English

• 1. INTRODUCTION

  Anxiety and insomnia refer to the difficulty in falling asleep and frequent awakening, waking up combined with dreams, difficulty in falling asleep after waking up, and feeling of fear after awakening in a dream^[1]. It is the most common type of insomnia in the clinic. Insomnia seriously affects the normal work and quality of patients' life^[2]. The dysfunction of insomnia patients is mainly characterized by mental and emotional problems, autonomic dysfunction and loss of attention^[3]. Sleep rhythm and mood regulation are regulated by neurotransmitters such as acetylcholine, serotonin, gamma-aminobutyric acid, and norepinephrine^[4]. Anxiety can cause and aggravate insomnia, which in turn can increase the degree of anxiety.

  Coordination polymers (CPs) are essentially polymeric structures achieved by the self-assembly process of the metal ion/ions with the organic ligand involving a coordination bond leading to diverse dimensionalities^[5-7]. They exhibit a hybrid nature of both the components (metal ion as well as organic ligand) involved in the relevant synthesis. CPs, in general, have attracted enormous attention because of their versatile applications in the areas of gas storage and sequestration, magnetism, sensing, catalysis, luminescence, nonlinear optics (NLO), proton conductivity, drug delivery, and biomedicine^[8-11]. The judicious selection of the ligand systems enables the fine-tuning of ligand induced properties of the resulting materials. The design and selection of organic linkers proved to be an efficient routine in the assembly of functional coordination polymers. Notably, the polycarboxylates and nitrogen heterocyclic compounds are two most selective candidates in building high-dimensional architectures for their strong coordination abilities and versatile bridging fashions. However, bifunctional organic ligands, which contain both polycarboxylate and triazole ring, were rarely reported, comparatively^[12-16]. Herein, a bifunctional bridging ligand combined with triazole and carboxylate groups, 5-(1H-1, 2, 4-triazol-1-yl)-1, 3-benzenedicarboxylic acid was used to target a new coordination polymer, a new coordination polymer, [Co₂(L)₂(H₂O)₂]_n·H₂O (1) constructed by hydrothermal condition reaction of Co(NO₃)₂·6H₂O and H₂L at the pH value of 5.6. The as-prepared complex 1 was characterized by elemental analysis, IR and single-crystal X-ray diffraction, which reveals that complex 1 displays an unusual 3D coordination network which exhibits an intriguing self-interpenetrating (3, 6)-connected topological net with the Schläfli symbol of (4.6²)₂(4².6⁹.8³.10). Furthermore, a green hand grinding technique has been implemented to reduce the particle size of complex 1 to generate nanoscale 1 (denoted as nano 1 hereafter) with spherical morphology. In biological functional study, the protective effect of the compound on the insomnia rat was evaluated. Firstly, the enzyme-linked immunosorbent assay (ELISA) was used to detect the content of serotonin, gamma-aminobutyric acid in the brain after compound treatment. The results indicated that the compound could obviously reduce the sympathetic excitability. Besides, the Rat sleep phase detection was determined by pentobarbital synergistic sleep experiment. Results revealed the compound significantly shortened the sleeping latency and extended sleep duration.

  2. EXPERIMENTAL

  2.1 Apparatus and materials

  All reagents and solvents were commercially available and used as received without further purification. Elemental analyses for C, H and N were performed on a CHN-O-Rapid analyzer or an Elementar Vario MICRO analyzer. IR spectra were recorded with a Thermo Scientific Nicolet 5700 FT-IR spectrophotometer with KBr pellets from 400~4000 cm^-1. The morphology of the as-prepared samples was obtained by a Hitachi S-4800 field-emission scanning electron microscope (FE-SEM).

  2.2 Synthesis and characterization of [Co₂(L)₂(H₂O)₂]_n·H₂O (1)

  Compound 1 was prepared by the hydrothermal reaction of Co(NO₃)₂·6H₂O (0.0297 g, 0.1 mmol), H₂L (0.0233 g, 0.1 mmol) and NaOH (0.08 g, 0.2 mmol) in distilled water (10 mL) and used with 0.5 mol·L⁻¹ HNO₃ aqueous solution to adjust the pH to 5.6 that was placed in a Teflon-lined stainless-steel vessel (25 mL), heated to 140 ℃ for 72 h and then cooled to room temperature at a rate of 5 ℃/h. The purple block crystals were obtained, washed with distilled water (5 mL), and dried in air to give 0.0128 g, yield 49.2% based on Co. Elemental anal. calcd for C₂₀H₁₈N₆O₁₃Co₂ (%): C, 35.95; H, 2.72; N, 12.58. Found: C, 35.66, H, 2.73, N, 12.42%.

  2.3 Crystal structure determination

  A green block-shaped single crystal of complex 1 (0.24mm × 0.21mm × 0.22mm) was placed on an APEX II CCD area detector equipped with a graphite-monochromatic MoKα radiation (λ = 0.71073 Å) at 293 (2) K. A total of 10160 reflections were collected for complex 1, of which 1933 (R_int = 0.0760) were independent in the φ-ω ranges of 1.947~25.047º, and 1291 observed reflections with I > 2σ(I) were employed for structure refinements.

  The empirical absorption corrections by SADABS were carried out. The structures were solved by direct methods with SHELXS-97 program and refined with SHELXL-97 by full-matrix least-squares techniques. The non-hydrogen atoms were refined anisotropically, and the hydrogen ones were determined with theoretical calculations. For complex 1, the final R = 0.0457, wR = 0.1286 (w = 1/[σ²(F_o²) + (0.1000P)² + 0.0000P], where P = (F_o² + 2F_c²)/3), (Δ/σ)_max = 0.001, S = 1.034, (Δρ)_max = 0.602 and (Δρ)_min = –0.440 e/ų. Complex 1 crystallizes in orthorhombic, space group Pbcn with a = 15.327(4), b = 6.821(2), c = 20.923(3) Å, V = 2187.5(9) ų, Z = 4, F(000) = 1280, D_c = 1.926 mg/m³ and μ = 1.597 mm^-1.

  2.4 ELISA assay

  40 mice used in this experiment were purchased from Model Animal Research Center of Nanjing University (Nanjing, China). All the animals were kept at 45% humidity and 20~25 ℃ temperature environment. All the experiments were approved by the Ethics Committee of the Affiliated Hospital of Nanjing University (Nanjing, China). The experimental animals used in this experiment were randomly divided into 3 groups: blank control group, model group, and compound treatment group. The latter two groups were injected with 120 mg/kg/d of chlorophenylalanine (PCPA) for 8 d to induce the insomnia model, followed by the compound treatment for 7 days. The sleep waves in mice were detected to assess the success of the model. The content of the brain of the rats was collected and the serotonin and gamma-aminobutyric acid in the brain was measured with ELISA detection kit. This preformation was conducted under the guidance of the manufactures' instructions, and repeated at least three times. The results were presented as mean ± SD.

  2.5 Rat sleep phase detection

  To explore the effect of synthetic compound on the sleeping latency and sleep duration of the rats after treatment, the pentobarbital synergistic sleep experiment was performed in this study. This experiment was performed according to the protocols with some modification. In brief, the rats were injected with 120 mg/kg/d of PCPA for 8 d to induce the insomnia model, followed by compound treatment for 7 days. Then, the pentobarbital was injected and the sleeping latency and sleep duration of the rats were observed and recorded. This study was carried out in triplicate and the data were showed as mean ± SD.

  3. RESULTS AND DISCUSSION

  3.1 Molecular structure

  The title complex 1 could be afforded by the reaction of Co(NO₃)₂·6H₂O, H₂L and NaOH in water with HNO₃ as the pH modulator. It should be noted that suitable pH value of the reaction surrounding plays a key role in forming the final targeted product. The structural solution and refinement results based on the single crystal data collected around room temperature shows that compound 1 crystallizes in the orthorhombic system with Pbcn space group and exhibits an interesting achiral self-interpenetrating 3D framework structure. The asymmetric unit of 1 contains one crystallo-graphically independent Co(II) ion, one L^2- anion, one coordinate water molecule and half lattice water molecule. As shown in Fig. 1a, Co(1) is surrounded by three oxygen atoms (O(1), O(2A) and O(3A)) from three different L^2- anions, one nitrogen atom (N(1)) of one L^2- anion and one coordinate water molecule (O(5)). The coordination geometry of Co(1) center can be described as a distorted trigonal bipyramid, the O(1), O(2A), O(5) atoms comprise of the equatorial plane and the O(3A), N(1) atoms occupy the axial positions (O(3A)– Co(1)–N(1) = 134.62(05)°). The Co–O bond lengths are in the range of 1.928(4) to 2.146(5) Å and the Co–N distance is 1.967(3) Å. In 1, the phenyl group of L^2- anion is twisted with respect to the adjacent triazolyl ring with a dihedral angle of 31.86°, which may be a crucial factor of the formation for the helices (Fig. 1b). In 1, the H₂L ligand is deprotonated to form L^2- anion. The L^2- anions adopting a μ₄-η¹: η¹: η¹: η¹ coordination mode bridging two Co(II) ions through one triazolyl and carboxylate group to form the left- and right-handed 21 helical chains with the pitch of 6.728 Å (Fig. 1c). Interestingly, arbitrary two different types of helical chains are shared by Co(II) cations and L^2- anions, generating an achiral 2D layer. Such 2D layers are further shared by Co(II) cations and L^2- anions to extend a 3D framework. Obviously, if each Co(II) ion and L^2- anion act as a 3-connected node, the complicated architecture of 1 is simplified to a 3-connected 3D utp topological network with the Schläfli symbol of 10³. Notably, the two same 3D frameworks are linked by the Co–O bonds of L^2- anions (μ₄-η¹: η¹: η¹: η¹) to form a self-interpenetrating 3D framework structure containing a binuclear Co unit (Co₂O₄) with the Co⋯Co distance of 4.728 Å. From the topological perspective, if each binuclear zinc unit (Co₂O₄) acts as a node, the complicated architecture of 1 is simplified to a non-interpenetrating (3, 6)-connected 3D scu topological network with the Schläfli symbol of (4.6²)₂(4².6⁹.8³.10). It is noteworthy that there are still voids although the self-inter-penetration happened (Fig. 1d). The effective free volume of 1 calculated by PLATON analysis is 5.9% (2206.7 ų per unit) filled by water molecules.

  Figure 1

  

  Figure 1.  (a) Coordination surrounding of the Co(II) ion in 1. (b) Coordination pattern for the L^2- ligand. (c) Left- and right-handed 21 helical chains in 1. (d) 2-Fold interpenetrated network of 1

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  3.2 Preparation of the nanostructure of 1

  Nano coordination complexes possess several advantageous features over the existing nanosystems. For example, their size, shape, and composition could be easily tuned via synthetic manipulations, highly porous and oriented structures for efficient loading properties, etc. Moreover, the nano coordination complexes are intrinsically biodegradable since the metal-ligand bonds are labile in nature and thus could be easily excreted from the system after its biofunction. In view of the following bioactivity test, it is necessary to prepare complex 1 in the nanoscale, which could facilitate the release of reagents to the whole body and is absorbed by the specific tissues by intravenous administration. Interestingly, for single crystals of 1 when subjected to a mechanical grinding in a mortar and pestle for about 30 min, crystalline nanoscale 1 (denoted as nano 1 hereafter) are obtained. The formation of nano 1 has been further confirmed by scanning electron microscopy (SEM) studies that are obtained by drop-casting a DMSO-dispersed solution of the nano 1 on a glass surface, which shows that nano 1 exhibits spherical morphology with the average size distribution around 200 nm (Fig. 2).

  Figure 2

  

  Figure 2.  SEM diagram for the nano 1

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  3.3 Compound reducing the serotonin and gamma-aminobutyric acid in the brain

  After the synthesis of the compound with total novel structure, its protective effect on the anxiety and insomnia was evaluated in rat model. Sleep rhythm and mood regulation are regulated by neurotransmitters such as acetylcholine, serotonin, gamma-aminobutyric acid, and norepinephrine.

  Thus, in this experiment, the content of the serotonin and gamma-aminobutyric acid in the brain was measured with ELISA detection kit. As the results shown in Fig. 3, we can see the level of the serotonin and gamma-aminobutyric acid in the model group was much higher than the normal group with p less than 0.001. However, after compound treatment, the increase of neurotransmitters was significantly reduced. This result indicated that the compound could reduce the sympathetic excitability.

  Figure 3

  

  Figure 3.  Reduced content of serotonin and gamma-aminobutyric acid in the brain. The rats were injected with 120 mg/kg/d of chlorophenylalanine (PCPA) for 8 d to induce the insomnia model, followed by the compound treatment for 7 days. The content of the serotonin and gamma-aminobutyric acid in the brain was measured by ELISA kit

  DownLoad: Full-Size Img PowerPoint

  3.4 Compound shortening the sleeping latency and extending the sleep duration

  In the previous study, we have confirmed the inhibitory effect of the compound on the sympathetic excitability in vivo. But the detailed influence of the compound on the rat sleeping latency and extending the sleep duration was still unclear. So, in this experiment, the pentobarbital synergistic sleep experiment was performed, and the sleeping latency and extending sleep duration of rats were measured. From the results in Fig. 4, we got this information that the sleeping latency was shortened and the sleep duration was extended after compound treatment. This result revealed the protective effect of the compound on insomnia rat.

  Figure 4

  

  Figure 4.  Shortened sleeping latency and extended sleep duration after compound treatment. The rats were injected with 120 mg/kg/d of PCPA for 8 d to induce the insomnia model, followed by the compound treatment for 7 days. The pentobarbital synergistic sleep experiment was performed, and the sleeping latency and sleep duration were measured

  DownLoad: Full-Size Img PowerPoint

  4. CONCLUSION

  In summary, we have successfully prepared a new Co(II)-bearing coordination polymer by using a bifunctional organic ligand. The as-prepared complex 1 has been fully determined via the elemental analysis along with the single-crystal X-ray diffraction. The structural solution and refinement results reveal complex 1 shows an unusual 3D coordination network which exhibits an intriguing self-interpenetrating (3, 6)-connected topological net with the Schläfli symbol of (4.6²)₂(4².6⁹.8³.10). Furthermore, a green hand grinding technique has been implemented to reduce the particle size of complex 1 to generate nanoscale 1 with morphology morphology. In biological study, the treatment effect of the compound on the insomnia rat was evaluated. Firstly, the ELISA was used to detect the content of serotonin, gamma-aminobutyric acid in the brain. The results indicated that the compound could reduce the sympathetic excitability. Besides, the Rat sleep phase detection was determined by pentobarbital synergistic sleep experiment. And we found the compound significantly shortened the sleeping latency and extended the sleep duration.

  
  
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  Figure 1  (a) Coordination surrounding of the Co(II) ion in 1. (b) Coordination pattern for the L^2- ligand. (c) Left- and right-handed 21 helical chains in 1. (d) 2-Fold interpenetrated network of 1

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  Figure 2  SEM diagram for the nano 1

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  Figure 3  Reduced content of serotonin and gamma-aminobutyric acid in the brain. The rats were injected with 120 mg/kg/d of chlorophenylalanine (PCPA) for 8 d to induce the insomnia model, followed by the compound treatment for 7 days. The content of the serotonin and gamma-aminobutyric acid in the brain was measured by ELISA kit

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  Figure 4  Shortened sleeping latency and extended sleep duration after compound treatment. The rats were injected with 120 mg/kg/d of PCPA for 8 d to induce the insomnia model, followed by the compound treatment for 7 days. The pentobarbital synergistic sleep experiment was performed, and the sleeping latency and sleep duration were measured

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