Brabec Viktor, Pracharova Jitka, Novakova Olga, Gibson Dan, Kasparkova Jana
Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i.., Kralovopolska 135, CZ-61265 Brno, Czech Republic.
Dalton Trans. 2015 Feb 28;44(8):3573-82. doi: 10.1039/c4dt02603a.
The toxicity of the new derivative of transplatin, namely trans-[PtCl2(DEA)(NH3)] (DEA = diethylamine), in which only one NH3 group was replaced by a small, non-bulky DEA ligand, in the cisplatin sensitive and resistant tumor cell lines was examined. The results indicate that this very small modification of the transplatin molecule results in a considerable enhancement of toxicity in the cancer cells. Thus, this finding is consistent with the thesis that the trans geometry in Pt(II)-dichlorido compounds can also be effectively activated by the replacement of only one NH3 ligand in transplatin by the non-bulky ligand, such as the short aliphatic amine, (C2H5)2NH. We also demonstrate that trans-[PtCl2(DEA)(NH3)], in contrast to transplatin, can be grouped with the coordination compounds exhibiting antitumor activity and capable of inducing lysis in lysogenic bacteria. Thus, these results afford, for the first time, experimental support for the view that DNA is the potential cellular target also for antitumor derivatives of transplatin. DNA binding mode of trans-[PtCl2(DEA)(NH3)] in cell-free media was examined as well. The results show that the small aliphatic DEA ligand has significant consequences for the DNA conformational changes. Unlike 'classical' transplatin, modification of DNA with trans-[PtCl2(DEA)(NH3)] leads to mainly bifunctional cross-links. The extent and destabilization of the double-helical structure of DNA by this new trans-platinum complex are similar to those induced by cisplatin. As a consequence the lesions effectively inhibit transcription of template DNA similarly to the lesions of cisplatin, but markedly more than the lesions of transplatin. The stronger inhibition of DNA transcription by the adducts of trans-[PtCl2(DEA)(NH3)] in comparison with the adducts of transplatin adds a new dimension to the impact of the activated trans geometry in platinum compounds on biological processes, possibly including DNA transcription.
研究了反式铂的新衍生物，即反式-[PtCl2(二乙胺)(NH3)]（二乙胺 = 二乙胺）的毒性，其中顺铂敏感和耐药肿瘤细胞系中只有一个NH3基团被一个小的、非庞大的二乙胺配体取代。结果表明，反式铂分子的这种非常小的修饰导致癌细胞毒性显著增强。因此，这一发现与以下论点一致：在Pt(II)-二氯化合物中，反式构型也可以通过用非庞大配体（如短脂肪胺(C2H5)2NH）取代反式铂中的仅一个NH3配体而有效激活。我们还证明，与反式铂不同，反式-[PtCl2(二乙胺)(NH3)]可以与具有抗肿瘤活性并能够诱导溶原性细菌裂解的配位化合物归为一类。因此，这些结果首次为DNA也是反式铂抗肿瘤衍生物的潜在细胞靶点这一观点提供了实验支持。还研究了反式-[PtCl2(二乙胺)(NH3)]在无细胞培养基中的DNA结合模式。结果表明，小脂肪族二乙胺配体对DNA构象变化有显著影响。与“经典”反式铂不同，用反式-[PtCl2(二乙胺)(NH3)]修饰DNA主要导致双功能交联。这种新的反式铂配合物对DNA双螺旋结构的破坏程度和稳定性与顺铂诱导的相似。因此，这些损伤与顺铂的损伤类似，有效地抑制了模板DNA的转录，但明显比反式铂的损伤更有效。与反式铂加合物相比，反式-[PtCl2(二乙胺)(NH3)]加合物对DNA转录的更强抑制为铂化合物中活化的反式构型对生物过程（可能包括DNA转录）的影响增加了一个新的维度。
