双吗啉取代吡啶锌和铜配合物的合成、表征及抗癌活性初步研究

Preliminary Studies of Synthesis,Characterization and Anticancer Activity of Zinc and Copper Complexes Based on Bis-Morpholine Substituted Pyridine

目的研究双吗啉取代吡啶锌、铜配合物(Mor_(2)-Py-Zn和Mor_(2)-Py-Cu)的合成,并探讨其抗癌活性。方法以进入临床试验的拮抗剂AMD3100为先导化合物,设计、合成Mor_(2)-Py-Zn和Mor_(2)-Py-Cu,并以高分辨质谱法对它们进行表征。利用X射线单晶衍射法测定晶体结构,紫外-可见吸收光谱分析配合物与小牛胸腺DNA(CT-DNA)的相互作用,并利用形态学和MTT实验探索配合物对胶质瘤细胞的毒活性。结果Mor_(2)-Py-Zn的晶体结构属于正交晶系,Pbca空间群,吡啶N、两个吗啉N及两个硝酸根的O原子与Zn^(2+)形成了N3O2五配位的三角双锥构型。Mor_(2)-Py-Zn和Mor_(2)-Py-Cu均与CT-DNA在溶液中有一定的相互作用。Mor_(2)-Py-Zn和Mor_(2)-Py-Cu对U87的抑制活性都较弱,而对于U251则能显著抑制其增殖。MTT实验表明,Mor_(2)-Py-Zn和Mor_(2)-Py-Cu对于U251细胞的IC_(50)分别为18.11μmol/L和14.66μmol/L。结论Mor_(2)-Py-Zn和Mor_(2)-Py-Cu均表现出对U251胶质瘤细胞的抑制活性,具有继续深入研究其抗癌机理的价值。

Objective To research the synthesis and anticancer activities of zinc and copper complexes based on bis-morpholine substituted pyridine(Mor_(2)-Py-Zn and Mor_(2)-Py-Cu).Methods Taking the antagonist AMD3100,which entered the clinical trial,as the lead compound,Mor_(2)-Py-Zn and Mor_(2)-Py-Cu were designed and synthesized,and characterized by high resolution mass spectrometry.The crystal structure was determined by X-ray single crystal diffraction.The interaction between complexes and calf thymus DNA(CT-DNA)was studied by UV-Vis absorption spectroscopy,and the cytotoxicity against glioblastoma cells was further studied by morphological analysis and MTT assays.Results Mor_(2)-Py-Zn belongs to the orthorhombic system,pbca space group,pyridine N,two morpholine N and two nitrate O atoms form a triangular bipyramidal configuration of N3O2 pentagram with Zn~(2+).Both Mor_(2)-Py-Zn and Mor_(2)-Py-Cu interacted with CT-DNA in solution to some extent.The two complexes showed weak inhibitory activity against U87,but obviously inhibited the proliferation of U251.Further,MTT assay showed that the IC_(50)of Mor_(2)-Py-Zn and Mor_(2)-Py-Cu for U251 cells were 18.11μmol/L and 14.66μmol/L,respectively.Conclusion Both Mor_(2)-Py-Zn and Mor_(2)-Py-Cu are valuable for further study of their anticancer mechanism,especially for U251 cells.