Inorganic Chemistry I - Bioinorganic Chemistry, Faculty of Chemistry and Biochemistry, Ruhr-University Bochum, Universitätsstraße 150, 44801 Bochum, Germany.
Dalton Trans. 2018 Nov 21;47(43):15465-15476. doi: 10.1039/c8dt03082k. Epub 2018 Oct 18.
Herein we present platinum(iv) bioconjugates with polyarginine peptides as prospective prodrug delivery systems. Asymmetrical platinum(iv) complexes 3 were obtained via oxidation of parent platinum(ii) complexes 2 with N-bromosuccinimide (NBS) in the presence of succinic anhydride. The combination of these two oxidation reagents furnishes the platinum(iv) environment with two different axial ligands, one of which bears a free carboxylic acid. All platinum(ii) and (iv) compounds were characterized by FT-IR, ESI-MS, HPLC, H-, C- and Pt-NMR. Standard solid-phase peptide chemistry was used for the synthesis of polyarginine (R) peptides. Coupling of the platinum complexes with peptides N-terminally afforded peptide monoconjugates, which were purified by semi-preparative HPLC and characterized by analytical HPLC and ESI-MS. Platinum(iv)-peptide bioconjugates as well as platinum(ii) and platinum(iv) complexes were tested as cytotoxic agents against two different human cancer cell lines (MCF-7, HepG2) and normal human fibroblasts cell lines (GM5657T). Preliminary in vitro data showed that all platinum(iv) complexes exhibit lower activity than their platinum(ii) precursors towards most cell lines. Interestingly, in the case of HepG2 cells, the Pt(iv)-(R)-G-A-L bioconjugate (4a) showed even higher activity compared to the non-targeting platinum(iv) parent compound.
在此，我们展示了带有聚精氨酸肽的铂（IV）缀合物，作为有前途的前药传递系统。通过在琥珀酸酐存在下用 N-溴代丁二酰亚胺（NBS）氧化母体铂（II）配合物 2，获得不对称铂（IV）配合物 3。这两种氧化试剂的结合为铂（IV）环境提供了两个不同的轴向配体，其中一个配体带有游离羧酸。所有铂（II）和（IV）化合物均通过 FT-IR、ESI-MS、HPLC、H-、C- 和 Pt-NMR 进行了表征。标准固相肽化学用于合成聚精氨酸（R）肽。将铂配合物与肽的 N 端偶联得到肽单缀合物，通过半制备 HPLC 进行纯化，并通过分析 HPLC 和 ESI-MS 进行表征。铂（IV）-肽缀合物以及铂（II）和铂（IV）配合物被测试为针对两种不同的人癌细胞系（MCF-7、HepG2）和正常人成纤维细胞系（GM5657T）的细胞毒性剂。初步的体外数据表明，所有铂（IV）配合物的活性均低于其铂（II）前体对大多数细胞系的活性。有趣的是，在 HepG2 细胞中，Pt(iv)-(R)-G-A-L 缀合物（4a）的活性甚至高于非靶向铂（IV）母体化合物。
