Ramos-Lima Francisco J, Vrána Oldrich, Quiroga Adoración G, Navarro-Ranninger Carmen, Halámiková Anna, Rybnícková Hana, Hejmalová Lenka, Brabec Viktor
Institute of Biophysics, Academy of Sciences of the Czech Republic, CZ-61265 Brno, Czech Republic.
J Med Chem. 2006 Apr 20;49(8):2640-51. doi: 10.1021/jm0602514.
We report in the present work new analogues of clinically ineffective transplatin in which one ammine group was replaced by aliphatic and the other by a planar heterocyclic ligand, namely trans-[PtCl(2)(isopropylamine)(3-(hydroxymethyl)-pyridine)], 1, and trans-[PtCl(2)(isopropylamine)(4-(hydroxymethyl)-pyridine)], 2. The new compounds, in comparison with parent transplatin, exhibit radically enhanced activity in tumor cell lines both sensitive and in particular resistant to cisplatin. Concomitantly, the DNA binding mode of 1 and 2 compared to parent transplatin and other antitumor analogues of transplatin in which only one ammine group was replaced is also different. The results also suggest that the reactions of glutathione and metallothionein-2 with compounds 1 and 2 do not play a crucial role in their overall biological effects. In addition, the monofunctional adducts of 1 and 2 are quenched by glutathione considerably less than the adducts of transplatin, which may potentiate cytotoxic effects of these new platinum complexes.
我们在本研究中报告了临床上无效的反式铂的新类似物，其中一个氨基团被脂肪族取代，另一个被平面杂环配体取代，即反式-[PtCl₂(异丙胺)(3 - (羟甲基)吡啶)]，1，和反式-[PtCl₂(异丙胺)(4 - (羟甲基)吡啶)]，2。与母体反式铂相比，这些新化合物在对顺铂敏感尤其是耐药的肿瘤细胞系中表现出显著增强的活性。同时，与母体反式铂以及仅一个氨基团被取代的反式铂的其他抗肿瘤类似物相比，1和2的DNA结合模式也有所不同。结果还表明，谷胱甘肽和金属硫蛋白-2与化合物1和2的反应在它们的整体生物学效应中并不起关键作用。此外，1和2的单功能加合物被谷胱甘肽淬灭的程度远低于反式铂的加合物，这可能增强了这些新铂配合物的细胞毒性作用。
