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The influence of the ethane-1,2-diamine ligand on the activity of a monofunctional platinum complex
Journal of Inorganic Biochemistry ( IF 3.8 ) Pub Date : 2017-07-29 , DOI: 10.1016/j.jinorgbio.2017.07.029
Marcus E. Graziotto , Mia C. Akerfeldt , Adam P. Gunn , Kylie Yang , Mark V. Somerville , Nicholas V. Coleman , Blaine R. Roberts , Trevor W. Hambley , Elizabeth J. New

The continued use of platinum-based chemotherapeutic drugs in the clinic mandates the need for further investigation of the biological activity of structural analogues of the clinically approved complexes. Of interest are monofunctional platinum(II) complexes, which bear only one labile ligand, for which it is believed that each complex binds to DNA only once. Pyriplatin ([PtCl(NH3)2(py)]+) and enpyriplatin ([PtCl(en)(py)]+) are both monofunctional platinum(II) complexes that bear a pyridine ligand and a labile chlorido ligand, differing in their cis‑ammine and ethane-1,2-diamine (en) ligands respectively. Despite their similar structure, the complexes exhibit dramatically different cytotoxicities. In this study, we synthesized and characterized both complexes in terms of their cytotoxicity, lipophilicity, DNA binding and cellular accumulation. There was no significant difference between the lipophilicities of the complexes and both complexes exhibited monofunctional type binding, but it was the temporal accumulation profiles of the two complexes which differed greatly. The complexes were further analyzed with size exclusion chromatography coupled with inductively coupled plasma mass spectrometry (SEC-ICP-MS) to determine the platination state of the proteins. Consistent with the accumulation studies, pyriplatin bound to proteins in far greater amounts than enpyriplatin, and this study also revealed some different protein targets between the bifunctional cisplatin and monofunctional pyriplatin. This study highlights the need for more sophisticated techniques, such as SEC-ICP-MS, to determine not only how much of a platinum complex accumulates in cells, but also the speciation and metabolites of platinum anticancer drugs.



中文翻译:

乙烷-1,2-二胺配体对单官能铂络合物活性的影响

在临床上继续使用基于铂的化学治疗药物要求进一步研究临床批准的复合物的结构类似物的生物学活性。令人感兴趣的是单官能的铂(II)配合物,其仅带有一个不稳定的配体,据信每个配合物仅与DNA结合一次。Pyriplatin([PtCl(NH 32(py)] +)和enpyriplatin([PtCl(en)(py)] +)都是带有吡啶配体和不稳定的氯代配体的单官能铂(II)配合物,不同之处在于他们的顺式-氨基和乙烷-1,2-二胺(en)配体。尽管它们的结构相似,但复合物仍显示出显着不同的细胞毒性。在这项研究中,我们根据细胞毒性,亲脂性,DNA结合和细胞积累对两种复合物进行了合成和表征。配合物的亲脂性之间没有显着差异,并且两种配合物均表现出单功能型结合,但是两种配合物的时间积累曲线差异很大。使用尺寸排阻色谱结合电感耦合等离子体质谱法(SEC-ICP-MS)进一步分析该复合物,以确定蛋白质的电镀状态。与积累研究一致,吡铂与蛋白质的结合量远高于恩吡铂,这项研究还揭示了双功能顺铂和单功能吡铂之间存在一些不同的蛋白质靶标。这项研究强调需要更复杂的技术,例如SEC-ICP-MS,不仅可以确定细胞中积累了多少铂络合物,而且还可以确定铂抗癌药的形态和代谢产物。

更新日期:2017-07-29
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