Abstract

Topoisomerase IIα (topo2α) is an essential nuclear enzyme involved in DNA replication, transcription, recombination, chromosome condensation, and highly expressed in many tumors. Thus, topo2α-targeting has become a very efficient and well-established anticancer strategy. Herein, we investigate the cytotoxic and DNA-damaging activity of thiomaltol-containing ruthenium-, osmium-, rhodium- and iridium-based organometallic complexes in human mammary carcinoma cell lines by means of several biological assays, including knockdown of topo2α expression levels by RNA interference. Results suggest that inhibition of topo2α is a key process in the cytotoxic mechanism for some of the compounds, whereas direct induction of DNA double-strand breaks or other DNA damage is mostly rather minor. In addition, molecular modeling studies performed for two of the compounds (with Ru(II) as the metal center) evinces that these complexes are able to access the DNA-binding pocket of the enzyme, where the hydrophilic environment favors the interaction with highly polar complexes. These findings substantiate the potential of these compounds for application as antitumor metallopharmaceuticals.

Graphic abstract

中文翻译：

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新型的基于硫代麦芽酚的有机金属配合物作为拓扑异构酶IIα抑制剂的生物学评估。

摘要

拓扑异构酶IIα（topo2α）是参与DNA复制，转录，重组，染色体浓缩并在许多肿瘤中高表达的必需核酶。因此，以topo2α为靶点已成为一种非常有效且建立良好的抗癌策略。在这里，我们通过几种生物学方法研究了含硫代麦芽酚的钌，，铑和铱基有机金属配合物在人乳腺癌细胞系中的细胞毒性和DNA损伤活性，包括通过RNA抑制topo2α表达水平干扰。结果表明，对某些化合物的细胞毒性机制中，对topo2α的抑制是关键过程，而直接诱导DNA双链断裂或其他DNA损伤的作用很小。此外，对其中两种化合物（以Ru（II）为金属中心）进行的分子建模研究表明，这些配合物能够进入酶的DNA结合口袋，而亲水环境有利于与高极性配合物的相互作用。这些发现证实了这些化合物用作抗肿瘤金属药物的潜力。

图形摘要