English

• 1. INTRODUCTION

  Cancer is a serious threat to human life and health as one of the important causes of human disease death. In the process of clinical use, cisplatin^[1], a metal chemotherapy drug for early cancer treatment, has exposed some problems such as high toxicity and drug resistance. With further understanding of pharmacological action, many new metal compounds with anti-cancer activities have been synthesized^[2-4]. Dialkyltin compounds have been concerned due to their similar structures to cisplatin and better anticancer activities in vitro than cisplatin and other platinum drugs^{[5, 6]}. Researches show the biological activity of organotin compounds has been determined with the organic groups connected to tin atoms and the ligands coordinated with them^{[7, 8]}. Therefore, we can obtain metal anticancer compounds with different activities with different organic groups or ligands.

  Hydrazone is obtained by dehydration after nucleophilic addition reaction between hydrazine and aldehyde or ketone, and is a special class of Schiff base compounds with –CONHN=CH–. In addition, the groups are found such acyl, sub-amino and imide in the hydrazone compounds. The stability of these compounds is good because the unshared electron of nitrogen atom on sub-amino group can form p-π conjugation system with C=N groups of acyl group and imide. Furthermore, hydrazone compounds contain imino-nitrogen and carbonyl-oxygen atoms, as well as other coordination atoms with strong coordination ability, which can form stable compounds with transition metals, rare earth metals, major metals and nonmetals. Many experiments showed that the biological activity of acylhydrazone compounds was enhanced significantly compared with the corresponding ligands, and the compounds had extensive biological and drug activities^[9-11].

  Based on the previous researches, in the work, two new dibenzyltin compounds have been synthesized by the microwave "one pot" with benzoylhydrazine (or p-methyl benzhydrazine), phenylglyoxylic acid and di-m-chlorobenzyltin dichloride. The groups of aroyl hydrazone ligands to inhibit cancer cell activity have been investigated preliminarily, which lay a foundation for screening new organic-metallic compounds with high anticancer activity.

  2. EXPERIMENTAL

  2.1 Instruments and reagents

  Italian MILESTONE microwave synthesizer was employed for the compounds. IR spectra were recorded using the Shimadzu Prestige 21 infrared spectrometer in the range of 4000~400 cm^–1 (KBr pellets). ¹H, ¹³C and ¹¹⁹Sn NMR were measured by Bruker AVANCE-500 NMR. Elemental analysis was performed by the PE-2400(Ⅱ) element analyzer. H RMS was determined by the Thermo Scientific LTQ Orbitrap XL (ESI source). Melting point was measured by Beijing Tektronix X-4 binocular photomicrograph (thermometer not corrected). Thermogravimetric analyses were executed on a NETZSCH TG 209 F3 thermogravimetric analyzer.

  The di-m-chlorobenzyltin dichloride was obtained according the literature^[12]. Carboplatin was purchased from Balinway technologies Co. LTD. NCI-H460, HepG2 and MCF7 cells were obtained from the U.S. tissue culture library (ATCC). RPMI 1640 medium with 10% fetal bovine serum was purchased from GIBICO.

  2.2 Syntheses of the compounds

  The methanol solution (20.0 mL) of benzoylhydrazine (or p-methyl benzoylhydrazine, 1.0 mmol), phenylglyoxylic acid (1.0 mmol) and di-m-chlorobenzyltin dichloride (1.0 mmol) was added into 100.0 mL microwave reaction tank with microwave reaction for 30 min at 100 ℃, then the mixture was cooled to room temperature and filtered into a conical flask. The solvent was controlled for volatilezation into crystals 1, 2a and 2b.

  Crystal 1: The product was yellow crystal. Yield: 68%. m. p.: 108~110 ℃. Anal. Calcd. (C₃₀H₂₆Cl₂N₂O₄Sn): C, 53.93; H, 3.92; N, 4.19%. Found: C, 53.94; H, 3.92; N, 4.20%. FT-IR (KBr, cm^–1): 3489, 3057, 2961, 2941, 1618, 1593, 1566, 1493, 1479, 1435, 1425, 1391, 1317, 1287, 1252, 1173, 1155, 1088, 1070, 1020, 999, 866, 804, 781, 731, 712, 687, 631, 594, 577, 498, 476, 432. ¹H NMR (500 MHz, CDCl₃, δ/ppm): 7.97 (d, J = 7.3 Hz, 2H), 7.52~7.55 (m, 6H), 7.40~7.43 (m, 2H), 7.09 (s, 2H), 6.88 (s, 6H), 3.39 (s, 4H). ¹³C NMR (126 MHz, CDCl₃, δ/ppm): 176.06, 168.79, 147.38, 138.77, 134.35, 132.47, 132.31, 131.40, 130.98, 129.70, 129.19, 128.38, 128.31, 128.18, 127.47, 126.43, 125.72, 35.81. ¹¹⁹Sn NMR (Me₄Sn, 187 MHz, CDCl₃, δ/ppm): –638.95. H RMS (ESI) m/z calcd. for C₂₉H₂₃Cl₂N₂O₃Sn⁺ [M-CH₃OH+H]⁺ 637.01022, found 637.01093.

  Crystal 2a: The product was yellow crystal in the yield of 37%. m. p.: 144~146 ℃. Anal. Calcd. (C₃₁H₂₈Cl₂N₂O₄Sn): C, 54.58; H, 4.14; N, 4.11%. Found: C, 54.60; H, 4.16; N, 4.10%. FT-IR (KBr, cm^–1): 3462, 3049, 3011, 2938, 2828, 1624, 1609, 1595, 1584, 1570, 1476, 1427, 1393, 1306, 1281, 1250, 1177, 1155, 1090, 1078, 1063, 1018, 870, 806, 781, 745, 729, 691, 619, 594, 575, 471, 432. ¹H NMR (500 MHz, CDCl₃, δ/ppm): 7.86 (d, J = 7.9 Hz, 2H), 7.51~7.52 (m, 5H), 7.21 (d, J = 7.6 Hz, 2H), 7.09 (s, 2H), 6.84~6.89 (m, 6H), 3.40 (s, 4H), 2.43 (s, 3H). ¹³C NMR (126 MHz, CDCl₃, δ/ppm): 176.20, 169.51, 146.39, 143.09, 138.96, 134.23, 131.33, 130.75, 129.62, 129.29, 128.91, 128.57, 128.37, 128.17, 127.40, 126.45, 125.59, 36.57, 21.82. ¹¹⁹Sn NMR (Me₄Sn, 187 MHz, CDCl₃, δ/ppm): –637.74. HRMS (ESI) m/z calcd. for C₃₀H₂₅Cl₂N₂O₃Sn⁺ [M-CH₃OH+H]⁺ 651.02587, found 651.02594.

  Crystal 2b: The product was red-brown crystal in 35% yield. m.p.: 144~146 ℃. Anal. Calcd. (C₃₁H₂₈Cl₂N₂O₄Sn): C, 54.58; H, 4.14; N, 4.11%. Found: C, 54.55; H, 4.13; N, 4.12%. FT-IR (KBr, cm^–1): 3433, 3059, 3013, 2951, 1624, 1595, 1570, 1493, 1476, 1443, 1425, 1391, 1310, 1290, 1254, 1175, 1155, 1088, 1078, 1016, 866, 837, 804, 785, 746, 729, 692, 621, 594, 573, 488, 473, 434. ¹H NMR (500 MHz, CDCl₃, δ/ppm): 7.86 (d, J = 7.9 Hz, 2H), 7.50~7.54 (m, 5H), 7.21 (d, J = 7.6 Hz, 2H), 7.09 (s, 2H), 6.84~6.89 (m, 6H), 3.38 (s, 4H), 2.43 (s, 3H). H RMS (ESI) m/z calcd. for C₃₀H₂₅Cl₂N₂O₃Sn⁺ [M-CH₃OH+H]⁺ 651.02587, found 651.02661.

  2.3 Crystal structure determination

  The suitable samples (1: 0.23 × 0.21 × 0.21 mm³, 2a: 0.22 × 0.21 × 0.21 mm³ and 2b: 0.22 × 0.21 × 0.21 mm³) were chosen for crystallographic study and then mounted at the Bruker SMART APEX Ⅱ CCD single crystal diffractometer with graphite-monochromated Mo-Kα radiation (λ = 0.071073 nm) with a φ-ω scan mode. All the data were corrected by Lp factors and empirical absorbance. The structure was solved by direct methods. All non-hydrogen atoms were determined in successive difference Fourier synthesis, and all hydrogen atoms were added according to theoretical models. All hydrogen and non-hydrogen atoms were refined by their isotropic and anisotropic thermal parameters through full-matrix least-squares techniques. All calculations were completed by the SHELXTL-97 program^[13]. The selected bond lengths and bond angles for 1, 2a, 2b are listed in Tables 2, respectively.

  2.4 Thermogravimetry studies

  Thermogravimetric analyses were executed on a NETZSCH TG 209 F3 thermogravimetric analyzer with the heating speed at 20 ℃·min^–1 and gas flow rate of 20 mL·min^–1 in the air.

  2.5 Anticancer activity studies

  The drug was dissolved in a small amount of DMSO. The mixture was diluted with water to the required concentration, and maintain the final concentration of DMSO < 0.1%. NCI-H460, HepG2 and MCF7 cells were cultured in vitro using RPMI 1640 (GIBICO) culture medium containing 10% fetal bovine serum in a 5% (volume fraction) CO₂, 37 ℃ saturated humidity incubator. In vitro anticancer drug sensitivity test was determined by MTT assay. Graph Pad Prism version 7.0 program was used for data processing, and IC₅₀ was obtained by fitting the nonlinear regression model with S-shaped dose response in the program.

  3. RESULTS AND DISCUSSION

  3.1 Syntheses

  The synthetic routes of compounds are depicted in Fig. 1. As we know, the conventional synthesis methods of organotin compound include the reflux method, solvent-thermal and interfacial diffusion one^[14], while the first one is the most common. However, we adopted the microwave "one pot", which has the characteristics of short reaction time, simple reaction steps, easy purification and good reproducibility compared with traditional heating reflux method. Moreover, the yields of dibenzyltin compounds are around 70%, suggesting the yield of microwave methods is improved greatly^[15].

  Figure 1

  

  Figure 1.  Synthesis routes of the compounds

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  In addition, in the syntheses of 2, two kinds of crystals with different colors and shapes were precipitated at the same time. One is a yellow fine-block crystal (2a), and the other a red-brown rod-shaped crystal (2b), with their crystal morphology shown in Fig. 2. Two crystals were characterized by elemental analysis, IR, NMR, and X-ray single-crystal diffraction, showing their chemical compositions and molecular structures are the same, but the cell parameters were different, indicating 2a and 2b are homogeneous polycrystalline.

  Figure 2

  

  Figure 2.  Crystal appearance of 2a and 2b

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  3.2 Spectra analyses

  In the infrared spectra, the absorption bands at 3489 (1), 3462 (2a) and 3433 (2b) cm^–1 indicate the O–H stretching of coordinated methanol molecules. The peaks of 1566, 1570 and 1570 cm^–1 can be attributed to the C=N–N=C of acyl hydrazone^{[16, 17]}. The carboxylate group appeared at 1618 (1), 1624 (2a) and 1624 (2b) cm^–1 for the antisymmetric stretching vibration and 1391 (1), 1393 (2a) and 1391 (2b) cm^–1 for symmetric stretching vibration. Furthermore, the Δν values (Δν = ν_asym(COO^–) – ν_sym(COO^–)) are 227 (1), 231 (2a), 233 (2b) cm^–1 (2b), respectively, suggesting all Sn atoms of compounds coordinated the O atoms of carboxylic with a monodentate chelating modes^[18], which are consistent with their crystal structures. The characteristic peaks of Sn–O–Sn, Sn–O, Sn–N and Sn–C are located at 619~631, 573~577, 471~476 and 432~434 cm^–1, respectively, which are consistent with the peak locations of similar compounds reported in the literature^{[19, 20]}, indicating preliminarily that 1, 2a and 2b have similar structures.

  In ¹H NMR spectrum, the ratio of the integral area of each group of the three crystals is consistent with the number of protons in each group of the expected structure^[21]. Furthermore, it can be found the chemical displacements and peak shapes of all hydrogen protons in 2a and 2b remain the same, which further suggests 2a and 2b have the same asymmetric units. While the peak situation of hydrogen protons in 1 is similar to that of 2a and 2b, which speculated 1 has similar asymmetric unit structure to 2a and 2b.

  In the ¹³C NMR spectrum, the peak positions of carboxyl carbon, hydrazine carbon and imino carbon in compounds 1 and 2a are consistent, and the peaks of the remaining groups are consistent with the number of carbon atoms in the theoretical structure^[21]. Based on the ¹H NMR and ¹³C NMR spectra, it can be further inferred that the structures of 1 and 2a are similar, which is consistent with the X-ray single-crystal diffraction results.

  In ¹¹⁹Sn NMR spectrum, the single peak of tin atoms present at 638.95 and 637.74 ppm in 1 and 2a, respectively indicate 1 and 2a show only a class of tin, and their chemical shifts of the tin atoms are close. Therefore, tin atoms have similar chemical environments with similar structures.

  In HRMS spectrum, the mass peaks at m/z 637.01093 (1), 651.02594 (2a) and 651.02661 (2b) are attributed to the absorption peaks of [M– CH₃OH+H]⁺, indicating the weak Sn–O bonds will be broken in the solution state and present monomer structure in three crystals, which also further suggests 2a and 2b show similar structures in solution state.

  3.3 Description of the structure

  As shown in Table 1, compound 2 has different crystal systems. 2a crystallizes in the triclinic P$ \overline 1 $ space group while 2b is in monoclinic C2/c. Both compounds have the same molecular structures but different cell parameters. The asymmetry unit contains one tin atom, one hydrazine ligand, two m-Cl–C₆H₄CH₂ ligands and two methanol molecules. Each Sn atom is seven-coordinated by two oxygen atoms from the ligand, one amino nitrogen atom, one oxygen atom from the coordination methanol, two methylene carbon atoms from two di-m-chlorobenzyl groups, and O(2)^ⅰ from another ligand molecule, showing a pentagonal dipyramidal configuration (Fig. 3). The carboxyl oxygen atoms adopt μ³-bridging chelating modes to bind two tin atoms to form a four-membered ring Sn₂O₂ plane, whose center is the center of symmetry of the whole molecule. The bond lengths around Sn atoms are different: Sn(1)–O(2): 2.280(1) Å in 2a, Sn(1)–O(2): 2.298 (1) Å in 2b, which belong to the normal Sn–O covalent bond length; however the distances of Sn(1)–O(2)^ⅰ (2.818(1) Å (2a), i = 1–x, –y, –z) and Sn(1)–O(2)^ⅰ (2.763(1) Å (2b), i = 1–x, 1–y, 1–z) are larger than the covalent bond length of Sn–O, but smaller than the sum of van der waals radius of tin and oxygen atoms, which is consist with the similar compounds reported in literature^{[22, 23]}. The axial bond angles C(17)–Sn(1)–C(24) are 160.82(11)° (2a) and 161.57(8)° (2b), which are deviated from 180°, and the bond lengths and bond angles around Sn atom in the equatorial plane are not equal, which suggests the pentagonal bipyramidal configuration is distorted.

  Table 1

  

  Table 1.  Crystallographic Data of the Compounds

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  Compounds		1		2a		2b
  Empirical formula		C30H26Cl2N2O4Sn		C31H28Cl2N2O4Sn		C31H28Cl2N2O4Sn
  Mr		668.12		682.14		682.14
  Temperature/K		296(2)		296(2)		296(2)
  Crystal system		Triclinic		Triclinic		Monoclinic
  Space group		P$ \overline 1 $		P$ \overline 1 $		C2/c
  a/Å		9.5731(15)		8.0846(13)		33.4153(13)
  b/Å		11.0889(18)		13.129(2)		11.7891(5)
  c/Å		15.431(3)		15.013(2)		16.6328(7)
  α/°		95.938(2)		109.084(2)		90
  β/°		104.805(2)		92.354(2)		113.608(1)
  γ/°		110.500(2)		94.379(2)		90
  Volume/Å3		1449.4(4)		1497.9(4)		6003.9(4)
  Z		2		2		8
  Dc (mg/m3)		1.531		1.512		1.509
  Absorption coefficient/mm–1		1.103		1.069		1.067
  F(000)		672		688		2752
  Crystal size/mm		0.23 × 0.21 × 0.21		0.22 × 0.21 × 0.21		0.22 × 0.21 × 0.21
  θ range/°		2.36~25.10		2.52~ 25.09		1.85~25.10
  Limiting indices		–11≤h≤11, –13≤k≤13, –18≤l≤18		–9≤h≤9, –15≤k≤15, –17≤l≤17		–39≤h≤39, –14≤k≤≤9, –19≤l≤19
  Reflections collected/unique		14980/5141(Rint = 0.0191)		15471/5319 (Rint = 0.0144)		14916/5338 (Rint = 0.0140)
  Completeness		99.6%		99.7%		99.9%
  Max/min. transmission		0.8014, 0.7854		0.8066, 0.7988		0.8069, 0.7991
  Data/restraints/parameters		5141/40/357		5319/0/367		5338/0/367
  Goodness-of-fit on F2		1.032		1.038		1.050
  Final R indices (I > 2σ(I))		R = 0.0343, wR = 0.1015		R = 0.0260, wR = 0.0698		R = 0.0207, wR = 0.0501
  R indices (all data)		R = 0.0375, wR = 0.1042		R = 0.0278, wR = 0.0712		R = 0.0252, wR = 0.0523
  (Δρ)max (e·Å–3)		2.102		0.729		0.375
  (Δρ)min (e·Å–3)		–0.817		–0.952		–0.352

  Figure 3

  

  Figure 3.  Molecular structures of compounds (Symmetry codes: 1, ^ⅰ –x, –y, –z; 2a, ^ⅰ 1–x, –y, –z; 2b, ^ⅰ 1–x, 1–y, 1–z)

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  Compounds 1 and 2 have similar structural units, showing a distorted seven-coordinated pentagonal bipyramidal configuration with only little difference in bond parameters, which is consistent with the conclusion obtained by spectral characterization.

  3.4 Thermal stability

  Thermal analyses were performed for the synthesized compounds under an air atmosphere, as shown in Fig. 4. Three crystals exhibit similar weight loss processes with three stages. At the initial stage of 40~180 ℃, the weight loss of 1 was 5.1% (calcd. 4.8%), 2a was 4.9% (calcd. 4.7%) and 2b was 4.9% (calcd. 4.7%), which are attributed to the removal of methanol molecules. And further weight loss begins at 180 ℃, corresponding to the elimination of organic molecules by assuming a SnO₂ 21.0% (1, calcd. 22.4%), 21.1% (2a, calcd. 21.9%) and 21.8% (2b, calcd. 21.9%) phase as the final residue. As a result, three crystals are stable until 100 ℃, and 2a and 2b have the same weight loss processes and ratios, indicating they are homogeneous polycrystalline.

  Figure 4

  

  Figure 4.  TG-DTG curves of 1, 2a and 2b

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  3.5 Anticancer activity

  Table 3 lists the inhibitory activities of 1, 2a and 2b and carboplatin on the cultured cancer cells NCI-H460, HepG2 and MCF7 in vitro. It can be seen that the approximation IC₅₀ of 2a and 2b to three cancer cells indicates that different crystal systems have little influence on the activity of compounds. In addition, compared with IC₅₀, a conclusion can be drawn that the inhibitory activities of 1, 2a and 2b on NCI-H460 are similar with no significant difference, and are weaker than one of carboplatin. However, for HepG2 and MCF-7, the inhibitory activities of 2a and 2b were significantly better than that of 1, and even the one on MCF7 was better than that of carboplatin. Therefore, three crystals had certain inhibitory effects on the three cancer cells, and 2a and 2b are stronger than 1. Furthermore, combined with the structures of 1, 2a and 2b, they have similar structures, but only the aromatic ring of the hydrazone ligand is different. The aromatic ring of 1 is phenyl, while the aromatic ring of 2a and 2b is p-methyl phenyl, which indicates the different aromatic ring of ligand has also certain influence on the anticancer activity of the compound.

  Table 2

  

  Table 2.  Parts of the Bond Lengths (Å) and Bond Angles (°) of (1), (2a) and (2b)

  DownLoad: CSV

  1
  Bond	Dist.		Bond	Dist.		Bond	Dist.
  Sn(1)–C(16)	2.134(4)		Sn(1)–O(1)	2.136(2)		Sn(1)–C(23)	2.150(4)
  Sn(1)–N(2)	2.222(3)		Sn(1)–O(2)	2.277(2)		Sn(1)–O(4)	2.433(3)
  Sn(1)–O(2)ⅰ	2.837(2)
  Angle	(°)		Angle	(°)		Angle	(°)
  C(16)–Sn(1)–O(1)	94.02(12)		C(16)–Sn(1)–C(23)	161.91(15)		O(1)–Sn(1)–C(23)	94.74(13)
  C(16)–Sn(1)–N(2)	98.67(11)		O(1)–Sn(1)–N(2)	71.52(9)		C(23)–Sn(1)–N(2)	99.11(14)
  C(16)–Sn(1)–O(2)	92.92(12)		O(1)–Sn(1)–O(2)	142.18(9)		C(23)–Sn(1)–O(2)	89.83(13)
  N(2)–Sn(1)–O(2)	70.69(9)		C(16)–Sn(1)–O(4)	82.75(15)		O(1)–Sn(1)–O(4)	77.41(10)
  C(23)–Sn(1)–O(4)	83.76(17)		N(2)–Sn(1)–O(4)	148.92(10)		O(2)–Sn(1)–O(4)	140.39(9)
  O(2)–Sn(1)–O(2)ⅰ	66.27(2)		O(2)ⅰ–Sn(1)-C(16)	84.81(9)		O(2)ⅰ–Sn(1)–C(23)	79.95(11)
  O(2)ⅰ–Sn(1)–O(4)	74.1 (1)
  Symmetry code: ⅰ –x, –y, –z
  2a
  Bond	Dist.		Bond	Dist.		Bond	Dist.
  Sn(1)–O(1)	2.137(2)		Sn(1)–C(17)	2.138(3)		Sn(1)–C(24)	2.141(3)
  Sn(1)–N(2)	2.234(1)		Sn(1)–O(2)	2.280(1)		Sn(1)–O(4)	2.430(2)
  Sn(1)–O(2)ⅰ	2.818(1)
  Angle	(°)		Angle	(°)		Angle	(°)
  O(1)–Sn(1)–C(17)	93.96(9)		O(1)–Sn(1)–C(24)	97.56(9)		C(17)–Sn(1)–C(24)	160.82(11)
  O(1)–Sn(1)–N(2)	71.04(6)		C(17)–Sn(1)–N(2)	99.80(8)		C(24)–Sn(1)–N(2)	98.43(9)
  O(1)–Sn(1)–O(2)	141.48(6)		C(17)–Sn(1)–O(2)	89.75(9)		C(24)–Sn(1)–O(2)	90.72(9)
  N(2)–Sn(1)–O(2)	70.55(6)		O(1)–Sn(1)–O(4)	76.95(7)		C(17)–Sn(1)–O(4)	85.47(9)
  C(24)–Sn(1)–O(4)	82.27(10)		N(2)–Sn(1)–O(4)	147.81(7)		O(2)–Sn(1)–O(4)	141.57(6)
  O(2)–Sn(1)–O(2)ⅰ	65.071(51)		O(2)ⅰ–Sn(1)–C(17)	82.52(8)		O(2)ⅰ–Sn(1)–C(24)	80.31(8)
  O(2)ⅰ–Sn(1)–O(4)	76.495(63)
  Symmetry code: ⅰ 1–x, –y, –z
  2b
  Bond	Dist.		Bond	Dist.		Bond	Dist.
  Sn(1)–C(17)	2.137(2)		Sn(1)–O(1)	2.140(1)		Sn(1)–C(24)	2.144(2)
  Sn(1)–N(2)	2.2370(1)		Sn(1)–O(2)	2.2980(1)		Sn(1)–O(4)	2.461(2)
  Sn(1)–O(2)ⅰ	2.763(1)
  Angle	(°)		Angle	(°)		Angle	(°)
  C(17)–Sn(1)–O(1)	94.92(7)		C(17)–Sn(1)–C(24)	161.57(8)		O(1)–Sn(1)–C(24)	95.51(7)
  C(17)–Sn(1)–N(2)	100.11(7)		O(1)–Sn(1)–N(2)	71.14(5)		C(24)–Sn(1)–N(2)	97.63(7)
  C(17)–Sn(1)–O(2)	89.07(6)		O(1)–Sn(1)–O(2)	141.54(5)		C(24)–Sn(1)–O(2)	92.16(7)
  N(2)–Sn(1)–O(2)	70.50(5)		C(17)–Sn(1)–O(4)	84.97(7)		O(1)–Sn(1)–O(4)	76.05(5)
  C(24)–Sn(1)–O(4)	82.86(8)		N(2)–Sn(1)–O(4)	147.09(6)		O(2)–Sn(1)–O(4)	142.38(5)
  O(2)–Sn(1)–O(2)ⅰ	64.59(5)		O(2)ⅰ–Sn(1)–C(17)	82.40(6)		O(2)ⅰ–Sn(1)–C(24)	81.54 (7)
  O(2)ⅰ–Sn(1)–O(4)	77.81(6)
  Symmetry code: ⅰ 1–x, 1–y, 1–z

  Table 3

  

  Table 3.  Inhibition Action of Compounds to Cancer Cell in Vitro

  DownLoad: CSV

  	IC50 / μM
  	NCI-H460	HepG2	MCF-7
  1	8.67 ± 0.10	10.20 ± 0.18	9.41 ± 0.22
  2a	9.19 ± 0.17	8.40 ± 0.20	6.82 ± 0.15
  2b	9.33 ± 0.10	8.28 ± 0.15	6.87 ± 0.08
  Carboplatin	7.26 ± 0.32	7.70 ± 0.25	8.22 ± 0.41

  4. CONCLUSION

  Two dibenzyltin compounds have been synthesized by the microwave "one pot" method. Compound 2 has two crystals of 2a and 2b with different colors and shapes. Three crystals contain four-membered ring Sn₂O₂ plane as the center of symmetry to construct a distorted pentagonal bipyramidal configuration. Three crystals can exist stably until 100 ℃. The in vitro inhibitory activity on cancer cells NCI-H460, HepG2 and MCF7 showed the inhibitory activity of 2a and 2b is the same, and three crystals have obvious inhibitory effect on the three cancer cells, and the inhibitory effects of 2a and 2b are better than that of 1.

  
  
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  Figure 1  Synthesis routes of the compounds

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  Figure 2  Crystal appearance of 2a and 2b

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  Figure 3  Molecular structures of compounds (Symmetry codes: 1, ^ⅰ –x, –y, –z; 2a, ^ⅰ 1–x, –y, –z; 2b, ^ⅰ 1–x, 1–y, 1–z)

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  Figure 4  TG-DTG curves of 1, 2a and 2b

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  Table 1.  Crystallographic Data of the Compounds

  Compounds		1		2a		2b
  Empirical formula		C30H26Cl2N2O4Sn		C31H28Cl2N2O4Sn		C31H28Cl2N2O4Sn
  Mr		668.12		682.14		682.14
  Temperature/K		296(2)		296(2)		296(2)
  Crystal system		Triclinic		Triclinic		Monoclinic
  Space group		P$ \overline 1 $		P$ \overline 1 $		C2/c
  a/Å		9.5731(15)		8.0846(13)		33.4153(13)
  b/Å		11.0889(18)		13.129(2)		11.7891(5)
  c/Å		15.431(3)		15.013(2)		16.6328(7)
  α/°		95.938(2)		109.084(2)		90
  β/°		104.805(2)		92.354(2)		113.608(1)
  γ/°		110.500(2)		94.379(2)		90
  Volume/Å3		1449.4(4)		1497.9(4)		6003.9(4)
  Z		2		2		8
  Dc (mg/m3)		1.531		1.512		1.509
  Absorption coefficient/mm–1		1.103		1.069		1.067
  F(000)		672		688		2752
  Crystal size/mm		0.23 × 0.21 × 0.21		0.22 × 0.21 × 0.21		0.22 × 0.21 × 0.21
  θ range/°		2.36~25.10		2.52~ 25.09		1.85~25.10
  Limiting indices		–11≤h≤11, –13≤k≤13, –18≤l≤18		–9≤h≤9, –15≤k≤15, –17≤l≤17		–39≤h≤39, –14≤k≤≤9, –19≤l≤19
  Reflections collected/unique		14980/5141(Rint = 0.0191)		15471/5319 (Rint = 0.0144)		14916/5338 (Rint = 0.0140)
  Completeness		99.6%		99.7%		99.9%
  Max/min. transmission		0.8014, 0.7854		0.8066, 0.7988		0.8069, 0.7991
  Data/restraints/parameters		5141/40/357		5319/0/367		5338/0/367
  Goodness-of-fit on F2		1.032		1.038		1.050
  Final R indices (I > 2σ(I))		R = 0.0343, wR = 0.1015		R = 0.0260, wR = 0.0698		R = 0.0207, wR = 0.0501
  R indices (all data)		R = 0.0375, wR = 0.1042		R = 0.0278, wR = 0.0712		R = 0.0252, wR = 0.0523
  (Δρ)max (e·Å–3)		2.102		0.729		0.375
  (Δρ)min (e·Å–3)		–0.817		–0.952		–0.352

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  Table 2.  Parts of the Bond Lengths (Å) and Bond Angles (°) of (1), (2a) and (2b)

  1
  Bond	Dist.		Bond	Dist.		Bond	Dist.
  Sn(1)–C(16)	2.134(4)		Sn(1)–O(1)	2.136(2)		Sn(1)–C(23)	2.150(4)
  Sn(1)–N(2)	2.222(3)		Sn(1)–O(2)	2.277(2)		Sn(1)–O(4)	2.433(3)
  Sn(1)–O(2)ⅰ	2.837(2)
  Angle	(°)		Angle	(°)		Angle	(°)
  C(16)–Sn(1)–O(1)	94.02(12)		C(16)–Sn(1)–C(23)	161.91(15)		O(1)–Sn(1)–C(23)	94.74(13)
  C(16)–Sn(1)–N(2)	98.67(11)		O(1)–Sn(1)–N(2)	71.52(9)		C(23)–Sn(1)–N(2)	99.11(14)
  C(16)–Sn(1)–O(2)	92.92(12)		O(1)–Sn(1)–O(2)	142.18(9)		C(23)–Sn(1)–O(2)	89.83(13)
  N(2)–Sn(1)–O(2)	70.69(9)		C(16)–Sn(1)–O(4)	82.75(15)		O(1)–Sn(1)–O(4)	77.41(10)
  C(23)–Sn(1)–O(4)	83.76(17)		N(2)–Sn(1)–O(4)	148.92(10)		O(2)–Sn(1)–O(4)	140.39(9)
  O(2)–Sn(1)–O(2)ⅰ	66.27(2)		O(2)ⅰ–Sn(1)-C(16)	84.81(9)		O(2)ⅰ–Sn(1)–C(23)	79.95(11)
  O(2)ⅰ–Sn(1)–O(4)	74.1 (1)
  Symmetry code: ⅰ –x, –y, –z
  2a
  Bond	Dist.		Bond	Dist.		Bond	Dist.
  Sn(1)–O(1)	2.137(2)		Sn(1)–C(17)	2.138(3)		Sn(1)–C(24)	2.141(3)
  Sn(1)–N(2)	2.234(1)		Sn(1)–O(2)	2.280(1)		Sn(1)–O(4)	2.430(2)
  Sn(1)–O(2)ⅰ	2.818(1)
  Angle	(°)		Angle	(°)		Angle	(°)
  O(1)–Sn(1)–C(17)	93.96(9)		O(1)–Sn(1)–C(24)	97.56(9)		C(17)–Sn(1)–C(24)	160.82(11)
  O(1)–Sn(1)–N(2)	71.04(6)		C(17)–Sn(1)–N(2)	99.80(8)		C(24)–Sn(1)–N(2)	98.43(9)
  O(1)–Sn(1)–O(2)	141.48(6)		C(17)–Sn(1)–O(2)	89.75(9)		C(24)–Sn(1)–O(2)	90.72(9)
  N(2)–Sn(1)–O(2)	70.55(6)		O(1)–Sn(1)–O(4)	76.95(7)		C(17)–Sn(1)–O(4)	85.47(9)
  C(24)–Sn(1)–O(4)	82.27(10)		N(2)–Sn(1)–O(4)	147.81(7)		O(2)–Sn(1)–O(4)	141.57(6)
  O(2)–Sn(1)–O(2)ⅰ	65.071(51)		O(2)ⅰ–Sn(1)–C(17)	82.52(8)		O(2)ⅰ–Sn(1)–C(24)	80.31(8)
  O(2)ⅰ–Sn(1)–O(4)	76.495(63)
  Symmetry code: ⅰ 1–x, –y, –z
  2b
  Bond	Dist.		Bond	Dist.		Bond	Dist.
  Sn(1)–C(17)	2.137(2)		Sn(1)–O(1)	2.140(1)		Sn(1)–C(24)	2.144(2)
  Sn(1)–N(2)	2.2370(1)		Sn(1)–O(2)	2.2980(1)		Sn(1)–O(4)	2.461(2)
  Sn(1)–O(2)ⅰ	2.763(1)
  Angle	(°)		Angle	(°)		Angle	(°)
  C(17)–Sn(1)–O(1)	94.92(7)		C(17)–Sn(1)–C(24)	161.57(8)		O(1)–Sn(1)–C(24)	95.51(7)
  C(17)–Sn(1)–N(2)	100.11(7)		O(1)–Sn(1)–N(2)	71.14(5)		C(24)–Sn(1)–N(2)	97.63(7)
  C(17)–Sn(1)–O(2)	89.07(6)		O(1)–Sn(1)–O(2)	141.54(5)		C(24)–Sn(1)–O(2)	92.16(7)
  N(2)–Sn(1)–O(2)	70.50(5)		C(17)–Sn(1)–O(4)	84.97(7)		O(1)–Sn(1)–O(4)	76.05(5)
  C(24)–Sn(1)–O(4)	82.86(8)		N(2)–Sn(1)–O(4)	147.09(6)		O(2)–Sn(1)–O(4)	142.38(5)
  O(2)–Sn(1)–O(2)ⅰ	64.59(5)		O(2)ⅰ–Sn(1)–C(17)	82.40(6)		O(2)ⅰ–Sn(1)–C(24)	81.54 (7)
  O(2)ⅰ–Sn(1)–O(4)	77.81(6)
  Symmetry code: ⅰ 1–x, 1–y, 1–z

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  Table 3.  Inhibition Action of Compounds to Cancer Cell in Vitro

  	IC50 / μM
  	NCI-H460	HepG2	MCF-7
  1	8.67 ± 0.10	10.20 ± 0.18	9.41 ± 0.22
  2a	9.19 ± 0.17	8.40 ± 0.20	6.82 ± 0.15
  2b	9.33 ± 0.10	8.28 ± 0.15	6.87 ± 0.08
  Carboplatin	7.26 ± 0.32	7.70 ± 0.25	8.22 ± 0.41

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