摘要
本文报道了5种多苯并咪唑锌配合物,即[Zn(TDB)_2]Cl_2(1)、[Zn(NTB)Cl]Cl(2)、[Zn(EDTB)]Cl_2(3)、[Zn_2(EGTB)Cl_2]Cl_2(4)和[Zn_2(DTPB)Cl_3]Cl(5),其中TDB=1,2-二(2-苯并咪唑)-1,2-二羟基乙烷、NTB=N,N,N-三(2-甲基苯并咪唑)胺、EDTB=N,N,N′,N′-四(2-苯并咪唑亚甲基)-1,2-乙二胺、EGTB=N,N,N′,N′-四(2-苯并咪唑甲基)-1,4-二乙胺基乙二醚以及DTPB=N,N,N′,N″,N″-五(2-苯并咪唑甲基)-二乙三胺,对5种蛋白酪氨酸磷酸酶(PTP1B、TCPTP、PTP-MEG2、SHP-1和SHP-2)的抑制作用,结果显示这些配合物强烈抑制PTP1B的活性,其IC_(50)值在0.15~0.28μmol·L^(-1)范围内,但对PTP-MEG2和SHP-1抑制较弱,几乎不抑制SHP-2,而配合物1、3、5对与PTP1B高度同源的TCPTP的抑制明显强于2和4,因而2和4对PTP1B表现较强的选择性,对PTP1B抑制活性是TCPTP的7~12倍、PTP-MEG2的10~15倍、SHP-1的20~40倍,大约是SHP-2的1 000倍,表明配合物的结构影响其对PTP1B的选择性。酶促动力学实验显示2和4对高度同源的PTP1B和TCPTP抑制类型不同,对PTP1B的抑制为竞争型,而对TCPTP的抑制为非竞争型,推测其选择性可能与其抑制方式有关。荧光滴定表明2和4与PTP1B和TCPTP发生了1∶1结合作用。结合常数分别为1.12×10~6、5.47×10~5、1.19×10~6和4.95×10~5 L·mol^(-1),表明它们与PTP1B的结合能力强于TCPTP,与它们对这两种酶的抑制能力一致。
The inhibitory effects against human protein tyrosine phosphatase 1B（PTP1B）, T-cell protein tyrosine phosphatase（TCPTP）, megakaryocyte protein tyrosine phosphatase 2（PTP-MEG2）, srchomology phosphatase 1（SHP-1） and srchomology phosphatase 2（SHP-2） of five zinc（Ⅱ） complexes with multi-benzimidazole derivatives,[ZnTDB2]Cl2（1）, [Zn（NTB）Cl]Cl（2）, [Zn（EDTB）]Cl-2（3）, [Zn-2（EGTB）Cl-2]Cl-2（4） and [Zn-2（DTPB）Cl3]Cl（5）（TDB =1,2-bis（1H-benzo-imidazol-2-yl）ethane-1,2-diol, NTB=tris（1H-benzoimidazol-2-ylmethyl）amine, EDTB=N,N,N′,N′-tetrakis（1H-benzoimidazol-2-ylmethyl）ethane-1,2-diamine, EGTB=bis（1H-benzoimidazol-2-ylmethyl）-[2-（2-{2-[bis-（1H-benzoimidazol-2-ylmethyl）-amino]ethoxy}ethoxy）ethyl]amine and DTPB=1,1,4,7,7-pentakis（1H-benz-imidazol-2-ylmethyl）-1,4,7-triazaheptane）, were evaluated in vitro in this paper. The five zinc（Ⅱ） complexes potently inhibit PTP1 B with IC50 at range from 0.15 to 0.28 μmol·L^-1,but show weaker inhibition against PTP-MEG2, SHP-1,almost no inhibition against SHP-2. It is interesting that complexes 2 and 4 exhibit weaker inhibition than 1, 3and 5 against TCPTP that is highly homologous with PTP1 B. Therefore, 2 and 4 display obvious selective against PTP1 B with 7-12 times stonger than against TCPTP, 10-15 times stonger than against PTP-MEG2, 20-40 times stonger than against SHP-1 and about 1 000 times stonger than against SHP-2, suggesting the structure of zinc（Ⅱ）complexes influence the selectivity against PTP1 B. Kinetic analysis indicates that complexes 2 and 4 are reversible competitive inhibitors of PTP1 B but noncompettitive inhibitors for TCPTP. Fluorescence study on the interaction between complex 2 or 4 and PTP1 B or TCPTP suggests that the complexes bind to PTP1 B or TCPTP with the formation of a 1∶1 complex. The binding constant are about 1.12 ×10^6, 5.47×10^5, 1.19×10^6, and 4.95×10^5L·mol^-1respectively, showing stronger binding ability of 2 and 4 to PTP1 B than to T
出处
《无机化学学报》
SCIE
CAS
CSCD
北大核心
2016年第6期1001-1008,共8页
Chinese Journal of Inorganic Chemistry
基金
国家自然科学基金(No.21271121)
山西省回国留学人员科研项目(No.2013-026)资助
关键词
锌配合物
蛋白酪氨酸磷酸酶
抑制
选择性
zinc（Ⅱ） complex
protein tyrosine phosphatase
inhibition
selectivity
