Probing the interaction of bisintercalating (2,2':6',2"-terpyridine)platinum(II) complexes with glutathione and rabbit plasma
Probing the interaction of bisintercalating (2,2':6',2"-terpyridine)platinum(II) complexes with glutathione and rabbit plasma
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DOI：
10.1016/j.jinorgbio.2016.06.004
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发表时间：
2016-10-01
影响因子：
3.9
通讯作者：
Aldrich-Wright, Janice R.
中科院分区：
文献类型：
--
作者：
Harper, Benjamin W. J.;Morris, Thomas T.;Aldrich-Wright, Janice R.
铂（II）络合物在癌症治疗中已显示出相当大的成功，但严重的毒副作用促使人们寻找具有增加的肿瘤选择性和更好疗效的新络合物。在设计新型Pt络合物的背景下必须考虑的一个关键概念是它们与DNA以外的生物分子的相互作用。为此，本文用（1）H和Pt-195 NMR研究了16个先前报道的双插层（2，2 '：6'，2”-三联吡啶）铂（10）配合物[{Pt（terpy））（2）mu-（X）（n+）（其中X为连接基）与谷胱甘肽（GSH）的相互作用。在各[（Pt（三联吡啶））（2）μ-（X）（n+）复合物与GSH（8 mM）孵育后测定GSH半衰期（GSH尖端）。观察到配合物1-7、11、12和14-16比顺铂反应更快，而配合物8- 10、13和17反应更慢（>= 200分钟）。接头长度与GSH t（1/2）无明显相关性。为了理解这些相互作用，将两种复合物：1（t（1/2）< 1 min）和先前研究的17 [Pt（5，6-二甲基-1，10-菲咯啉）（1 S，2S-二氨基环己烷）]（56 MESS）（GSH t（1/2）= 4080 min）与兔血浆一起孵育。使用“金属组学”方法在5和60 min时间点分析所有铂物质的血浆，并提供与所选Pt络合物与GSH的反应一致的结果。我们的研究表明，NMR光谱，细胞毒性研究和金属组学方法的组合应用可以有助于更好地理解[{Pt（terpy）}（2）mu-（X）]（n+）配合物与生物分子的相互作用，以更好地评估哪些化合物可以进行体内研究。(C)2016 Elsevier Inc. All rights reserved.
Platinum(II) complexes have demonstrated considerable success in the treatment of cancer, but severe toxic side effects drive the search for new complexes with increased tumour selectivity and better efficacy. A critical concept that has to be considered in the context of designing novel Pt complexes is their interactions with biomolecules other than DNA. To this end, here the interactions of 16 previously reported bisintercalating (2,2':6',2"-terpyridine)platinum(10 complexes, [{Pt(terpy))(2)mu-(X)(n+) (where X is a linker) with glutathione (GSH) by means of(1)H and Pt-195 NMR spectroscopy were investigated. The GSH half-life (GSH tip) was determined following the incubation of each [{Pt(terpy))(2)mu-(X)(n+) complex with GSH (8 mM). It was observed that complexes 1-7, 11,12 and 14-16 reacted more rapidly than cisplatin, whereas complexes 8-10,13 and 17 reacted more slowly (>= 200 min). There was no apparent correlation between linker length and the GSH t(1/2). In order to understand these interactions, two complexes: 1 (t(1/2) < 1 min) and a previously studied 17 [Pt(5,6-dimethy1-1,10-phenanthroline)(1S,2S-diaminocyc.lohexane)] (56MESS) (GSH t(1/2) = 4080 min) were incubated with rabbit plasma. A "metallomics" approach was used to analyse plasma for all platinum species at the 5 and the 60 min time point and provided results that were congruent with the reaction of the selected Pt complexes with GSH. Our studies demonstrate that the combined application of NMR spectroscopy, cytotoxicity studies and a metallomics approach can contribute to better understand the interaction of [{Pt(terpy)}(2)mu-(X)](n+) complexes with biomolecules to better assess which compounds may be advanced to in vivo studies. (C) 2016 Elsevier Inc. All rights reserved.