Department of Biosciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore 632014, India.
Department of Chemistry, School of Advanced Science, Vellore Institute of Technology, Vellore 632014, India.
Inorg Chem. 2021 Dec 6;60(23):17593-17607. doi: 10.1021/acs.inorgchem.1c02193. Epub 2021 Nov 12.
In this work, we have synthesized a series of novel C,N-cyclometalated 2-indazole-ruthenium(II) and -iridium(III) complexes with varying substituents (H, CH, isopropyl, and CF) in the R position of the phenyl ring of the 2-indazole chelating ligand. All of the complexes were characterized by H, C, high-resolution mass spectrometry, and elemental analysis. The methyl-substituted 2-indazole-Ir(III) complex was further characterized by single-crystal X-ray analysis. The cytotoxic activity of new ruthenium(II) and iridium(III) compounds has been evaluated in a panel of triple negative breast cancer (TNBC) cell lines (MDA-MB-231 and MDA-MB-468) and colon cancer cell line HCT-116 to investigate their structure-activity relationships. Most of these new complexes have shown appreciable activity, comparable to or significantly better than that of cisplatin in TNBC cell lines. R substitution of the phenyl ring of the 2-indazole ligand with methyl and isopropyl substituents showed increased potency in ruthenium(II) and iridium(III) complexes compared to that of their parent compounds in all cell lines. These novel transition metal-based complexes exhibited high specificity toward cancer cells by inducing alterations in the metabolism and proliferation of cancer cells. In general, iridium complexes are more active than the corresponding ruthenium complexes. The new Ir(III)-2-indazole complex with an isopropyl substituent induced mitochondrial damage by generating large amounts of reactive oxygen species (ROS), which triggered mitochondrion-mediated apoptosis in TNBC cell line MDA-MB-468. Moreover, this complex also induced G2/M phase cell cycle arrest and inhibited cellular migration of TNBC cells. Our findings reveal the key roles of the novel C-N-cyclometalated 2-indazole-Ir(III) complex to specifically induce toxicity in cancer cell lines through contributing effects of ROS-induced mitochondrial disruption along with chromosomal and mitochondrial DNA target inhibition.
在这项工作中，我们合成了一系列新型的 C,N-环金属化 2-吲哚钌(II)和-铱(III)配合物，其中 2-吲哚螯合配体的苯基环的 R 位置上的取代基为 H、CH、异丙基和 CF。所有配合物均通过 H、C、高分辨率质谱和元素分析进行了表征。进一步通过单晶 X 射线分析对甲基取代的 2-吲哚-Ir(III)配合物进行了表征。新的钌(II)和铱(III)化合物的细胞毒性活性已在一组三阴性乳腺癌(TNBC)细胞系(MDA-MB-231 和 MDA-MB-468)和结肠癌细胞系 HCT-116 中进行了评估，以研究它们的构效关系。这些新的配合物大多数表现出相当大的活性，与顺铂在 TNBC 细胞系中的活性相当或显著更好。与母体化合物相比，2-吲哚配体的苯基环上的 R 取代基用甲基和异丙基取代后，在所有细胞系中，钌(II)和铱(III)配合物的活性均有所提高。这些新型过渡金属基配合物通过诱导癌细胞代谢和增殖的改变，对癌细胞表现出高特异性。一般来说，铱配合物比相应的钌配合物更活跃。具有异丙基取代基的新型 Ir(III)-2-吲哚配合物通过产生大量活性氧(ROS)诱导线粒体损伤，从而触发 TNBC 细胞系 MDA-MB-468 中线粒体介导的细胞凋亡。此外，该配合物还诱导 G2/M 期细胞周期停滞并抑制 TNBC 细胞的细胞迁移。我们的研究结果表明，新型 C-N-环金属化 2-吲哚-Ir(III)配合物通过 ROS 诱导的线粒体破坏以及染色体和线粒体 DNA 靶抑制的协同作用，特异性诱导癌细胞系产生毒性，发挥关键作用。
