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Insights into the antiproliferative mechanism of (C^N)-chelated half-sandwich iridium complexes
Dalton Transactions ( IF 4 ) Pub Date : 2020-11-19 , DOI: 10.1039/d0dt03414b
Robin Ramos 1 , Jérémy M Zimbron , Serge Thorimbert , Lise-Marie Chamoreau , Annie Munier , Candice Botuha , Anthi Karaiskou , Michèle Salmain , Joëlle Sobczak-Thépot
Affiliation  

Transition metal-based anticancer compounds, as an alternative to platinum derivatives, are raising scientific interest as they may present distinct although poorly understood mechanisms of action. We used a structure–activity relationship-based methodology to investigate the chemical and biological features of a series of ten (C^N)-chelated half-sandwich iridiumIII complexes of the general formula [IrCp*(phox)Cl], where (phox) is a 2-phenyloxazoline ligand forming a 5-membered metallacycle. This series of compounds undergoes a fast exchange of their chlorido ligand once solubilised in DMSO. They were cytotoxic to HeLa cells with IC50 values in the micromolar range and induced a rapid activation of caspase-3, an apoptosis marker. In vitro, the oxidative power of all the complexes towards NADH was highlighted but only the complexes bearing substituents on the oxazoline ring were able to produce H2O2 at the micromolar range. However, we demonstrated using a powerful HyPer protein redox sensor-based flow cytometry assay that most complexes rapidly raised intracellular levels of H2O2. Hence, this study shows that oxidative stress can partly explain the cytotoxicity of these complexes on the HeLa cell line and gives a first entry to their mechanism of action.

中文翻译:

深入了解(C^N)螯合半夹心铱配合物的抗增殖机制

作为铂衍生物的替代品,基于过渡金属的抗癌化合物引起了科学界的兴趣,因为它们可能表现出不同但知之甚少的作用机制。我们使用基于结构-活性关系的方法研究了一系列具有通式 [IrCp*(phox)Cl]的十个 (C^N) 螯合半夹心铱III配合物的化学和生物学特征,其中( phox) 是形成 5 元金属环的 2-苯基恶唑啉配体。这一系列的化合物一旦溶解在 DMSO 中就会经历它们的氯配体的快速交换。它们对 HeLa 细胞具有细胞毒性,IC 50值在微摩尔范围内,并诱导 caspase-3(一种凋亡标记物)的快速激活。体外,突出显示了所有配合物对 NADH 的氧化能力,但只有在恶唑啉环上带有取代基的配合物能够产生微摩尔范围的H 2 O 2。然而,我们展示了使用强大的基于 HyPer 蛋白氧化还原传感器的流式细胞术检测,大多数复合物可以迅速提高细胞内 H 2 O 2 的水平。因此,这项研究表明,氧化应激可以部分解释这些复合物对 HeLa 细胞系的细胞毒性,并首次介绍了它们的作用机制。
更新日期:2020-11-23
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