Cytotoxic BODIPY-Appended Half-Sandwich Iridium(III) Complex Forms Protein Adducts and Induces ER Stress,Journal of Medicinal Chemistry

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Cytotoxic BODIPY-Appended Half-Sandwich Iridium(III) Complex Forms Protein Adducts and Induces ER Stress
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-11-11 , DOI: 10.1021/acs.jmedchem.1c01335
Robin Ramos _{1,

2} , Jean-François Gilles ₃ , Romain Morichon ₂ , Cédric Przybylski ₁ , Benoît Caron ₄ , Candice Botuha ₁ , Anthi Karaiskou ₂ , Michèle Salmain ₁ , Joëlle Sobczak-Thépot ₂

Affiliation

Half-sandwich complexes of iridium(III) are currently being developed as anticancer drug candidates. In this context, we introduce IrBDP for which the C^N chelating phenyloxazoline ligand carries a fluorescent and lipophilic BODIPY reporter group, designed for intracellular tracking and hydrophobic compartment tropism. High-resolution analysis of cells cultured with IrBDP showed that it quickly permeates the plasma membrane and accumulates in the mitochondria and endoplasmic reticulum (ER), generating ER stress, dispersal of the Golgi apparatus, cell proliferation arrest and apoptotic cell death. Moreover, IrBDP forms fluorescent adducts with a subset of amino acids, namely histidine and cysteine, via coordination of N or S donor atoms of their side chains. Consistently, in vivo formation of covalent adducts with specific proteins is demonstrated, providing a molecular basis for the observed cytotoxicity and cellular response. Collectively, these results provide a new entry to the development of half-sandwich iridium-based anticancer drugs.

中文翻译：

细胞毒性 BODIPY 附加半三明治铱 (III) 复合物形成蛋白质加合物并诱导 ER 应激

目前正在开发铱（III）的半三明治复合物作为抗癌药物候选物。在这种情况下，我们介绍了IrBDP，其 C^N 螯合苯恶唑啉配体带有荧光和亲脂性 BODIPY 报告基团，设计用于细胞内跟踪和疏水区室趋向性。用IrBDP培养的细胞的高分辨率分析表明，它迅速渗透质膜并在线粒体和内质网 (ER) 中积聚，产生 ER 应激、高尔基体分散、细胞增殖停滞和凋亡细胞死亡。此外，IrBDP与一部分氨基酸（即组氨酸和半胱氨酸）形成荧光加合物，通过侧链的 N 或 S 供体原子的配位。一致地，证明了与特定蛋白质在体内形成共价加合物，为观察到的细胞毒性和细胞反应提供了分子基础。总的来说，这些结果为半夹心铱基抗癌药物的开发提供了新的途径。

更新日期：2021-11-25

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