7-nitro-2,1,3-benzoxadiazole derivatives, a new class of suicide inhibitors for glutathione S-transferases -: Mechanism of action of potential anticancer drugs
7-nitro-2,1,3-benzoxadiazole derivatives, a new class of suicide inhibitors for glutathione S-transferases -: Mechanism of action of potential anticancer drugs
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DOI：
10.1074/jbc.m503295200
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发表时间：
2005-07-15
影响因子：
4.8
通讯作者：
Caccuri, AM
中科院分区：
文献类型：
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作者：
Ricci, G;De Maria, F;Caccuri, AM
通过光谱和快速动力学实验研究了人谷胱甘肽S-转移酶GSTA 1 -1、GSTM 2 -2和GSTP 1 -1与6-（7-硝基-2，1，3-苯并恶二唑-4-基硫基）己醇（NBDHEX）的相互作用。该化合物是一类新的7-硝基-2，1，3-苯并恶二唑（NBD）衍生物（非GSH肽模拟物化合物）的代表性分子，其被设计为提供强GST抑制并在肿瘤细胞中积累，避免由多药耐药蛋白泵介导的挤出机制。我们最近发现，亚微摩尔量的NBDHEX通过JNK的解离在几种人类肿瘤细胞系中触发凋亡。GSTP 1 -1复合物（Turella，P.，塞雷拉角，菲洛梅尼，G.，Bullo，A.，De Maria，F.，吉贝利湖Ciriolo，M. R.，Cianfriglia，M.，Mattei，M.，Federici，G.，Ricci，G.，和Caccuri，A. M.（2005）Cancer Res.65，3751-3761）。在本研究中报告的结果表明，NBDHEX的行为就像一个自杀抑制剂的GST。它与H位点结合，并与GSH缀合，在苯并恶二唑环的C-4处形成σ复合物。该复合物在GSTP 1 -1和GSTM 2 -2的活性位点中紧密稳定，而在GSTA 1 -1中，从σ复合物释放6-巯基1-己醇是有利的事件。对接研究表明，可能的本地化的σ复合物的GST活性位点，并提供了一个结构上的解释，其强大的稳定。
Spectroscopic and rapid kinetic experiments were performed to detail the interaction of human glutathione S-transferases GSTA1-1, GSTM2-2, and GSTP1-1 with 6-(7-nitro- 2,1,3-benzoxadiazol-4-ylthio) hexanol ( NBDHEX). This compound is a representative molecule of a new class of 7-nitro- 2,1,3-benzoxadiazole (NBD) derivatives (non-GSH peptidomimetic compounds) that have been designed both to give strong GST inhibition and to accumulate in tumor cells avoiding the extrusion mechanisms mediated by the multidrug resistance protein pumps. We have recently shown that submicromolar amounts of NBDHEX trigger apoptosis in several human tumor cell lines through the dissociation of the JNK (.) GSTP1-1 complex ( Turella, P., Cerella, C., Filomeni, G., Bullo, A., De Maria, F., Ghibelli, L., Ciriolo, M. R., Cianfriglia, M., Mattei, M., Federici, G., Ricci, G., and Caccuri, A. M. ( 2005) Cancer Res. 65, 3751-3761). Results reported in the present study indicated that NBDHEX behaves like a suicide inhibitor for GSTs. It bound to the H-site and was conjugated with GSH forming a sigma complex at the C-4 of the benzoxadiazole ring. This complex was tightly stabilized in the active site of GSTP1-1 and GSTM2-2, whereas in GSTA1-1 the release of the 6- mercapto1-hexanol from the sigma complex was the favored event. Docking studies demonstrated the likely localization of the sigma complex in the GST active sites and provide a structural explanation for its strong stabilization.