Synthesis, crystal structure and in vitro anticancer studies of two bis(8-quinolinolato-N,O)-platinum(II) complexes European Journal of Chemistry 10 (1) (2019) 37-44 European Journal of Chemistry View Journal Online View Article Online Synthesis, crystal structure and in vitro anticancer studies of two bis(8-quinolinolato-N,O)-platinum(II) complexes Hong Chen 1,2 and Mingguo Liu 2,* 1 Key Laboratory of Radiation Physics and Technology of Ministry of Education, Institute of Nuclear Science and Technology, Sichuan University, Chengdu 610064, P. R. China chenhong3041@126.com (H.C.) 2 Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002, P. R. China mgliu1966@163.com (M.L.) * Corresponding author at: Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002, P. R. China. Tel: +86.717.6395580 Fax: +86.717.6395580 e-mail: mgliu1966@163.com (M. Liu). 10.5155/eurjchem.10.1.37-44.1814 Received: 06 November 2018 Received in revised form: 15 December 2018 Accepted: 18 December 2018 Published online: 31 March 2019 Printed: 31 March 2019 Two bis(8-quinolinolato-N,O)-platinum(II) complexes, C18H12N2O2Pt (1) and C20H16N2O2Pt (2), were synthesized and characterized by FT-IR, elementary analysis and X-ray single crystal diffraction. Complex 1 crystallizes in monoclinic, space group P21/c with a = 9.3413(7), b = 10.3893(9), c = 14.8495(12) Å, β = 100.574(7)°, V = 1416.7(2) Å3. Complex 2 crystallizes in monoclinic, space group P21/n with a = 9.5115(11), b = 15.5692(18), c = 16.720(2) Å, β = 94.544(2)°, V = 2468.3(5) Å3. Intermolecular C-H···O hydrogen bonding interactions, as well as Pt···Pt and π-π stacking interactions, help to stabilize the crystal structures. The preliminary in vitro anticancer activity of complexes 1 and 2 and the corresponding ligands (L1 and L2) were investigated using human cervical (Hela) and hepatocellular carcinoma (Hep-G2) cancer cell lines. The platinum(II) complexes can greatly inhibit the cell proliferation and show stronger cytotoxic activities against the tested cancer cell lines than both ligands. DFT calculations Crystal structure Anticancer activity 8-Hydroxyquinoline Platinum(II) complexes 8-Hydroxy-2-methylquinoline Cite this: Eur. J. Chem. 2019, 10(1), 37-44 Journal website: www.eurjchem.com 1. Introduction The application of inorganic chemistry to medicine is a rapidly developing field, and novel therapeutic and diagnostic metal complexes are now having an impact on medical practice. Advances in bio-coordination chemistry are crucial for improving the design of compounds to reduce toxic side effects and understand their mechanisms of action [1-4]. Among this, platinum-based anticancer agents are a mainstay of clinical drugs for the treatment of various solid tumors such as genitourinary, colorectal, and non-small cell lung cancers [5-9]. The leading anticancer drug, cis-platin, has been used for more than three decades in standard chemotherapy regimens either as a single therapeutic modality or in combination with other cytotoxic agents or radiotherapy [10-12]. However, the chemotherapy is associated with severe side effects because of intrinsic or acquired resistance and toxicity [13,14], which has motivated the inorganic chemists to find more effective, less toxic, and target-specific metal-based anticancer drugs [15]. Over the last 40 years, thousands of platinum complexes have been prepared in the hope of finding new drugs with a more tolerable toxicological profile and higher efficacy [16]. These efforts have brought a series of drugs into clinical use, i.e. carboplatin, oxaliplatin, nedaplatin, lobaplatin, and heptaplatin (Figure 1), and about 10 other complexes are currently under clinical trials [17]. Inspired by the predecessor’s excellent work [18-25], our laboratory is engaged in the search of discovering new types of platinum-based compounds and other organic anticancer compounds, not only for providing better anticancer drugs but also for mitigating the drawbacks [26-28]. In this paper, we report in detail the synthesis, crystal structure and antitumor activity in vitro of two bis(8- quinolinolato-N,O)-platinum(II) complexes. 2. Experimental 2.1. Materials and apparatuses 8-Hydroxyquinoline, 2-methyl-8-hydroxyquinoline and mitomycin were purchased from Sigma-Aldrich and used as received without further purification. ABSTRACT RESEARCH ARTICLE KEYWORDS European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2019 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. http://dx.doi.org/10.5155/eurjchem.10.1.37-44.1814 http://dx.doi.org/10.5155/eurjchem.10.1.37-44.1814 https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.10.1.37-44.1814&domain=pdf&date_stamp=2019-03-31 http://www.eurjchem.com/ http://dx.doi.org/10.5155/eurjchem.10.1.37-44.1814 mailto:chenhong3041@126.com mailto:mgliu1966@163.com mailto:mgliu1966@163.com http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.10.1.37-44.1814&domain=pdf&date_stamp=2019-03-31� 38 Chen and Liu / European Journal of Chemistry 10 (1) (2019) 37-44 Pt H3N Cl H3N Cl Pt H3N H3N O O O O Pt O O O O NH2 NH2 O O Pt H3N H3N O O O Pt O O O NH2 NH2 Pt O O O H2 N N H2 O Cis-platin Carboplatin Heptaplatin Nedaplatin Lobaplatin Oxaliplatin Figure 1. The structure of six platinum-based anticancer drugs. N OH K2[PtCl4] Reflux N O N Pt O R R R Complex 1, R = H Complex 2, R = CH3 Scheme 1. Synthetic procedure for complexes 1 and 2. K2[PtCl4] was purchased from Alfa Aesar of 99.99% purity and the other starting materials were of analytical grade. Doubly distilled water was used to prepare the buffer solution. Dimethyl sulphoxide (DMSO) and cell culture reagents and media were purchased from Solarbio Beijing Ltd. FT-IR spectra were recorded on a PE-983 infrared spectrometer as KBr pellets with absorption in cm−1. Elemental analysis (C, H, N) were taken on a Vario EL III elemental analysis instrument. Single-crystal X-ray diffraction data were collected on a SuperNova, Single source at offset, EOS diffractometer or Bruker APEX−II CCD diffractometer equipped with a graphite- monochromatic MoKα radiation (λ = 0.71073 Å). 2.2. Synthesis Complexes 1 and 2 were synthesized according to the literature method reported by Scandola et al. [29,30], as depicted in Scheme 1. To an aqueous solution of K2[PtCl4] adjusted to ca pH = 10, two equimolar amounts of organic ligand (L1 or L2) were added and the solution heated to reflux for a few minutes. After cooling to room temperature, a dark- orange precipitate was deposited. This precipitate was recrystallized from dimethyl sulfoxide to give small red crystals of the title complexes. The filtrate of the reaction solution was allowed to stand for several days at room temperature to give more crystals. Then, the crystals were collected, washed with ethanol and dried in vacuum. Based on K2[PtCl4], the obtained yields of complexes 1 and 2 were 57 and 63%, respectively. The IR spectra of complex 1 revealed absorption bands at 1014 cm-1 may probably due to the C-O or C-N group. The IR spectra of complex 2 revealed absorption bands at 1572 and 1485 cm-1 may probably due to the C=C group. Bis(8-Quinolinolato-N,O)-platinum(II) (1): Color: Red. Yield: 57% based on K2[PtCl4]. M.p.: 287-289 °C. Anal. calcd. for C18H12N2O2Pt: C, 44.73; H, 2.50; N, 5.80. Found: C, 44.56; H, 2.46; N, 5.66 %. FT-IR (KBr, ν, cm−1): 2939 (w), 2893 (w), 1680 (vs), 1561 (vs), 1489 (s), 1456 (m), 1263 (m), 1127 (m), 1014 (s), 953 (m), 745 (s), 700 (m). Bis(2-Methylquinolin-8-olato)-platinum(II) (2): Color: Red. Yield: 63%, based on K2[PtCl4]. M.p.: 298-300 °C. Anal. calcd. for C20H16N2O2Pt: C, 46.97; H, 3.15; N, 5.48. Found: C, 46.83; H, 3.27; N, 5.69 %. FT-IR (KBr, ν, cm−1): 3106 (w), 2939 (w), 1710 (vs), 1572 (vs), 1485 (vs), 1465 (s), 1383 (m), 1214 (m), 1105 (s), 936 (s), 751 (s), 623 (m). 2.3. X-ray crystal structure determination of complexes 1 and 2 Crystals suitable for X-ray diffraction were obtained by successfully selection of a single crystal from mostly tiny twin crystals and polycrystalline powder. A red single crystal of complex 1 with dimensions of 0.31×0.23×0.12 mm was selected and mounted on the top of a glass fiber. The data were collected by a SuperNova, Single source at offset, EOS diffractometer equipped with a graphite-monochromatic MoKα (λ = 0.71073 Å) radiation using a ω scan mode in the range of 3.0 ≤ θ ≤ 26.4° (−11 ≤ h ≤ 10, −12 ≤ k ≤ 12, −18 ≤ l ≤18) at 200.15 K. A total of 6148 reflections were collected, of which 2881 were independent (Rint = 0.036) and 2198 were observed with I > 2σ(I). A red single crystal of complex 2 with dimensions of 0.22×0.20×0.18 mm was selected and mounted on the top of a glass fiber. The data were collected by a Bruker APEX-II CCD diffractometer equipped with a graphite- monochromatic MoKα (λ = 0.71073 Å) radiation using a ψ-ω scan mode in the range of 1.8 ≤ θ ≤ 26.4° (−9 ≤ h ≤ 11, −18 ≤ k ≤ 19, −20 ≤ l ≤20) at 296.15 K. A total of 14172 reflections were collected, of which 5025 were independent (Rint = 0.035) and 4153 were observed with I > 2σ(I). Using Olex2 [31], the two structures were solved with the ShelXS structure solution program using Patterson Methods and refined with the ShelXL refinement package using Least Squares minimization [32]. The non-hydrogen atoms were refined isotropically and all hydrogen atoms were positioned geometrically. For complex 1, the final R = 0.030, wR = 0.069 (w = 1/[σ2(Fo2) + (0.0225P)2], where P = (Fo2 + 2Fc 2)/3). (Δ/σ)max < 0.001, S = 1.030, (Δρ)max = 1.18 and (Δρ)min = −1.10 e/Å3. For complex 2, the final R = 0.031, wR = 0.107 (w = 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.1.37-44.1814 javascript:; Chen and Liu / European Journal of Chemistry 10 (1) (2019) 37-44 39 1/[σ2(Fo2) + (0.0623P)2], where P = (Fo2 + 2Fc 2)/3). (Δ/σ)max = 0.002, S = 1.130, (Δρ)max = 1.58 and (Δρ)min = −1.13 e/Å3. 2.4. Anticancer activity The anti-proliferative effects were tested by MTT assay [33-36] in human cervical cancer cells (Hela) and hepato- cellular carcinoma (Hep-G2). The cancer chemotherapeutic potential of mitomycin, Pt(II) complexes (1 and 2) and the corresponding ligands (L1 and L2) were evaluated according to an established procedure [37]. Hela and Hep-G2 were purchased from the ATCC (American Type Culture Collection). These two cells were grown in 1640 medium under aseptic conditions, supplemented with 100 U/cm3 penicillin and 100 μg/cm3 streptomycin containing 10% (v:v) fetal bovine serum. All cells were grown at 37 °C in a cell culture incubator in the presence of 5% CO2, relative humidity: 95%. According to the cell growth situation, the culture medium was exchanged every two days. When the cell grew well, MTT assay could be carried out. The logarithmic phases of Hela and Hep-G2 were seeded at a density of 5×104 cells/cm3 into sterile 96-well flat-bottomed plates (CORNING, USA), and the side holes were filled with aseptic PBS buffer. Then the cells were placed in a 37 °C incubator with 5% CO2. The test ligand (L1 and L2) and mitomycin were dissolved in RPMI 1640 medium with the concentration of 1000 μmol/L and filtrated to remove bacteria by 0.22 μm separate film. Complex 1 (60.00 mg) or complex 2 (60.00 mg) was added to DMSO (500 μL) and centrifuged after sufficient oscillation. The supernatant was got and the precipitation was weighed after drying, then the concentration was calculated using difference method. After that, the solution was diluted into 1000 μmol/L with RPMI 1640 medium, then filtrated to remove bacteria by 0.22 μm separate film. Positive drug cis-platin solution was prepared with sterile saline into 1000 μmol/L as the mother liquor, and then diluted into the required concentration with complete RPMI 1640 medium. In each hole of the 96-well flat-bottomed plates, the highest content of DMSO was 0.2% (v:v). The four test compounds, cis-platin and mitomycin were diluted to 100 μmol/L before spotting with complete medium RPMI 1640. At the same time, the blank wells (medium, DMSO) were set. Each assay compound was carried out by using four replicates, and each compound solution (100 μL) was added to the replicate wells in the concentration of 100 μmol/L. Hela and Hep-G2 were incubated for 48 h. After that, 20 μL of MTT (5 mg/mL) was added. Four hours later, the supernatant of 96-well plates was carefully blotted, and the DMSO (150 μL) was added to solve the formazan produced [38,39]. Colorimetry was performed at the wavelength of 570 nm. Each hole absorbance (OD value) was determined, and the cell inhibition rate was calculated by using OD value averaged by four replicates. At the same time, the half inhibitory concentration (IC50) was drawn. Experiment was repeated on at least three separate occasions. The survival rate is calculated as follows: Viability as control (%) = [ODadministration group – (ODcontrol – ODDMSO)] / ODcontrol ×100% (1) 2.5. Statistical analysis The data were expressed as means±standard deviations [40]. The significance of difference was evaluated with one- way ANOVA, followed by the Student-Newman-Keuls or Games-Howell test by SPSS 13.0 software [41]. p-Values less than 0.05 were considered to be statistically significant. 2.6. Electronic structures calculations The first-principles DFT calculations of five Pt(II) comp- lexes were done using the Vienna ab-initio simulation package (VASP 5.2.2) [42-44] performing a variational solution of the KohnSham equations in a plane-wave basis with energy cutoff of 300.0 eV. All atomic positions in the Pt(II) complexes were fully relaxed without symmetry restrictions in a fixed unit cell parameters using a conjugate-gradient algorithm. For modeling of complexes 1 and 2, the unit cell parameters used were taken from the single crystal X-ray diffraction measurements. The unit cell parameters of other Pt(II) complexes were obtained from the Cambridge Crystallo- graphic Data Centre via www.ccdc.cam.ac.uk/conts/ retrieving.html. Electron exchange correlation interactions were treated using the generalized gradient approximation (GGA) as parameterized by Perdew, Burke and Ernzerhof (PBE) [45]. The electron ion interactions were described using the projector-augmented-wave (PAW) method [46]. The number of 10 valence electrons for each Pt (5d96s1), 6 for O atom (2s22p4) and 5 for N atom (2s22p3) were treated explicitly and the remaining core electrons together with the nuclei were described by PAW pseudopotentials. To describe correctly the strong Coulomb repulsion (U) between the localized d electrons of Pt, the DFT + U approach, adding a Hubbard-like term to the effective potential was applied in all calculations as implemented in VASP package. In the present work, the approach described by Dudarev et al. [47] was applied, where an effective Hubbard parameter Ueff = U - J enters the Hamiltonian, with U and J being the Coulomb (of 4 eV) and exchange interaction parameter (of 1 eV), respectively. The density of states (DOS) of various Pt(II) complexes is shown in Figure 2. Band structure calculations for complexes 1 and 2 predicted gaps at the Fermi level of 1.63163 and 0.63302 eV, consistent with the magnitude and order of the experimental results. Band structure calculations for the other three Pt(II) complexes predicted gaps at the Fermi level of - 0.29988, 1.90544 and 1.85686 eV, respectively. 3. Results and discussion 3.1. Crystal structure of complexes 1 and 2 Crystals of complexes 1 and 2 that suitable for single- crystal X-ray structure determination were obtained by recrystallization in the mixed solvent of dimethyl sulfoxide and ethanol. Both of the organic ligands are in a trans geometry in the crystal structure of complexes 1 and 2. In the crystal structure of complex 1, the molecule is essentially planar with a maximum deviation of 0.0046 Å for the Pt atom. As for complex 2, the molecule is also essentially planar with a maximum deviation of -0.0071 Å for the Pt atom. Figure 3 and 4 show a perspective view of complexes 1 and 2 with atomic numbering. Figure 5 shows the fragment of the crystal packing structure in a unit cell. The crystallographic data, details of data collection and structure refinement parameters for complexes 1 and 2 are listed in Table 1. The hydrogen bond lengths and bond angles of complexes 1 and 2 are listed in Table 2. Although the crystal structure of complex 1 has been reported by Masako Kato et al. [48] and Chi-Ming Che et al. [49], the lattice parameters described in this work are really different from the literature values. Complex 1 crystallized in the P21/c space group of monoclinic system with V = 1416.7(2) Å3, while it’s P21/n with V = 703.0(3) Å3 in the literature report. It has a planar geometry with the molecules stacked in an inclined fashion with an interplanar spacing of 3.5111, 3.6042 and 3.6433 Å, revealing three kinds of weak intermolecular π−π stacking interactions [50] (Figure 5a and Table 3). The crystal structure display herringbone-like crystal packing arrangement, in which the molecules are held together in an edge-to-face orientation, and the intermolecular 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.1.37-44.1814 http://www.ccdc.cam.ac.uk/conts/%20retrieving.html http://www.ccdc.cam.ac.uk/conts/%20retrieving.html javascript:; javascript:; javascript:; javascript:; 40 Chen and Liu / European Journal of Chemistry 10 (1) (2019) 37-44 Figure 2. Density of states (DOS) for various Pt(II) complexes obtained by DFT calculation. The corresponding molecular structure and Fermi energy level were inserted in (a)-(e). Pt···Pt distance is 3.8695(4) Å. The Pt atoms are four- coordinated planar by the N and O atoms from two 8- hydroxyquinoline, and the length of Pt(1)−O(1) (2.023(4) Å) and Pt(1)−O(2) (2.021(4) Å) is very close to the normal Pt−O coordination bond (2.01 Å) [51]. The angel of N(1)−Pt(1)−N(2) and N(1)−Pt(1)−O(1) is 179.03 and 82.15(18)°, respectively. Other selected bond length and bond angles are listed in Table 4. Complex 2 crystallized in the P21/n space group of monoclinic system with V = 2468.3(5) Å3. The crystal structure of complex 2 determined in this work shows one and a half molecules in a dimeric form connected by weak inter- molecular C–H···O hydrogen bonding interactions. The packing structure of complex 2 adopts a brick-wall-type face-to-face coplanar molecular arrangement with an interplanar separation of 3.3451(4) Å, thereby revealing the presence of intermolecular Pt···Pt short contacts (Figure 5b). The distance of π−π stacking between two 2-methyl-8-hydroxyquinoline rings is 3.5405 and 3.6794 Å (Table 3). The distance between C(24) to the ring (Pt(1)−O(2)−C(19)−C(20)−N(2)) is 3.8615 Å, suggesting the existence of weak C–H···π stacking interactions. The length of Pt(1)−O(1) (2.016(5) Å) and Pt(2)−O(2) (2.015(5) Å) is very close to the normal Pt−O coordination bond (2.01 Å). The angel of N(1)−Pt(1)−N(2) and N(1)−Pt(1)−O(1) is 178.4(2) and 81.8(2)°, respectively. In each of the asymmetric unit, the planes of two molecular form dihedral angles of 87.24°. 3.2. Effects of complexes 1 and 2 on the anticancer activity In this work, the anticancer effects of complexes 1 and 2, mitomycin and the ligands (L1 and L2) against two human cancer cells, cervical cancer (Hela) and carcinoma (Hep-G2), were investigated. Cell viability against drug concentrations was established, from which the IC50 values were calculated, and this allows a direct comparison of the cytotoxicity of the complexes. 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.1.37-44.1814 javascript:; Chen and Liu / European Journal of Chemistry 10 (1) (2019) 37-44 41 Table 1. Crystallographic data, details of data collection and structure refinement parameters for complexes 1 and 2. Complex 1 2 Empirical formula C18H12N2O2Pt 1.5(C20H16N2O2Pt) Formula weight (g.mol-1) 483.38 767.16 Crystal system Monoclinic Monoclinic Space group P21/c P21/n Morphology Block Block Size (mm) 0.31×0.23×0.12 0.22×0.20×0.18 a (Å) 9.3413(7) 9.5115(11) b (Å) 10.3893(9) 15.5692(18) c (Å) 14.8495(12) 16.720(2) α (o) 90.00 90.00 β (o) 100.574(7) 94.544(2) γ (o) 90.00 90.00 V (Å3) 1416.7(2) 2468.3(5) Z 4 4 T (K) 200 296 Dc (g.cm-3) 2.266 2.064 μ (mm-1) 9.916 8.543 F(000) 912.0 1464.0 Theta range for data collection (°) 1.7 ≤ θ ≤ 26.4 1.8 ≤ θ ≤ 26.4 h, k, lmax 11, 12, 18 11, 19 20 Reflections collected / unique 6148/2881 [Rint=0.036] 14172/5025 [Rint=0.035] Data/restraints/parameters 2881/0/208 5025/0/343 R indices (all data) R1=0.030, wR2=0.069 R1=0.031, wR2=0.107 Largest diff. peak and hole (e Å-3) 1.18 and -1.10 1.58 and -1.13 S (GOF on F2) 1.03 1.13 Table 2. Hydrogen bond lengths (Å) and bond angles (°) of complexes 1 and 2. Complex D−H···A d(D−H) d(H···A) d(D···A) ∠ D−H···A 1 C(7)−H(7)···O(1) i 0.95 2.54 3.302(8) 137 C(12)−H(12)···O2 ii 0.95 2.59 3.446(8) 150 2 C11−H(11C)···O1 0.96 1.97 2.755(9) 137 C1−H(1A)···O2 0.96 2.31 2.758(10) 107 Symmetry codes: (i) x, −y+1/2, z+1/2; (ii) −x+1, y+1/2, −z+1/2. Figure 3. ORTEP drawing of the complex 1 with atom numbering scheme. Thermal ellipsoids for non-hydrogen atoms are drawn at the 35% probability level and H atoms are shown as small sphere. Figure 4. ORTEP drawing of the complex 2 with atom numbering scheme. Thermal ellipsoids for non-hydrogen atoms are drawn at the 35% probability level and H atoms are shown as small sphere. 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.1.37-44.1814 42 Chen and Liu / European Journal of Chemistry 10 (1) (2019) 37-44 Table 3. π−π Stacking Interactions in the crystal of complexes 1 and 2 (Å, °). Complex Cg(I) ··· Cg(J) Symmetry code Cg−Cg (Å) Alpha (°) 1 Cg(4) [1]···Cg(4) 1−x, 1−y, −z 3.5111 0 Cg(5) [1]···Cg(3) −x, −y, −z 3.6042 0.048 Cg(5) [1]···Cg(5) −x, −y, −z 3.6433 0 2 Cg(4) [1]···Cg(12) 3/2−x, −1/2+y, 1/2−z 3.5405 1.397 Cg(3) [1]···Cg(12) 1/2+x, 1/2−y, 1/2+z 3.5696 4.472 Cg(6) [1]···Cg(11) 3/2−x, −1/2+y, 1/2−z 3.5686 1.491 Cg(11) [2]···Cg(5) −1/2+x, 1/2−y, −1/2+z 3.6275 3.157 Complex 1: Cg(3): N1−C8−C7−C6−C5−C9; Cg(4): N2−C17−C16−C15−C14−C13; Cg(5): C1−C2−C3−C4−C5−C9. Complex 2: Cg(3): N1−C2−C3−C4−C5−C10; Cg(4): N2−C12−C13−C14−C15−C20; Cg(5): C5−C6−C7−C8−C9−C10; Cg(6): C15−C16−C17−C18−C19−C20; Cg(11): N3−C22−C23−C24−C25−C30; Cg(12): C25−C26−C27−C28−C29−C30. Table 4. Selected bond lengths (Å) and bond angles (°) of complexes 1 and 2. Complex Atom−Atom Bond distance Atom−Atom Bond distance Atom−Atom−Atom Angle 1 Pt(1)−O(1) 2.021(4) Pt(1)−O(2) 2.024(4) O(1)−Pt(1)−O(2) 179.03(17) Pt(1)−N(1) 2.003(5) Pt(1)−N(2) 2.004(5) N(1)−Pt(1)−O(1) 82.51(18) O(1)−C(1) 1.320(7) O(2)−C(10) 1.324(7) N(1)−Pt(1)−O(2) 97.49(18) N(1)−C(8) 1.326(7) N(1)−C(9) 1.373(7) N(1)−Pt(1)−N(2) 179.6(2) N(2)−C(17) 1.316(8) N(2)−C(18) 1.371(7) N(2)−Pt(1)−O(1) 97.85(18) C(1)−C(2) 1.361(8) C(1)−C(9) 1.430(8) C(8)−N(1)−Pt(1) 128.7(4) C(2)−C(3) 1.405(9) C(3)−C(4) 1.379(9) C(8)−N(1)−C(9) 120.0(5) C(4)−C(5) 1.402(9) C(5)−C(6) 1.422(9) C(9)−N(1)−Pt(1) 111.3(4) C(5)−C(9) 1.417(9) C(6)−C(7) 1.361(9) C(17)−N(2)−C(18) 119.8(5) C(10)−C(11) 1.365(8) C(10)−C(18) 1.433(8) O(1)−C(1)−C(2) 125.7(6) 2 Pt(1)−O(1) 2.015(5) Pt(1)−O(2) 2.016(5) O(1)−Pt(1)−O(2) 177.9(2) Pt(1)−N(2) 2.051(5) Pt(10−N(1) 2.037(6) O(1)−Pt(1)−N(2) 98.4(2) Pt(2)−O(3) 2.007(5) Pt(2)−O(3) i 2.007(5) O(1)−Pt(1)−N(1) 81.9(2) Pt(2)−N(3) 2.051(6) Pt(2)−N(3) i 2.051(6) O(2)−Pt(1)−N(2) 81.8(2) O(1)−C(9) 1.314(9) O(2)−C(19) 1.326 (9) O(2)−Pt(1)−N(1) 97.8(2) O(3)−C(29) 1.331(9) N(2)−C(12) 1.304(9) N(1)−Pt(1)−N(2) 178.4(2) N(2)−C(20) 1.384(9) N(1)−C(2) 1.325(9) O(3) i−Pt(2)−O(3) 180.00(1) N(1)−C(10) 1.396(9) N(3)−C(22) 1.354(9) O(3) i−Pt(2)−N(3) 98.7(2) N(3)−C(30) 1.374(9) C(12)−C(11) 1.466(11) O(3) i−Pt(2)−N(3) i 81.3(2) C(5)−C(4) 1.391(13) C(5)−C(10) 1.386(10) O(3)−Pt(2)−N(3) i 98.7(2) Symmetry code: (i) −x+1, −y+1, −z+2. Figure 5. (a) Packing diagram of complex 1 in a unit cell viewed down the a direction. The dashed lines demonstrate the intermolecular C−H···O hydrogen bonding interactions; (b) Packing diagram of complex 2 in a unit cell viewed down the a direction. The dashed lines demonstrate the intermolecular Pt···Pt stacking and C−H···O hydrogen bonding interactions. The IC50 value for each complex is presented in Table 5. The ligands (L1 and L2) are capable of killing both cancer derived cell lines only at higher concentration with an IC50 value greater than 1000 μmol/L, thus are essentially inactive to inhibit cancer cells. When the ligands react with K2[PtCl4], the resulting complexex 1 and 2 exhibit much better anticancer activity for both the Hep-G2 and Hela cell lines. For inhibition of the Hep-G2 cell, the IC50 of complexes 1 and 2 is 63.95 and 91.75 μmol/L, respectively, much lower than the ligands. For inhibition of the Hela cells, the IC50 is 57.39 and 73.45 μmol/L, also better than that of the ligands. For both cancer cells, cisplatin or mitomycin has IC50 of about 10-20 μmol/L, showing very good inhibitory effect. The better anticancer effect of complexes 1 and 2 may be ascribed to the Pt(II) complex to have stronger DNA binding and cleavage and induce apoptosis in cancer cells [52-54]. However, further investigation on the anticancer mechanism is underway in our laboratory, and the ligand may be further improved for enhancing the anticancer activity of platinum complexes. 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.1.37-44.1814 Chen and Liu / European Journal of Chemistry 10 (1) (2019) 37-44 43 Table 5. IC50 Values (μmol/L) for compounds against Hela and Hep-G2 cells. Compound Toxicities (IC50, μmol/L) Hela (48 h) Hep-G2 (48 h) Cis-platin 11.73±0.99 12.97±0.98 Mitomycin 20.85±0.97 19.73±0.99 Ligand 1 1583.77±10.19 1949.28±7.53 Ligand 2 1375.75±10.73 1684.07±5.85 Complex 1 57.39±2.67 63.95±3.15 Complex 2 73.45±2.77 91.75±3.00 4. Conclusion The reported work is concerned with the synthesis, crystal structure and in vitro anticancer studies of two bis(8- quinolinolato-N,O)-platinum(II) complexes. Both C18H12 N2O2Pt (1) and C20H16N2O2Pt (2) crystallized in monoclinic crystal system. Intermolecular C–H···O hydrogen bonding interact- tions, as well as Pt···Pt and π−π stacking interactions, help to stabilize the crystal structures of complexes 1 and 2. The preliminary in vitro anticancer activity of complexes 1 and 2 and the corresponding ligands (L1 and L2) were investigated using human cervical (Hela) and hepatocellular carcinoma (Hep-G2) cancer cell lines. The platinum(II) complexes can greatly inhibit the cell proliferation and show stronger cytotoxic activities against the tested cancer cell lines than both ligands. Acknowledgements The authors acknowledge the Analytical & Testing Center of China Three Gorges University for CCD X-ray single crystal diffractometer work. The authors are also grateful to Dr. Daichuan Ma for help with the single crystal measurements. The authors would like to thank the Institute of Nuclear Science and Technology, Sichuan University for the first- principles DFT calculations of five Pt(II) complexes by using the Vienna ab-initio simulation package (VASP 5.2.2). The authors also thank Dr. Jianchun Wu, Dr. Yu Zou and Dr. Huan Wang for valuable discussions and for the help on the electronic structures calculations. Supporting information CCDC 1042740 and 1042741 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via https://www.ccdc.cam.ac.uk/ structures/, or by e-mailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223- 336033. Disclosure statement Conflict of interests: The authors declare that they have no conflict of interest. Author contributions: All authors contributed equally to this work. Ethical approval: All ethical guidelines have been adhered. Sample availability: Samples of the compounds are available from the author. ORCID Hong Chen http://orcid.org/0000-0002-8415-7333 Mingguo Liu http://orcid.org/0000-0003-2686-3034 References [1]. Shi, X. C.; Chen, Z. Y.; Wang, Y. J.; Guo, Z. J.; Wang, X. Y. Dalton Trans. 2018, 47, 5049-5054. [2]. Hannon, M. J. Chem. Soc. Rev. 2007, 36, 280-295. [3]. Dyson, P. J.; Sava, G. Dalton Trans. 2006, 1929-1933. [4]. Guo, Z. J.; Sadler, P. J. Adv. Inorg. Chem. 2000, 49, 183-306. [5]. Zhang, S. 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Janiak, C. J. Chem. Soc., Dalton Trans. 2000, 3885-3896. [51]. Orpen, A. G.; Brammer, L.; Allen, F. H.; Kennard, O.; Watson, D. G.; Taylor, R. J. Chem. Soc. Dalton Trans. II 1989, S1-S83. [52]. Wong, E.; Giandomenico, C. M. Chem. Rev. 1999, 99, 2451-2466. [53]. Jamieson, E. R.; Lippard, S. J. Chem. Rev. 1999, 99, 2467-2498. [54]. Qin, Q. P.; Chen, Z. F.; Qin, J. L.; He, X. J.; Li, Y. L.; Liu, Y. C.; Huang, K. B.; Liang, H. Eur. J. Med. Chem., 2015, 92, 302-313. Copyright © 2019 by Authors. This work is published and licensed by Atlanta Publishing House LLC, Atlanta, GA, USA. The full terms of this license are available at http://www.eurjchem.com/index.php/eurjchem/pages/view/terms and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0). By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (http://www.eurjchem.com/index.php/eurjchem/pages/view/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.1.37-44.1814 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms http://creativecommons.org/licenses/by-nc/4.0 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms 1. Introduction 2. Experimental 2.1. Materials and apparatuses 2.2. Synthesis 2.3. X-ray crystal structure determination of complexes 1 and 2 2.4. Anticancer activity 2.5. Statistical analysis 2.6. Electronic structures calculations 3. Results and discussion 3.1. Crystal structure of complexes 1 and 2 3.2. Effects of complexes 1 and 2 on the anticancer activity 4. Conclusion Supporting information Disclosure statement ORCID PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField15: PrintField16: PrintField17: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: PrintField25: PrintField26: PrintField27: