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Two novel Mg(II)-based and Zn(II)-based complexes: inhibiting growth of human liver cancer cells.

Introduction

Cancer is presently responsible for about 25% of deaths in developed countries and for 15% of all deaths worldwide (1). It is therefore considered one of the foremost health problems, with about 1.45 million new cancer cases expected yearly (2,3). Antitumor chemotherapy is a very active field of research, and a large amount of information on the topic is generated every year (4,5). However, there is a clear need for new treatments, from the medicinal chemistry and drug design point of view (6).

In recent years, aromatic multi-carboxylate acid compounds have been widely used as versatile ligands involved in various metal chelation reactions to form transition metal complexes with interesting properties in material sciences and biological systems (7,8). These complexes can be easily synthesized from simple starting materials, where the metal ions, ligands, and coordination modes are the important factors for the self-assembly processes (9,10). 1,3,5-benzenetrisbenzoic acid is a versatile ligand, which acts as monodentate or bridging group with end-on or end-to-end coordination mode to form complexes with interesting structures.

In this work, two new kgd-type 2D bilayer and pillarlayered coordination polymers, namely {[[Mg.sub.3](BTB)[(DMA).sub.4]] [(DMA).sub.2]}n (1) and [{[([H.sub.2]N[Me.sub.2]).sub.2] [[Zn.sub.3][(BTB).sub.2](OH)(Im)][(DMF).sub.9] [(MeOH).sub.7]}.sub.n] (2), were obtained (Figure 1) and their anticancer activity was evaluated.

Material and Methods

Apparatus and materials

All starting materials and reagents used in this research were obtained commercially and used without further purification. To obtain infra-red (IR) spectra (400~4000 [cm.sup.-1]), we used a Brucker Equinox-55 spectrophotometer (Bruker, Germany). Element analyses (C, H, and N) were determined with a Vairo EL III analyzer (Elementar, Germany). Single crystal X-ray diffraction was carried out by an Oxford Xcalibur E diffractometer (Bruker Optics, Germany). A XT-4 micro melting apparatus (Ledon, China) was used to determine the melting points, and the thermometer remained uncorrected.

Synthesis and characterization of complexes 1 and 2

A mixture of Mg[(N[O.sup.3]).sub.2] x 6[H.sub.2]O (25.6 mg, 0.1 mmol), [H.sub.3]BTB (24.3 mg, 0.05 mmol), and DMA/[H.sub.2]O/C[H.sub.3]CN (V/V/ V = 2/1/1, 5 mL) was sealed in a Teflon-lined stainless-steel vessel (20 mL), and heated to 120[degrees]C in 12 h, kept at 120[degrees]C for 3 days then slowly cooled to room temperature in 24 h. The colorless block crystals were collected, washed with DMF, and air dried. Details are as follows: Yield: 25.3 mg, 36% (based on [H.sub.3]BTB ligand). Mp. >300[degrees]C. IR (KBr pellets) [cm.sup.-1]: 3440 (w), 2933 (w), 2433 (w), 1652 (w), 1103 (w), 930 (s), 810 (w), 682 (w), 597 (m).

Elemental analysis for the framework of 1 ([C.sub.51][H.sub.69][Mg.sub.3] [N.sub.6][O.sub.12]) was: C=59.23; H=6.44; N=8.2g%. Calculated: C=59.41; H=6.75; N=8.15%.

A mixture of Zn[(N[O.sub.3]).sub.2] x 6[H.sub.2]O (0.1 mmol, 0.031 g), [H.sub.3]BTB (10 mg, 2.2 mmol) and imidazole (4.65 mg, 6.6 mmol) was added to a solution of MeOH (1 mL), [H.sub.2]O (2 mL), and DMF (2.5 mL) in a 25 mL Teflon-lined stainless steel container. The container was heated at 120[degrees]C for 48 h, and then cooled to room temperature at 2[degrees]C/min. The resulting material, in the form of light yellow single crystals, was washed with MeOH and left to air dry. Details are as follows: Mp. >300[degrees]C. IR (KBr pellets) [cm.sup.-1]: 3134 (w), 2911 (w), 2410 (w), 1732 (w), 1143 (w), 976 (s), 808 (w), 689 (w), 590 (m). Analytical results found for compound 2 ([C.sub.137][H.sub.178][N.sub.21][O.sub.36][Zn.sub.6]) were: C=53.45; H=5.44; N=9.21%. Calculated: C=53.30; H=5.81; N=9.53%.

Crystal structure determination

Suitable single crystals of compounds 1 and 2 were carefully selected under optical microscope and glued on thin glass fibers. The intensity data of 1 and 2 was obtained on an Oxford Xcalibur E diffractometer. The empirical absorption corrections were applied to the data using the SADABS system. This structure was solved by direct method and refined by full-matrix least-squares method on [F.sup.2] using the SHELXS-97 program (11). All non-hydrogen atoms of 1 and 2 were refined anisotropically, and all the hydrogen atoms attached to carbon atoms were fixed at their ideal positions. Pertinent crystal data and structural refinement results for compounds 1 and 2 are summarized in Table 1.

Antitumor activity

Four human liver cancer cells (HB611, HHCC, BEL-7405 and SMMC-7721) were grown in a RPMI 1460 medium supplemented with 10% fetal calf serum, 100 [micro]g/mL penicillin and 100 [micro]g/mL streptomycin. Cells were incubated at the temperature of 37[degrees]C in a moist incubator with 95% air and 5% C[O.sub.2]. Cells at exponential growth were diluted to 5 x [10.sup.4] cells/mL with RPMI1640, and then seeded on 96-well plates at a volume of 100 [micro]L per well, and incubated for 24 h at 37[degrees]C in 5% C[O.sub.2]. After incubation of cells for up to 96 h, the medium was removed from each cell and 150 [micro]L of MTT (0.5 mg/mL) solution, diluted 10-fold by RPMI 1460 was subsequently added. The [IC.sub.50] values were measured by depicting the ratio viability versus concentration on a logarithmic chart and obtaining the concentration where 50% of cells were inhibited. In order to get mean values, each experiment was conducted at least three times in the same way.

Results and Discussion

Molecular structure

As shown in Figure 2A, the asymmetric unit of 1 contains two crystallographically independent Mg(II) with 1/2 (Mg1) and 1 (Mg2) occupancies, one [BTB.sup.3-] ligand, two coordinated DMA and one lattice DMA molecule.

Both Mg1 and Mg2 reveal similar six-coordinated octahedral geometries. Mg1 is located at an inversion center of (-1/2, 0, 1/2) and surrounded by six carboxylate O atoms from six different BTB ligands with the Mg-O lengths ranging from 2.021(2) to 2.037(2) [Angstrom]. Mg2 is coordinated by four carboxylate O atoms from three [BTB.sup.3-] ligands and two O atoms from two coordinated DMA molecules with the Mg-O lengths in the range of 2.031(2)-2.203(3) [Angstrom]. With the aid of a bridged carboxylate, two symmetry-related Mg2 ions and one Mg1 ion are held together to generate a [[Mg.sub.3][(COO).sub.6]] congregation (Figure 2B). Due to the restriction of the terminal solvent molecules of Mg2, only a discrete [[Mg.sub.3][(COO).sub.6]] subunit is achieved. These trimeric clusters are further extended by [BTB.sup.3-] ligands along the ab plane to give a 2D bilayer pattern (Figure 2C). The Mg2 *** Mg2 distance in the linearly arranged [Mg.sub.3] array is about 7.199 (2) [Angstrom], which is long enough to accommodate the bilayer network. These 2D bilayers adopt a parallel stacking arrangement to afford a 3D supramolecular architecture without classic H-bonding or pi-pi interaction. Topologically, the [Mg.sub.3] SBUs and BTB ligands can be regarded as 6-and 3-connected nodes, respectively, and afford a binodal (3,6)-connected kgd network with the point symbol of [{[4.sup.3]}.sub.2] {[4.sup.6] x [6.sup.6] x [8.sup.3]} (Figure 2D).

The structural analysis results indicate that compound 2 crystallizes in the monoclinic space group P[2.sub.1]/c, and shows a 2-fold interpenetrated network. The asymmetric unit of 2 consists of six Zn(II) ions, three [BTB.sup.3]-ligands, Ave deprotonated Im ligands, two coordinated DMF molecules, and two lattice disordered [H.sub.2]N[Me.sub.2] cations. The six Zn(II) ions exhibit two different coordinating modes (Figure 3A): Zn1, Zn2, Zn4 and Zn5 atoms are four-coordinated by three O atoms from three different carboxylic acid groups on the [BTB.sup.3-] ligands and one N atom from the deprotonated Im ligand, forming a distorted tetrahedral coordination mode; atoms Zn3 and Zn6 are five-connected by one(two) N atom(s) from the Im ligand(s) and three(two) O atoms from the carboxylic acid groups, resulting in a pyrometric geometry. Zn1-Zn6, Zn2-Zn3 and Zn4-Zn5 atoms are linked by the carboxylic groups to afford the binuclear Zn secondary building units (SBUs), which are joined by the Im pillars along the c axis to give rise to the 1D SBU chains (Figure 3B). In addition, the [BTB.sup.3-] ligand links with the binuclear Zn SBUs along bc plane to give the [6.sup.3] layer, and the Im ligands act as pillars between 2D sheets to form the three-dimensional (3D) framework. Due to its large solvent-accessible volume, such a framework might be large enough to accommodate another identical one to be interpenetrated, thus forming a doubly interpenetrated 3D framework with one-dimensional (1D) channel (Figure 3C). Notably, the 1D channels are decorated with Im groups, which might be favorable for the formation of a H-bond interaction. The calculated void space per unit cell for guest-free framework is 40% as revealed by the PLATON analysis [probe radius: 1.4 [Angstrom]]. From the topological point of view, the 3D structure of 2 can be rationalized as a 2-fold interpenetrated hms-type (3,5)-connected network by considering the [BTB.sup.3-] ligand, binuclear Zn unit and the Im pillar as a 3, 5 and 2-connected node. (Figure 3D).

Anticancer activity

The cytotoxicity of the title compounds 1 and 2, reference drug carboplatin, organic ligands H3BTB and Im against HB611, HHCC, BEL-7405 and SMMC-7721 cell lines were evaluated by MTT assay, and the IC50 values derived from the experimental data are shown in Table 2. The two organic ligands were ineffective against all cell lines ([IC.sub.50] >100 mM). At this concentration, [H.sub.3]BTB and Im would exert high cytotoxicity against normal cells, thus we conclude that it did not exert inactivation towards these cell lines.

However, after the cancer cells were incubated in the presence of compounds 1 and 2 for 72 h, the [IC.sub.50] values for the compound ranged from 20 to 35 [micro]M, which is similar or even lower than that of carboplatin (25-40 [micro]M), indicating that the title compounds 1 and 2 exhibited anticancer activity against these cell lines in different degrees.

According to the above-mentioned data, it can be concluded that compared with organic ligands [H.sub.3]BTB and Im, the anticancer activity of compounds 1 and 2 was more effective. However, additional studies are needed to define the mechanism underlying the antitumor activity of these compounds and evaluate their efficacy in vivo.

doi:10.1590/1414-431X20176929

Received July 18, 2017 | Accepted October 20, 2017

References

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(2.) Morsy SA, Farahat AA, Nasr MNA, Tantawy AS. Synthesis, molecular modeling and anticancer activity of new coumarin containing compounds. Saudi Pharm J 2017; 25: 873-883, doi: 10.1016/j.jsps.2017.02.003.

(3.) Wang Y, Wang Y, Wu AA, Zhang L, Hu Z, Huang H, et al. New 12,8-Eudesmanolides from Eutypella sp. 1-15. J Antibiot 2017; 70: 1029-1032, doi: 10.1038/ja.2017.89.

(4.) Zhang S, Guan J, Sun M, Zhang D, Zhang H, Sun B, et al. Self-delivering prodrug-nanoassemblies fabricated by disulfide bond bridged oleate prodrug of docetaxel for breast cancer therapy. Drug Deliv 2017; 24: 1460-1469, doi: 10.1080/10717544.2017.1381201.

(5.) Chi KQ, Wei ZY, Wang KS, Wu J, Chen WQ, Jin XJ, et al. Design, synthesis, and evaluation of novel ursolic acid derivatives as HIF-1[alpha] inhibitors withanticancer potential. Bioorg Chem 2017; 75: 157-169, doi: 10.1016/j.bioorg.2017.09.013.

(6.) Kowalski S, Hac S, Wyrzykowski D, Zauszkiewicz-Pawlak A, Inkielewicz-Stepniak I. Selective cytotoxicity of vanadium complexes on human pancreatic ductal adenocarcinoma cell line by inducing necroptosis, apoptosis and mitotic catastrophe process. Oncotarget 2017; 8: 60324-60341, doi: 10.18632/oncotarget.19454.

(7.) Chen J, Peng F, Zhang Y, Li B, She J, Jie X, et al. Synthesis, characterization, cellular uptake and apoptosis-inducing properties of two highly cytotoxic cyclometalated ruthenium (II) [beta]-carboline complexes. Eur J Med Chem 2017; 140: 104-117, doi: 10.1016/j.ejmech.2017.09.007.

(8.) Dandash F, Leger DY, Fidanzi-Dugas C, Nasri S, Bregier F, Granet R, et al. In vitro anticancer activity of new gold(III) porphyrin complexes in colon cancer cells. J Inorg Biochem 2017; 177: 27-38, doi: 10.1016/j.jinorgbio.2017.08.024.

(9.) Kaulage MH, Maji B, Pasadi S, Bhattacharya S, Muniyappa K. Novel ruthenium azo-quinoline complexes with enhanced photonuclease activity in humancancer cells. Eur J Med Chem 2017; 139: 1016-1029, doi: 10.1016/j.ejmech.2017. 08.059.

(10.) Qi J, Zheng Y, Qian K, Tian L, Zhang GX, Cheng Z, et al. Synthesis, crystal structure and antiproliferative mechanisms of 2-acetylpyridine-thiosemicarbazones Ga(III) with a greater selectivity against tumor cells. J Inorg Biochem 2017; 177: 110-117, doi: 10.1016/j.jinorgbio.2017.09.012.

(11.) Sheldrick GM. SHELXL-97, Program for crystal structure solution and refinement. University of Gottingen: Gottingen, Germany, 1997.

N. Liu [1], D. Ding [2], L. Wang [3], H. Zhao [4], L. Zhu [4] and X. Geng [4]

[1] Department of Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China

[2] Department of Physiology, Anhui Medical College, Hefei, Anhui, China

[3] Department of Physiology, Basic Medical College of Anhui Medical University, Hefei, Anhui, China

[4] Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China

Correspondence: X. Geng: <xiaoping_geng666@aliyun.com>

Caption: Figure 1. Schematic representation of the [H.sub.3]BTB and Im ligands used in this research.

Caption: Figure 2. A, View of the asymmetric unit of 1; B, view of the [[Mg.sub.3][(COO).sub.6]] subunit of 1 (symmetry code A: 2-X, 1-Y, 2-Z); C, view of the 2D bi-layered structure of 1 ; D, the binodal (3, 6)-connected kgd network for 1.

Caption: Figure 3. A, View of the coordination modes of Zn(II) ions in 2; B, view of 1D secondary building unit chains and the 3D pillared framework; C, view of the 2-fold interpenetrated 3D framework of 2; D, the hms-type (3,5)-connected topology for 2.
Table 1. Crystal data and structure refinements for compounds
1 and 2.

                                    1                 2

Formula                       [C.sub.19.50]      [C.sub.99]
                               [H.sub.21]        [H.sub.71]
                              [Mg.sub.0.75]      [N.sub.10]
                              [N.sub.1.50]       [O.sub.20]
                               [O.sub.4.5]       [Zn.sub.6]

Mr                               366.61            2112.87
Temperature/K                    293 (2)           293 (2)
Crystal system                 Monoclinic        Monoclinic
Space group                       P21/n             P21/c
a/[Angstrom]                   12.4947 (4)       24.3437 (8)
b/[Angstrom]                   25.7603 (9)       28.0222 (6)
c/[Angstrom]                   13.7797 (5)       19.8450 (4)
[alpha]/[omicron]                  90                90
[beta]/[omicron]               99.622 (3)        102.182 (3)
[gamma]/[omicron]                  90                90
V/[[Angstrom].sup.3]           4372.8 (3)        13232.7 (6)
Z                                   8                 4
[D,sub.calc]/g x                  1.114             1.061
  [cm.sup.-3]
[mu](Mo K[alpha])                 0.098             1.647
  /[mm.sup.-1]
6 range/[omicron]            2.999 to 24.999   3.594 to 73.853
Reflections collected             15554             52557
No. unique data [R(int)]      7224 [0.0347]    26073 [0.0249]
No. data with I [greater          4924              21300
  than or equal to]
  2[sigma](I)
[R.sup.1]                        0.0681            0.0430
[omega][R.sup.2](all data)       0.1939            0.1320
CCDC                             1561061           1561062

Table 2. Growth inhibitory effects of 1, 2, carboplatin,
[H.sub.3]BTB and Im on HB611, HHCC, BEL-7405 and SMMC-7721
cancer cells.

Compounds      [IC.sub.50] ([micro]M)

               HB611   HHCC   BEL-7405   SMMC-7721

[H.sub.3]BTB   >100    >100     >100       >100
Im             >100    >100     >100       >100
1               20      25       30         32
2               26      23       27         35
Carboplatin     25      30       25         40
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Title Annotation:Research Article
Author:Liu, N.; Ding, D.; Wang, L.; Zhao, H.; Zhu, L.; Geng, X.
Publication:Brazilian Journal of Medical and Biological Research
Article Type:Report
Date:Feb 1, 2018
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