Bertrand Benoît, Stefan Loic, Pirrotta Marc, Monchaud David, Bodio Ewen, Richard Philippe, Le Gendre Pierre, Warmerdam Elena, de Jager Marina H, Groothuis Geny M M, Picquet Michel, Casini Angela
Dept. Pharmacokinetics, Toxicology and Targeting, Research Institute of Pharmacy, University of Groningen , Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Inorg Chem. 2014 Feb 17;53(4):2296-303. doi: 10.1021/ic403011h. Epub 2014 Feb 5.
A new series of gold(I) N-heterocyclic carbene (NHC) complexes based on xanthine ligands have been synthesized and characterized by mass spectrometry, NMR, and X-ray diffraction. The compounds have been tested for their antiproliferative properties in human cancer cells and nontumorigenic cells in vitro, as well as for their toxicity in healthy tissues ex vivo. The bis-carbene complex [Au(caffein-2-ylidene)2][BF4] (complex 4) appeared to be selective for human ovarian cancer cell lines and poorly toxic in healthy organs. To gain preliminary insights into their actual mechanism of action, two biologically relevant in cellulo targets were studied, namely, DNA (more precisely a higher-order DNA structure termed G-quadruplex DNA that plays key roles in oncogenetic regulation) and a pivotal enzyme of the DNA damage response (DDR) machinery (poly-(adenosine diphosphate (ADP)-ribose) polymerase 1 (PARP-1), strongly involved in the cancer resistance mechanism). Our results indicate that complex 4 acts as an efficient and selective G-quadruplex ligand while being a modest PARP-1 inhibitor (i.e., poor DDR impairing agent) and thus provide preliminary insights into the molecular mechanism that underlies its antiproliferative behavior.
基于黄嘌呤配体的一系列新型金（I）氮杂环卡宾（NHC）配合物已被合成，并通过质谱、核磁共振和X射线衍射进行了表征。这些化合物已在体外对人癌细胞和非致瘤细胞进行了抗增殖特性测试，以及在离体健康组织中进行了毒性测试。双卡宾配合物[Au（咖啡因-2-亚基）2][BF4]（配合物4）对人卵巢癌细胞系具有选择性，且在健康器官中的毒性较低。为了初步了解其实际作用机制，研究了两个在细胞内具有生物学相关性的靶点，即DNA（更确切地说是一种在肿瘤发生调控中起关键作用的高阶DNA结构，称为G-四链体DNA）和DNA损伤反应（DDR）机制中的一种关键酶（聚（腺苷二磷酸（ADP）-核糖）聚合酶1（PARP-1），强烈参与抗癌机制）。我们的结果表明，配合物4作为一种高效且选择性的G-四链体配体，同时是一种适度的PARP-1抑制剂（即对DDR损害作用较弱的试剂），从而为其抗增殖行为的分子机制提供了初步见解。
