplied by Aldrich. All solvents were of analytical grade.

2.2.

Measurements

The elemental analyses of carbon, hydrogen and nitrogen were analyzed at the micro analytical laboratory of Cairo University, Egypt. Electrochemical data were obtained using a CH Instrument 660 B Model Electrochemical Workstation. Infrared measurements of the solids were carried

out as KBr discs using Jasco FTIR-460 plus and Jasco FTIR-4000 (range 400-4000 cm-1), mass spectrometry analyses were conducted using GCMS-QP1000EX Shimadzu. The magnetic susceptibility measurements of the solid complexes were carried out using a Sherwood Scientific, Cambridge Science Park Cambridge-England magnetic susceptibility balance. Thermal analyses were carried out using a Shimadzu thermo-gravimetric analyzer TGA-60H; under a nitrogen atmosphere (20 mL/min) with a heating rate of 10 oC /min over a temperature range from room temperature up to 1000 oC.

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ACCEPTED MANUSCRIPT Geometric parameters and energies of prepared complexes were carried out using [GAUSSIAN

09W] software program. Molecular geometry of the singlet ground state of complexes was fully optimized in the gas phase at the B3LYP/LanL2DZ basis set.

2.3. Preparation of [PdL1Cl2](1), [PdL2Cl2](2), [PdL3Cl2]. H2O (3), and [PdL4Cl2].3/2H2O (4). (0.21g, 1.0 mmol), (0.19g, 1.0 mmol), (0.14g, 1.0 mmol) and (0.12g, 1.0 mmol) of ligands L1, L2, L3 and L4; respectively have been dissolved in separate 10 mL of ethanol and slightly mixed with 0.3g (1.0 mmol) of Na2PdCl4 dissolved in 10 mL of water. The mixture of binary complexes has been adjusted to pH 3.5 and refluxed at 60 oC for 4 hours under constant stirring. The complexes (1) (yield: 58%), complex (2) (yield: 54%), complex (3) (yield: 45%) and complex (4) (yield: 51%) were obtained as pale yellow solids. The solids have been subjected to elemental analysis: Anal. Calc. for (1); (C10H11Cl2N3PdS, Calc.: C, 31.39; H, 2.90; N, 10.98, Found: C, 31.19; H, 2.76; N, 10.89%); m.p >300 C°; (2)( C10H12Cl2N4Pd, Calc.: C, 32.86; H, 3.31; N, 15.33, Found: C, 31.98; H, 3.17; N, 15.18%); m.p >300 C°; (3)( C5H9Cl2N5Pd, Calc.: C, 18.98; H, 2.87; N, 22.13, Found: C, 18.87; H, 2.78; N, 21.95%); m.p >300 C°, and (4) (C6H10Cl2N3O1.5Pd, Calc.: C, 22.14; H, 3.10; N, 12.91. Found: C, 21.97; H, 2.99; N, 12.78); m.p >300 C°.

3. Results and discussion 3.1. IR Spectra. The most characteristic IR peaks of prepared complexes are given in Table 1. The strong bands appeared at 1600-1642 cm-1 in the spectra of all ligands have been assigned to the ν(C=N) of the azomethine group while those appeared at 1261-1276 cm-1 are assigned to ν(C-N) [14-16,17]. In the spectra of the investigated complexes, the above mentioned bands are shifted to frequencies of 1627-1635 cm-1 and 1122-1218 cm-1, respectively. New bands at 436-528 cm-1 were assigned to ν(M-N) vibrations [17]. Figure 1 shows the experimental and calculated IR spectra of the complex (1). There is an agreement between the calculated and experimental as shown in Table 1 with a relative error of 0.71-10.11%. This error may be explained on the basis of the different methodology used for getting the data; the experimental data are measured using the solid state complexes while the calculated data was deduced from the isolated gaseous molecular state.

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ACCEPTED MANUSCRIPT 3.2. Mass spectral analysis. The major mass fragmentations in the mass spectra of the synthesized complexes are given in Table 2. The spectrum of complex (1) (M.Wt=382.61) showed a parent peak at m/z=385 (M), peaks at m/z=205 (L1), m/z=189 (L-CH3), m/z=177 (L-2CH3) and m/z=163 (L-C(CH3)2). The spectrum of complex (2) (M.Wt= 395.56) gave a parent peak at m/z=396 (M), peaks at m/z=358 (M-(N(CH3)2, m/z=205 (M-L2), m/z =188 (L2), m/z=173 (L2-CH3) and m/z=144 (L2-(CH3)2). Mass spectrum of complex (3) (M.Wt=316.48) gave a parent peak at m/z=316 (M), peaks at m/z=300 (M-(CH3), m/z=285 (M-(CH3)2), m/z=272 (M-N(CH3)2), m/z=236 (M-H2NCN(CH3)2), and m/z=140 (L3). The spectrum of complex (4) (M.Wt =325.49) gave a parent peak at m/z=325 (M), peaks at m/z=312 (M-CH3), m/z=295 (M-(3/2H2O), m/z=259 (M-(3/2H2O+N(CH3)2), and m/z=122 (L4). The spectra of the complexes (1-4) showed also peaks at 106, 107, 108, 109, and 110 m/z which are assigned to the stable palladium isotopes [20].

3.4. Magnetic Susceptibility Measurements. Magnetic susceptibility measurements of palladium(II) formamidine complexes (1-4) showed that all complexes are diamagnetic which can be explained on the fact that Pd(II) is divalent (d8), in a square planar geometry (eg4 a1g2 b2g2) with all electrons in paired state [21].

3.5. Thermal Analysis. The thermogravimetric analysis (TGA) has been performed investigate the thermal stabilityof complexes. The derivative thermogravimetric analysis (DrTGA) has been also used to describe the steps ranges for better precision. The decomposition is consistent with the proposed complex formula. The thermogram of complex (2); are shown in Figure 2. The thermodynamic parameters were calculated using the Integral method using the Coats–Redfern and Approximation method using Horowitz–Metzger [22,23] considering the Ozawa correction [24]. The decomposition temperature ranges with mass losses are given in Table 3. The values of the thermodynamic parameters of the complexes are given in Table 4. The thermal stability of the studied complexes is indicated from the high overall activation energies (11.78-204.70 kJ mol-1). The entropy change, ΔS*, of the formation of the activated complexes from the starting reactants varied from positive to negative values within the decomposition steps. This variation in the sign of the entropy change from a decomposition step to another one consistent with the variation in the degree of structural ‘complexity’ (arrangement, ‘organization’) of the activated complex as the starting reactants are different [24-26]. 4

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3.6. Theoretical Studies. Molecular geometries of the singlet ground state of the complexes were fully optimized in the gas phase at the B3LYP/LanL2DZ basis set [27,28]. The optimized geometries of the complexes (1-4) are given in Figure 3 and relevant bond angles and bond lengths are listed in Table 5. The angles between Pd(ΙΙ) and the surrounded atoms of chloride and formamidine ligands vary from (83.89º to -94.27º) and dihedral angles (174.12° to 179.78°) which are deviated from those of perfect square planar (90o, 180o); indicating distorted square planar structures [33]. The Cl-Pd-Cl bond angles (89.05°-91.96°) have been found in the range of the palladium(II) diammine dichlorocomplex (93.3°) in cis-[PdCl2(Meox)2] (Meox=2-methyl-2-oxazoline) [15, 29]. The N-Pd-N bond angles (85.51°-90.22°) are also deviating from (90o). This deviation arose from the participation of the bulky formamidine ligands in coordination. The average values found for Pd-Cl (2.361-2.396 Å) is consistent with the range of values reported {2.383 cis-dichloro-{[ethyl (2E)-2-(pyridineilmethyledene) hydrazynil]acetate-k2N}Pd(II)}[ 30].

It is important to calculate the atomic

charges which may explain the potential donor and acceptor property of atoms [31]. It has been found that the higher charge density is allocated on ligand’s nitrogen atoms, which explain the expected their donor properties. On the other hand, palladium with its positive charge acts as the acceptor. The possibility of back donation is inferred from the increase of the negative charges of nitrogen atoms in the complexes compared with ligands. This may be explained as MLCT from the palladium to the π* orbitals of the ligands. The charge on the sulfur atom in both in L1 (+ 0.249) and in complex (1) (+0.403) render it difficult to act as donor and/or binding site [14]. The dipole moment vector is determined from the positive and negative centers in the complexes [1416,32]. The complexes have been found to be more polarized than ligand as indicated from values of the dipole moments of the complexes (6.50-15.71 Debye) and ligands (1.93-4.90 Debye) [1416,33]. The calculated electronic energy of the complexes as well as their dipole moments is tabulated in Table 6. Natural Bond Orbital (NBO) calculations [32] were performed at B3LYP/ LanL2DZ basis set. According to NBO analysis for complex (1) the electronic configuration of Pd is: [core] 5s0.33 4d8.96 5p0.36 5d0.01 6p0.01, 36 core electrons, 9.64 valence electrons, and 0.012 Rydberg electrons, which gives 45.65 total electrons and +0.348 e charge on Pd atom. The occupancies of Pd 4d orbitals are dxy 1.656; dxz 1.979; dyz 1.879; dx2-y2 1.476 and dz2 1.954. The 4d-electron populations of 8.944 is corresponding to oxidation state Pd(II), in agreement with dPd to ligand electron transfer. Similar trends are shown by complexes (2-4) with Pd 4d populations (9.626-9.643) confirming the metal to ligand electron transfer [32]. The electronic energies (a.u.) 5

ACCEPTED MANUSCRIPT of the complexes (-553.79 to -763.92) are more stable than ligands (-949 to -397) [14-16,34]. The HOMO and LUMO calculated energies of the palladium(II) complexes (1-4) are given in Table 6. The hardness (η) values are indication of the ease or difficulty to donate, it is calculated as (η=(IA)/2) where I is the ionization energy, A is the electron affinity and (I-A) equals to the gap between the HOMO and LUMO energy levels. The higher the value of (I-A) the harder is the molecules and vice versa [35,36]. The η values and ΔE (HOMO-LUMO) are given in Table 6. The transition is more easier in complexes than the ligands as indicated from ΔE of complexes (0.1090.136) to that of the ligands (0.106-0.310) [34] and hence the complexes are softer (η=(0.0540.068) than the ligands (0.053-0.155) [33]. The negative values of HOMO and the LUMO energy orbitals as well as the energy separation in both ligands and complexes indicated their stability. [34,35]. The plots of the isodensity surface of the HOMO and LUMO for complexes is represented by complex(1); Figure 4. The electron densities in L1 are localized on the benzthoizole part which may point to a mixed π→π* and n→π* transition [35]. The molecular electrostatic potential (MEP) has been calculated and shown in Figure 4, the red regions indicate an electrophilic reactivity and the blue regions indicate a nucleophilic reactivity. The nitrogen atoms of the ligands; with their negative (red) regions are the reactive sites for electrophilic attack [14-16,35]. On contrary, the negative (red) regions in complexes are mainly localized over the chlorine atoms.

3.7. In vitro cytotoxicity. In vitro cytotoxic activities of the three selected complexes (1, 3 and 4) were determined in aqueous solutions against the HepG-2 (liver carcinoma cell line), MCF-7 (human breast adenocarcinoma), HEp-2 (larynx carcinoma cell line), Hela (cervical carcinoma cell line) and HTC-116 (colon carcinoma cell line); Table 7. The IC50values of the tested complexes were deduced and compared with dioxorubicin as reference; Table 8. The complexes have good cytotoxicity with IC50 (M) against MCF-7 (0.0740), HEP-2 (0.0074-0.0082), and HepG-2 (0.0119-0.0144) cell lines. The complexes are promising antitumor candidates because of their high solubility in water which may ease their injection and/or may enhance the chance of oral administration trial.

4. Conclusion. The complexes (1-4) have distorted square planar geometry with N2-donor formamidine ligands and cis monodentate chlorine ligands. The distortion is indicated from the deviation of the Cl-PdCl, N-Pd-N angles from 90º. The values of the HOMO and LUMO energy orbitals of the complexes were negative which indicate that the complexes are stable. The complexes are 6

ACCEPTED MANUSCRIPT thermally stable as referred from their high overall activation energies (11.78-204.70 kJ mol-1). The good cytotoxicity of the complexes are indicated from their IC50 (M) against MCF-7 (0.0740), HEP-2 (0.0074-0.0082), and HepG-2 (0.0119-0.0144) cell lines. The complexes are promising antitumor candidates.

Acknowledgment The first author likes to thank Prof. Dr. Fahd Almuhanna, the Vice President of University of Imam Abdulrahman Alfaisal (X-Dammam University), Saudi Arabia for his continuous help and support to him during his work as consultant to the Vice Presidency.

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Scheme and Figures

N

N

N

HC N

N H

S (Z)-N'-(benzo[d]thiazol-2-yl)-N,N-dimethylformamidine (L1)

N

NH

N

N

N

(Z)-N,N-dimethyl-N'-(1H-1,2,4-triazol-3-yl)formamidine (L3)

N

N

(Z)-N'-(1H-benzo[d]imidazol-2- yl)-N,N- dimethylformamidine (L2)

NH

N

N H

N-(pyridin-2-yl)formamidine (L4)

Scheme 1. Structures of the ligands

1

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2916

1122

1627

0 20 40

304 120

60 80 100

165 120 4400

3900

3400

2900

2400

1900

1400

900

400

Fig. 1. The experimental and calculated IR spectra of [PdL1Cl2] complex (1).

2

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2.5

0.001 -0.001

Weight,mg

2

-0.002

DTG

1.5

-0.003 -0.004

DTG, mg/sec

0

-0.005

1

-0.006 -0.007

TG

0.5

-0.008 -0.009

0 0

100

200

300

400 500 600 700 Temperature C

800

900

-0.01 1000

Fig. 2. TG and DTG plot of [PdL1Cl2] complex (1).

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ACCEPTED MANUSCRIPT

Complex 1

Complex 2

Complex 3

Complex 4

Fig. 3. Optimized molecular structure and atomic charges of prepared Pd(II) formamidine complexes; Carbon (gray), Nitrogen (blue), Sulfur (yellow), Chlorine (green) and palladium (deep green). Hydrogen atoms are omitted for simplicity.

LUMO -0.127

E= -0.109

HOMO

-0.236

Fig. 4. The isodensity surface of [PdL1Cl2] complex (1) and energy splitting (isovalue 0.02).

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ACCEPTED MANUSCRIPT

Complex 1

Complex 2

Complex 3

Complex 4

Fig. 5. Molecular electronic potential (MEP) of Pd(II) formamidine complexes. (isocontour value=0.02). Hydrogen atoms are omitted for simplicity.

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ACCEPTED MANUSCRIPT

Tables

Table 1 The characteristic observed and calculated vibrational frequencies cm-1 for synthesized palladium(II) formamidine complexes. Complex

Obs.

[PdL1Cl2](1)

[PdL2Cl2] (2)

[PdL3Cl2] (3)

[PdL4Cl2].3/2H2O

(4)

1627 1122 2916 436 1635 1122 3463 2927 489 1635 1218 3413 2781 524 1627 1161 3420 3100 528

Calc. 1657 1202 3048 419 1674 1130 3234 3052 517 1723 1196 3385 3042 471 1651 1129 3515 3227 545

Relativ e error 1.84 7.13 4.52 -3.95 2.38 0.71 -6.61 4.27 5.72 5.38 -1.80 -0.82 9.38 -10.11 1.47 -2.75 2.77 4.09 3.12

Assignment υ(C=N) imin υ(C-N) υ(C-H) υ(M-N) υ(C=N) imin υ(C-N) υ(NH) υ(C-H) υ(M-N) υ(C=N) imin υ(C-N) υ(NH) υ(C-H) υ(M-N) υ(C=N) imin υ(C-N) υ(NH) υ(C-H) υ(M-N)

Relative error = {(calc –exp)/exp} x 100.

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ACCEPTED MANUSCRIPT Table 2 Mass fragments data of synthesized palladium(II) formamidine complexes complex

Molar mass

[PdL1Cl2](1)

382.61

385, 205, 189, 177, 163 Pd isotopes 104, 105, 106, 107, 108.

[PdL2Cl2] (2)

395.56

366, 358, 205, 188, 173, 144, Pd isotopes 104, 105, 106, 107, 108, 109

[PdL3Cl2] (3)

316.48

316, 300, 285, 272, 236, 140, Pd isotopes 106, 107, 108, 110

[PdL4Cl2].3/2H2O(4)

325.49

Important mass fragmentations (m/z) values

325, 312, 295, 259, 122, Pd isotopes 106, 107, 108, 110

Table 3 Thermogravimetric decomposition of synthesized palladium(II) formamidine complexes. Complex

Molar mass

TG range (K)

DTA max(K)

382.61

438-622

564.68

Mass loss found (cal. %) 233.8

395.56

622-717 317-489

681.18 399.63

36.6 17.5

(C10H11N3S),1/ 2Cl2 Cl CH4

316.48

489-699 310-1272

641.94 717.88

231.8 201.7

C9H8N4Cl2 C5H11N5, Cl2

325.49

331-663

727.27

198.5

C8H11N3, Cl2

[PdL1Cl2](1) [PdL2Cl2] (2) [PdL3Cl2] (3) [PdL4Cl2].3/2H2O(4)

Removed species

Metallic residue found (cal. %) Pd 29.3% (27.7% calc.) Pd 31.8% (28.9% calc.) PdO 39.7% (36.4% calc.) PdN2 39.2% (41% calc.)

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ACCEPTED MANUSCRIPT Table 4 Thermodynamic data of the thermal decompositions of synthesized palladium(II) formamidine complexes Complex

Decomposition temperature (K)

438-622 [PdL1Cl2](1)

622-717

∆E/ KJ mol-1 98.5 106.2

R2

0.98 0.73

204.70

[PdL2Cl2](2)

317-489 489-699

∆S/ J K-1 mol-1

∆H/ KJ mol-1

∆G/ KJ mol-1

-87.3

93.8

143.1

-64.1

100.5

144.2

-151.4

194.3

287.3

15.58

0.84

-230.34

12.26

104.32

77.74

0.98

-145.78

72.4

95.21

-376.12

84.66

199.53

93.32

[PdL3Cl2] (3)

310-1272

11.78

0.59

-279.63

2.21

202.95

[PdL4Cl2].H2O (4)

331-663

34.97

0.89

-231.66

28.55

207.45

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ACCEPTED MANUSCRIPT Table 5 Equilibrium geometric parameters bond lengths (Å), bond angles (°) and dihedral angles (°) of optimized synthesized palladium(II) complexes by using DFT/B3LYP/SDD set basis. [PdL1Cl2] (1) Pd(15)-Cl(16) Pd(15)-Cl(17) Pd(15)-N(7) Pd(15)-N(12)

[PdL2Cl2] (2) Pd(14)-Cl(15) Pd(14)-Cl(16) Pd(14)-N(7) Pd(14)-N(11)

[PdL3Cl2] (3) Pd(11)-Cl(12) Pd(11)-Cl(13) Pd(11)-N(5) Pd(11)-N(8)

[PdL4Cl2].3/2H2O(4) Pd(10)-Cl(11) Pd(10)-Cl(12) Pd(10)-N(5) Pd(10)-N(9)

Bond Lengths 2.365 2.361 2.129 2.107

o

A Cl(16)-Pd(15)-Cl(17) N(7)-Pd(15)-N(12) N(7)-Pd(15)-Cl(16) N(12)-Pd(15)-Cl(17) N(7)-Pd(15)-Cl(17) N(12)-Pd(15)-Cl(16)

Bond Angles o 89.05 85.51 92.84 92.73 177.64 174.20

2.365 2.368 2.100 2.248

Cl(15)-Pd(14)-Cl(16) N(7)-Pd(14)-N(11) N(7)-Pd(14)-Cl(15) N(11)-Pd(14)-Cl(16) N(7)-Pd(14)-Cl(16) N(11)-Pd(14)-Cl(15)

89.26 85.65 92.43 92.65 178.29 177.37

2.375 2.396 2.034 2.169

Cl(12)-Pd(11)-Cl(13) N(5)-Pd(11)-N(8) N(5)-Pd(11)-Cl(13) N(8)-Pd(11)-Cl(12) N(8)-Pd(11)-Cl(13) N(5)-Pd(11)-Cl(12)

91.96 89.69 87.82 90.51 177.52 179.78

2.378 2.389 2.131 2.009

Cl(11)-Pd(10)-Cl(12) N(5)-Pd(10)-N(9) N(5)-Pd(10)-Cl(12) N(9)-Pd(10)-Cl(11) N(5)-Pd(10)-Cl(11) N(9)-Pd(10)-Cl(12)

91.60 90.22 94.27 83.89 174.12 174.49

Table 6 Quantum chemical parameters forthe synthesized palladium(II) formamidine complexes Compound

[Pd(L1)Cl2] (1) [Pd(L2)Cl2] (2) [Pd(L3)Cl2] (3) [Pd(L4)Cl2].3/2H2O(4)

HOMO a.u -0.236 -0.226 -0.250 -0.223

LUMO a.u -0.127 -0.116 -0.114 -0.091

η 0.054 0.056 0.068 0.066

ΔE Electronic a.u energy a.u 0.109 -718.65 0.110 -763.92 0.136 -626.31 0.132 -553.79

D.M Debye 10.60 12.77 6.50 15.71

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ACCEPTED MANUSCRIPT

Table 7 Cytotoxicity activity of synthesized palladium(II) formamidine complexes. complexes

[Pd(L1)Cl2] [Pd( L2)Cl2] [Pd( L3)Cl2] [Pd( L4)Cl2]. 3/2H2O

HEPG-2 (liver carcinoma cell line) Inhibition% 74.88 71.58 66.33 63.49

HEP-2 (larynx carcinoma cell line) Inhibition% 75.07 76.07 68.23 65.96

HELA (cervical carcinoma cell line) Inhibition% 71.36 66.18 64.13 65.25

HCT-116 (colon carcinoma cell line) Inhibition% 66.80 73.04 64.91 65.58

MCF-7 (breast carcinoma cell line) Inhibition% 81.36 78.64 72.37 78.20

Table 8 IC50 values of synthesized palladium(II) formamidine complexes. Complex

IC50 µM MCF-7

HCT-116

HEP-2

HEPG-2

[Pd(L1)Cl2]

--

--

0.0082

--

[Pd(L2)Cl2]

--

--

0.0074

0.0144

[Pd(L4)Cl2]

0.0740

--

--

0.0119

(0.008)

(0.008)

(0.008)

Ref. (Doxorubicin) (0.008)

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