Pracharova Jitka, Saltarella Teresa, Radosova Muchova Tereza, Scintilla Simone, Novohradsky Vojtech, Novakova Olga, Intini Francesco P, Pacifico Concetta, Natile Giovanni, Ilik Petr, Brabec Viktor, Kasparkova Jana
Department of Biophysics, Centre of the Region Hana for Biotechnological and Agricultural Research, Palacky University , Slechtitelu 11, 783 41 Olomouc, Czech Republic.
J Med Chem. 2015 Jan 22;58(2):847-59. doi: 10.1021/jm501420k. Epub 2014 Dec 23.
The current work investigates the effect of new bifunctional and mononuclear Pt(II) compounds, the cis- and trans-isomers of [PtCl2(NH3)(L)] (L = 1-methyl-7-azaindole, compounds 1 and 2, respectively), on growth and viability of human carcinoma cells as well as their putative mechanism(s) of cytotoxicity. The results show that substitution of 1-methyl-7-azaindole for ammine in cisplatin or transplatin results in an increase of the toxic efficiency, selectivity for tumor cells in cisplatin-resistant cancer cells, and activation of the trans geometry. The differences in the cytotoxic activities of 1 and 2 were suggested to be due to their different DNA binding mode, different capability to induce cell cycle perturbations, and fundamentally different role of transcription factor p53 in their mechanism of action. Interestingly, both isomers make it possible to detect their cellular uptake and distribution in living cells by confocal microscopy without their modification with an optically active tag.
当前的研究工作考察了新型双功能单核铂（II）化合物，即[PtCl2(NH3)(L)]的顺式和反式异构体（L = 1-甲基-7-氮杂吲哚，分别为化合物1和2）对人癌细胞生长和活力的影响及其潜在的细胞毒性机制。结果表明，在顺铂或反铂中用1-甲基-7-氮杂吲哚取代氨会导致毒性效率增加、对顺铂耐药癌细胞中肿瘤细胞的选择性提高以及反式构型的活化。化合物1和2细胞毒性活性的差异被认为是由于它们不同的DNA结合模式、诱导细胞周期扰动的不同能力以及转录因子p53在其作用机制中根本不同的作用。有趣的是，两种异构体都能够通过共聚焦显微镜检测它们在活细胞中的细胞摄取和分布，而无需用光学活性标签对其进行修饰。
