Oliveira Katia M, Liany Luna-Dulcey, Corrêa Rodrigo S, Deflon Victor M, Cominetti Marcia R, Batista Alzir A
Departamento de Química, Universidade Federal de São Carlos, CP 676, CEP 13565-905, São Carlos, SP, Brazil.
Departamento de Gerontologia, Universidade Federal de São Carlos, CP 676, CEP 13565-905, São Carlos, SP, Brazil.
J Inorg Biochem. 2017 Nov;176:66-76. doi: 10.1016/j.jinorgbio.2017.08.019. Epub 2017 Aug 26.
New Ru(II) complexes with lawsone (law) characterized as trans-[Ru(law)(PPh)(N-N)]PF, where PPh means triphenylphosphine and N-N is 2,2'-bipyridine (1), 4,4'-dimethyl-2,2'-bipyridine (2), 4,4'-dimethoxy-2,2'-bipyridine (3), 1,10-phenanthroline (4) or 4,7-diphenyl-1,10-phenanthroline (5), induce apoptosis in tumor cells. Cytotoxicity of the complexes against the tumor cell lines DU-145 (prostate cancer cells), MCF-7 (breast cancer cells), A549 (lung cancer cells) and lung non-tumor cell line MRC-5 demonstrated promising IC values, lower than those found for the cisplatin, a drug used as a reference. Due to the high cytotoxic activity and selectivity against A549 cells line, complex (5) was selected for detailed assays. The complex (5) inhibits cells migration in concentrations in a nanomolar range, inducing tumor cell death by apoptosis, as confirmed by flow cytometry experiments. Furthermore, the antiproliferative activity of complex (5) on A549 tumor cells is attributed to a cell cycle arrest at the Sub G1 phase, followed by a decrease in the number of cells at the S phase. In addition, the interaction of the complexes (1-5) with CT-DNA was evaluated by circular dichroism, in which no changes in the secondary structure of DNA were observed, suggesting a weak interaction of the complexes with the biomolecule. On the other hand, complexes (1-5) showed a higher interaction with human serum albumin (HSA) by non-covalent van der Waals forces and hydrogen bonding, resulting in static quenching.
新的与拉索酸（law）形成的钌（II）配合物，其结构表征为反式-[Ru(law)(PPh)(N-N)]PF，其中PPh表示三苯基膦，N-N为2,2'-联吡啶（1）、4,4'-二甲基-2,2'-联吡啶（2）、4,4'-二甲氧基-2,2'-联吡啶（3）、1,10-菲咯啉（4）或4,7-二苯基-1,10-菲咯啉（5），可诱导肿瘤细胞凋亡。这些配合物对肿瘤细胞系DU-145（前列腺癌细胞）、MCF-7（乳腺癌细胞）、A549（肺癌细胞）和肺非肿瘤细胞系MRC-5的细胞毒性显示出有前景的半数抑制浓度（IC）值，低于用作参考药物的顺铂的IC值。由于对A549细胞系具有高细胞毒性活性和选择性，选择配合物（5）进行详细分析。如流式细胞术实验所证实，配合物（5）在纳摩尔浓度范围内抑制细胞迁移，通过凋亡诱导肿瘤细胞死亡。此外，配合物（5）对A549肿瘤细胞的抗增殖活性归因于细胞周期停滞在G1期亚群，随后S期细胞数量减少。另外，通过圆二色性评估了配合物（1 - 5）与CT-DNA的相互作用，其中未观察到DNA二级结构的变化，表明配合物与生物分子的相互作用较弱。另一方面,配合物（1 - 5）通过非共价范德华力和氢键与人血清白蛋白（HSA）表现出更强的相互作用，导致静态猝灭。
