Synthesis and anti-myocarditis activity in a multifunctional lanthanide microporous metal-organic framework with 1D helical chain building units

A new microporous lanthanide metal-organic framework, {[Yb(BTB)(H2O) (DEF)2}n (1, DEF=N,N-Diethylformamide), with 1D nano-sized channels has been constructed by bridging helical chain secondary building units with 1,3,5-benzenetrisbenzoic acid (H3BTB) ligand. Structural characterization suggests that this complex crystallizes in the hexagonal space group P6122 and possesses 1D triangular channels with coordinated water molecules pointing to the channel center. In addition, anti-myocarditis properties of compound 1 were evaluated in vivo. The results showed that compound 1 can improve hemodynamic parameters of, and it may be a good therapeutic option for heart failure in the future.


Introduction
Myocarditis, also known as inflammatory cardiomyopathy, is the inflammation of the heart muscle. Symptoms can include shortness of breath, chest pain, decreased ability to exercise, and an irregular heartbeat (1,2). The duration of problems can vary from hours to months. Complications may include heart failure due to dilated cardiomyopathy or cardiac arrest (3,4).
Metal-organic frameworks (MOFs) that are constructed by coordination of metal centers with multiorganic connectors represent an emerging class of inorganic-organic hybrid crystalline materials (5,6). Their structural tenability, well-defined single crystal architectures, functionalized pore environment and modifiable building blocks make them useful in many potential applications including biological activity, catalysis, and luminescent sensing materials (7)(8)(9). The organic ligand plays an important role in the construction of porous MOFs because it not only guides the formation of the secondary building units, but also determines the pore shapes and pore surroundings of the obtained products (10,11). MOFs prepared with ligands of high symmetry have been well studied because of synthetic and crystallographic considerations. As the elongated ligand of H 3 BTC, 1,3,5-benzenetrisbenzoic acid (H 3 BTB, Figure 1) has been widely used in the construction of porous MOFs (12,13). However, compared with the transition metal-BTB frameworks reported, the lanthanon metal-BTB frameworks are less studied (14).
Here, we present the synthesis and the structural analysis of a highly porous Yb-organic network {Yb(BTB)(H 2 O)] (DEF) 2 } n (1, DEF=N,N-diethylformamide). This MOF is composed of novel 1D helical chain building units and BTB 3-ligand, which represents the first example of Ln-MOFs based on 1D helical chain building units. In addition, in vivo anti-myocarditis activity of compound 1 was investigated.

Apparatus and materials
All the starting materials and reagents used in this work were obtained commercially and used without further purification. Element analyses (C, H, and N) were determined with an elemental Vairo EL III analyzer (Bruker, Germany). Powder X-ray diffraction data were collected using PANalytical X'Pert Pro powder diffractometer (Bruker) with Cu-Ka radiation and 5°p2y p50°. Thermogravimetric experiments were performed using a TGA/NETZSCH STA449C instrument heated from 30 to 800°C (heating rate of 10°C/min, nitrogen stream; Bruker). Single crystal X-ray diffraction was carried out by an Oxford Xcalibur E diffractometer (Bruker).

Crystal structure determination
Suitable single crystal of compound 1 was carefully selected under optical microscope and glued on thin glass fibers. The intensity data of 1 was collected 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 2 using the SHELXS-97 program (15). All non-hydrogen atoms of 1 were refined anistropically, and all the hydrogen atoms attached to carbon atoms were fixed at their ideal positions. Pertinent crystal data and structural refinement results for compound 1 are summarized in Table 1.
In vivo anti-myocarditis activity C57BL6/j mice were involved in our experiment. A total of 48 eight-week-old male mice were divided into four groups: control+PBS (G1, n=12), control+1 (G2, n=12), CVB3+PBS (G3, n=12), CVB3+1 (G4, n=12). G3 and G4 were infected by intraperitoneal (ip) injection of 1 Â10 5  Statistical analysis was performed using Prism 6 (Bruker). One-way analysis of variance (ANOVA) was used for statistical analysis of the data with correction for multiple comparisons via the Tukey's range test. Data are reported as means ± SD. Differences were regarded to be significant if the two-sided P-value was lower than 0.05.

Molecular structure
The solvothermal reaction of Yb(NO 3 ) 3 Á 6H 2 O and H 3 BTB in a mixed solvent of DEF and H 2 O provided complex 1 as colorless crystals. Single-crystal X-ray diffraction reveals that 1 crystallizes in a highly symmetric and chiral hexagonal space group P6 1 22 and the 3-D coordination network is constructed through the connection of infinite 1-D helical chain building units and the BTB 3ligands. The asymmetric coordination unit consists of one Yb ion situated on a symmetry site with one half occupancy, half BTB 3ligand and one coordinated water molecule. As shown in Figure 2A, the Yb(III) ion is sevencoordinated by six carboxylic acid O atoms from six different BTB 3-  Each Yb atom is connected with the neighboring ones though three carboxylic groups. Such a connection mode leads to the formation of a 1D right-handed chain along a 6 1 axis, which represent a rare case of Ln-based helical chain building units according to the Cambridge Crystallographic Data Centre database ( Figure 2B). The pitch of the helical chain is 21.832 (3) Å. Furthermore, such 1D helical chain building units are further linked by BTB ligand through its three carboxylate groups to afford a 3D noninterpenetrating framework with 1D triangular channels with coordinated water molecule pointing to the channel center ( Figure 2C). Based on the crystallographic data and considering the van der Waals radii of atoms, the pore size for the triangular channel is 5.4 Å. To understand the network of 1 more clearly, we use the software TOPOS to simplify its framework. Each Yb(III) ion is connected with six O atoms from six different BTBligands and each BTBligand binds with six different Yb(III) ions. Thus, both of the Yb(III) ions and the BTBligand could be viewed as 6-connected nodes. In this case, the whole framework of 1 can be simplified to a 2-nodal (6,6)-connected network with the point symbol of (4 10 .6 5 )(4 7 .6 8 ), which has not been observed in MOF chemistry ( Figure 2D). The effective free volume of 1 without guest water molecules is 58.3% of the crystal volume (3569 Å 3 of the 6126 Å 3 unit cell volume), calculated with PLATON software.
Powder X-ray diffraction analysis (PXRD) and thermal analysis PXRD experiment was carried out to verify the phase purity of the as-synthesized samples. As shown in Figure 3A, the diffraction peak of compound 1 is in good agreement with that of the simulated one based on the single crystal diffraction data, indicating the pure phase of the obtained samples. From the thermogravimetric curve of compound 1, we found that the first weight loss of 27.1% occurs from 25 to 210°C, which corresponds to the release of one coordinated water molecule and two lattice DEF molecules (Calcd: 26.5%). Then, the dissolved sample was stable up to 230°C, after which the framework began to collapse ( Figure 3B).

In vivo anti-myocarditis activity
To evaluate the impact of compound 1 in CVB3induced myocarditis, body weight, heart rate (HR), maximum left ventricle pressure (Pmax), maximum left ventricle pressure rise rate (dP/dtmax), and ejection fraction (EF) were analyzed in the present study. There was a significant difference in body weight between G3 and G1. Furthermore, there was a significant difference between G4 and G3 ( Table 2). In comparison to G1 and G2, there was a sharp decrease in G3 animals in HR, Pmax, dP/dtmax and EF. Oppositely, G4 had a downward  trend that compared to G1 and G2, but there was no significant difference between them ( Table 3). As known, human myocarditis can result in chest discomfort, palpitation, shortness of breath, dizziness, decreased activity, and poor appetite. CVB3-mice are a good myocarditis model that we can easily see reduced activity, and get body weight data through weighing; the decreased appetite indicates that the myocarditis model works. From our in vivo experiment, we found that the CVB3 group significantly lost body weight, but it seemed to reverse after application of compound 1. The CVB3 group had a significant decrease of HR, Pmax, dP/dtmax, and EF, which are essential factors of heart failure, especially systolic heart failure. In our investigation, compound 1 was effective in hemodynamics, indicating it could be a candidate for anti-myocarditis therapy.
In conclusion, we demonstrated the successful construction of a novel Yb-based MOF with 1D helical chain building units built up from 1,3,5-H 3 BTB ligand. Structural characterization suggests that this complex crystallizes in the hexagonal space group P6 1 22 and possesses 1D triangular channels with coordinated water molecules pointing to the channel center. In addition, the results showed that compound 1 can improve hemodynamic parameters, and may be a good therapeutic compound for heart failure in the future.