Novel lawsone-containing ruthenium(II) complexes: Synthesis, characterization and anticancer activity on 2D and 3D spheroid models of prostate cancer cells
Novel lawsone-containing ruthenium(II) complexes: Synthesis, characterization and anticancer activity on 2D and 3D spheroid models of prostate cancer cells
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DOI：
10.1016/j.bioorg.2019.02.010
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发表时间：
2019-04-01
影响因子：
5.1
通讯作者：
Pavan, Fernando Rogerio
中科院分区：
文献类型：
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作者：
De Grandis, Rone Aparecido;da Silva dos Santos, Patrick Wellington;Pavan, Fernando Rogerio
本研究描述了一系列新合成的膦/二亚胺钌络合物，其中含有指甲花酮作为生物配体，其对不同癌细胞具有增强的细胞毒性，并能诱导前列腺癌细胞 DU-145 凋亡。配合物 [Ru(law)(N-N)(2)]PF6，其中 N-N 为 2,2'-联吡啶 (1) 或 1,10-菲咯啉 (2) 和 [Ru(law)(dppm)(N-N)]PF6，其中 dppm 表示双(二苯基膦)甲烷，N-N 为 2,2'-联吡啶 (3) 或 1,10-菲咯啉(4) 法合成了指甲花酮，并通过元素分析、摩尔电导率、核磁共振、紫外可见分光光度计、红外光谱和循环伏安法进行了充分表征。通过圆二色性、凝胶电泳和荧光评价了配合物(1-4)与DNA的相互作用，配合物呈现出小沟DNA的相互作用。次膦酸系列复合物表现出非常广谱的抗癌活性，比顺铂高约34倍，比阿霉素高5倍，抑制3D肿瘤球体的生长并保持DU-145细胞集落存活的能力。此外，复合物 (4) 抑制 DU-145 细胞粘附和迁移潜力，表明具有抗转移特性。其抗癌活性的机制被发现与增加活性氧（ROS）的产生、增加BAX/BCL-2比率以及随后的细胞凋亡诱导有关。总体而言，这些发现表明复合物 (4) 可能是作为前列腺癌治疗中的化疗剂进行进一步评估的有希望的候选者。
This study describes a series of newly synthesized phosphine/diimine ruthenium complexes containing the lawsone as bioligand with enhanced cytotoxicity against different cancer cells, and apoptosis induction in prostatic cancer cells DU-145. The complexes [Ru(law)(N-N)(2)]PF6 where N-N is 2,2'-bipyridine (1) or 1,10-phenanthroline (2) and [Ru(law)(dppm)(N-N)]PF6, where dppm means bis(diphenylphosphino)methane, N-N is 2,2'-bipyridine (3) or 1,10-phenanthroline (4), and law is lawsone, were synthesized and fully characterized by elemental analysis, molar conductivity, NMR, UV-vis, IR spectroscopies and cyclic voltammetry. The interaction of the complexes (1-4) with DNA was evaluated by circular dichroism, gel electrophoresis, and fluorescence, and the complexes presented interactions by the minor grooves DNA. The phosphinic series of complexes exhibited a remarkably broad spectrum of anticancer activity with approximately 34-fold higher than cisplatin and 5-fold higher than doxorubicin, inhibiting the growth of 3D tumor spheroids and the ability to retain the colony survival of DU-145 cells. Also, the complex (4) inhibits DU-145 cell adhesion and migration potential indicating antimetastatic properties. The mechanism of its anticancer activity was found to be related to increased reactive oxygen species (ROS) generation, increased the BAX/BCL-2 ratio and subsequent apoptosis induction. Overall, these findings suggested that the complex (4) could be a promising candidate for further evaluation as a chemotherapeutic agent in the prostate cancer treatment.