| 多苯并咪唑锌配合物抑制蛋白酪氨酸磷酸酶(PTPs)的活性 |
| PTPs Inhibition by Zinc(Ⅱ) Complexes with Multi-benzimidazole Derivatives |
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| 摘要: 本文报道了5种多苯并咪唑锌配合物,即[Zn(TDB)2]Cl2(1)、[Zn(NTB)Cl]Cl(2)、[Zn(EDTB)]Cl2(3)、[Zn2(EGTB)Cl2]Cl2(4)和[Zn2(DTPB)Cl3]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IC50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1000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1.12×106、5.47×105、1.19×106和4.95×105L·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。 |
| 关键词: 锌配合物 蛋白酪氨酸磷酸酶 抑制 选择性 |
| 基金项目: 国家自然科学基金(No.21271121)和山西省回国留学人员科研项目(No.2013-026)资助。 |
| Abstract: 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, [Zn(TDB)2]Cl2 (1), [Zn(NTB)Cl]Cl (2), [Zn(EDTB)]Cl2 (3), [Zn2(EGTB)Cl2]Cl2 (4) and [Zn2(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 PTP1Bwith 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, 3 and 5 against TCPTPthat is highly homologous with PTP1B. Therefore, 2 and 4 display obvious selective against PTP1Bwith 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 1000 times stonger than against SHP-2, suggesting the structure of zinc(Ⅱ) complexes influence the selectivity against PTP1B. Kinetic analysis indicates that complexes 2 and 4 are reversible competitive inhibitors of PTP1Bbut noncompettitive inhibitors for TCPTP. Fluorescence study on the interaction between complex 2 or 4 and PTP1Bor TCPTPsuggests that the complexes bind to PTP1Bor TCPTPwith the formation of a 1:1 complex. The binding constant are about 1.12×106, 5.47×105, 1.19×106, and 4.95×105 L·mol-1 respectively, showing stronger binding ability of 2 and 4 to PTP1Bthan to TCPTP, agreeing with their inhibition against the two enzymes. |
| Keywords: zinc(Ⅱ) complex protein tyrosine phosphatase inhibition selectivity |
| 投稿时间：2015-12-11 修订日期：2016-02-09 |
| 摘要点击次数: 3410 |
| 全文下载次数: 1954 |
| 陈青,卢丽萍.多苯并咪唑锌配合物抑制蛋白酪氨酸磷酸酶(PTPs)的活性[J].无机化学学报,2016,32(6):1001-1008. |
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