Papadia Paride, Margiotta Nicola, Bergamo Alberta, Sava Gianni, Natile Giovanni
Dipartimento Farmaco-Chimico, Università degli Studi di Bari, Via E. Orabona 4, 70125 Bari, Italy.
J Med Chem. 2005 May 5;48(9):3364-71. doi: 10.1021/jm0500471.
The compounds Pt(Me(2)phen)(acy)(2)(2) (1), Pt(Me(2)phen)(pen)(2)(2), Pt(phen)(acy)(2)(2) (2), and Pt(phen)(pen)(2)(2), containing the bidentate 1,10-phenanthroline (phen) or 2,9-dimethyl-1,10-phenanthroline (Me(2)phen, neocuproine) and the antiviral agents acyclovir (acy) or penciclovir (pen), show different in vitro toxicity, the Me(2)phen complexes being appreciably more toxic than the phen complexes. To explain the different behavior, we investigated the reaction of complexes 1 and 2 with glutathione (gamma-glutamylcysteinylglycine, GSH), a peptide believed to play an important role in driving the cellular effects of platinum drugs. The reaction led to different products, the phen complexes forming a stable binuclear mu-thiol-bridged species still containing the phenanthroline and the Me(2)phen complexes releasing the neocuproine ligand and forming an insoluble material. In vitro tests confirmed that the greater cell toxicity of complex 1 is due to the displacement of the neocuproine ligand by GSH. The results highlight the great dependence of the glutathione reactivity upon relatively small changes in the platinum coordination sphere.
化合物Pt(Me(2)phen)(acy)(2)(2)（1）、Pt(Me(2)phen)(pen)(2)(2)、Pt(phen)(acy)(2)(2)（2）以及Pt(phen)(pen)(2)(2)，含有双齿的1,10 - 菲咯啉（phen）或2,9 - 二甲基 - 1,10 - 菲咯啉（Me(2)phen，新亚铜试剂）以及抗病毒药物阿昔洛韦（acy）或喷昔洛韦（pen），表现出不同的体外毒性，Me(2)phen配合物的毒性明显高于phen配合物。为了解释这种不同的行为，我们研究了配合物1和2与谷胱甘肽（γ - 谷氨酰半胱氨酰甘氨酸，GSH）的反应，谷胱甘肽是一种据信在推动铂类药物的细胞效应中起重要作用的肽。该反应产生了不同的产物，phen配合物形成了一种仍然含有菲咯啉的稳定双核μ - 硫醇桥连物种，而Me(2)phen配合物则释放出新亚铜试剂配体并形成一种不溶性物质。体外试验证实，配合物1更大的细胞毒性是由于GSH取代了新亚铜试剂配体。结果突出了谷胱甘肽反应性对铂配位球中相对较小变化的极大依赖性。
