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Convenient synthesis of zwitterionic calcium(II)-carboxylate metal organic frameworks with efficient activities for the treatment of osteoporosis
International Journal of Pharmaceutics ( IF 5.8 ) Pub Date : 2021-09-16 , DOI: 10.1016/j.ijpharm.2021.121083
Yu Hou 1 , Cai-Zhu Luo 1 , Deng-Hui Xie 2 , Jing-Jing Hu 1 , Jin-Xiang Chen 3 , Nai-Han Huang 3 , Hong Wang 4 , Shu-Qing Zhang 4 , Qun Zhang 1
Affiliation  

Calcium supplementation is effective in alleviating the process of osteoporosis and the occurrence of osteoporotic fractures for people with long-term calcium deficiency. Herein, five water-stable calcium carboxylate compounds, that is, mononuclear coordination compound [Ca(Cbdcp)(H2O)6]·0.5H2O (1, H3CbdcpBr = N-(4-carboxybenzyl)-(3,5-dicarboxyl)pyridinium bromide), and metal organic frameworks (MOFs) {[Ca3(Dcbdcp)2(H2O)12]·2H2O}n (2, H4DcbdcpBr = N-(3,5-dicarboxybenzyl)-(3,5-dicarboxyl)pyridinium bromide), {[Ca(Cmdcp)(H2O)4]·3H2O}n (3, H3CmdcpBr = N-carboxymethyl-(3,5-dicarboxyl)pyridinium bromide), {[Ca(Cdcbp)]·2H2O}n (4, H3CdcbpBr = 3-carboxyl-(3,5-dicarboxybenzyl)-pyridinium bromide) and {[Ca0.5(Cmcp)]·2H2O}n (5, H2CmcpBr = N-carboxymethyl-(3-carboxyl)pyridinium bromide), were synthesized from the reaction of CaCl2 with five different kinds of zwitterionic carboxylate ligands in the presence of NaOH, respectively. Compounds 15 were characterized by Fourier-transform infrared (FTIR) spectroscopy, elemental analyses, single-crystal X-ray crystallography, and inductively coupled plasma mass spectrometry (ICP-MS). Compound 1 features a mononuclear structure and MOF 2 with a one-dimensional (1D) structure while MOFs 3 and 5 with 2D layer structures and MOF 4 showing a 3D structure. Compounds 15 exhibited good water stability and possessed considerable biocompatibility with primary mice osteoblasts. The in vitro ability of compounds 15 in regulating osteoblastic differentiation was studied via alkaline phosphatase (ALP) staining, alizarin red S (ARS) staining, and quantitative real-time polymerase chain reaction (qPCR). Among these 5 compounds, MOF 4 showed the overall best in vitro osteogenic effects. Then, we administrated MOF 4 intragastrically to bilaterally ovariectomized mice for 8 weeks and found that bone loss caused by ovariectomy (OVX) was significantly alleviated. Besides, MOF 4 administration showed no toxic effects in the main organs of the mice. Altogether, zwitterionic carboxylate ligands-based calcium compounds provide a new strategy for calcium agents development.



中文翻译:

方便合成两性离子钙(II)-羧酸盐金属有机骨架,具有治疗骨质疏松症的有效活性

对于长期缺钙的人,补钙能有效缓解骨质疏松的进程和骨质疏松性骨折的发生。在此,五种水稳定的羧酸钙化合物,即单核配位化合物[Ca(Cbdcp)(H 2 O) 6 ]·0.5H 2 O ( 1 , H 3 CbdcpBr = N-(4-羧基苄基)-(3 ,5-二羧基)溴化吡啶鎓)和金属有机骨架(MOF){[Ca 3 (Dcbdcp) 2 (H 2 O) 12 ]·2H 2 O} n ( 2 , H 4DcbdcpBr = N-(3,5-二羧基苄基)-(3,5-二羧基)溴化吡啶鎓), {[Ca(Cmdcp)(H 2 O) 4 ]·3H 2 O} n ( 3 , H 3 CmdcpBr = N -羧甲基-(3,5-二羧基)溴化吡啶鎓)、{[Ca(Cdcbp)]·2H 2 O} n ( 4 , H 3 CdcbpBr = 3-羧基-(3,5-二羧基苄基)-溴化吡啶鎓)和{[Ca 0.5 (Cmcp)]·2H 2 O} n ( 5 , H 2 CmcpBr = N-羧甲基-(3-羧基)溴化吡啶鎓),由CaCl 2反应合成在NaOH存在下分别具有五种不同的两性离子羧酸盐配体。化合物1 - 5是由傅里叶变换红外(FTIR)光谱,元素分析,单晶X射线晶体学,和电感耦合等离子体质谱(ICP-MS)来表征。化合物1具有单核结构,MOF 2具有一维 (1D) 结构,而 MOF 35具有 2D 层结构,MOF 4具有 3D 结构。化合物1 - 5表现出良好的水稳定性和具有与伯小鼠成骨细胞相当大的生物相容性。在体外化合物的能力1 - 5在调节成骨细胞分化进行了研究通过碱性磷酸酶(ALP)染色,茜素红S(ARS)染色,和实时定量聚合酶链式反应(qPCR的)。在这 5 种化合物中,MOF 4显示出总体最佳的体外成骨作用。然后,我们对双侧卵巢切除的小鼠胃内施用 MOF 4 8 周,发现卵巢切除术 (OVX) 引起的骨质流失显着减轻。此外,MOF 4给药对小鼠的主要器官没有毒性作用。总之,基于两性离子羧酸盐配体的钙化合物为钙剂的开发提供了新的策略。

更新日期:2021-09-30
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