Bertrand Benoît, Romanov Alexander S, Brooks Mark, Davis Josh, Schmidt Claudia, Ott Ingo, O'Connell Maria, Bochmann Manfred
School of Chemistry, University of East Anglia, Norwich NR4 7TJ, UK.
Dalton Trans. 2017 Nov 21;46(45):15875-15887. doi: 10.1039/c7dt03189k.
A series of complexes of cyclic (alkyl)(amino)carbene (CAAC) complexes of copper, silver and gold have been investigated for their antiproliferative properties. A second series of acyclic carbene (ACC) complexes of gold(i) were prepared by nucleophilic attack on isocyanide complexes by amines and amino esters, to give (ACC)AuCl, [(ACC)Au(PTA)] (PTA = triazaphosphaadamantane), as well as mixed-carbene compounds [(CAAC)Au(ACC)]. Representative complexes were characterised by X-ray diffraction which confirmed the mononuclear linear structures without close intermolecular contacts or aurophilic interactions. The redox properties of these complexes have been determined. The compounds were tested against a panel of human cancer cell lines including leukemia (HL 60), breast adenocarcinoma cells (MCF-7) and human lung adenocarcinoma epithelial cell lines (A549), which show varying degrees of cisplatin resistance. The pro-ligand iminium salts and the PTA complexes were non-toxic. By contrast, the CAAC complexes show high cytotoxicity, with IC values in the sub-micromolar to ∼100 nanomolar range, even against cisplatin-insensitive MCF-7 and A549 cells. Cationic bis-carbene complexes [(CAAC)M] (6-8, M = Cu, Ag and Au) proved particularly effective. The mechanism of cell growth control by these complexes remains to be established, although possible modes of action such as inhibition of thioredoxin reductase (TrxR), which is a common pathway for gold NHC compounds, or the formation of reactive oxygen species (ROS) through redox processes, could be ruled out as primary pathways.
人们对一系列铜、银和金的环状（烷基）（氨基）卡宾（CAAC）配合物的抗增殖特性进行了研究。通过胺类和氨基酯对异腈配合物进行亲核进攻，制备了第二系列的金（I）无环卡宾（ACC）配合物，得到了（ACC）AuCl、[(ACC)Au(PTA)]（PTA = 三氮杂磷金刚烷）以及混合卡宾化合物[(CAAC)Au(ACC)]。通过X射线衍射对代表性配合物进行了表征，证实了其单核线性结构，不存在紧密的分子间接触或亲金相互作用。测定了这些配合物的氧化还原性质。这些化合物针对包括白血病（HL 60）、乳腺腺癌细胞（MCF-7）和人肺腺癌上皮细胞系（A549）在内的一组人类癌细胞系进行了测试，这些细胞系表现出不同程度的顺铂耐药性。前体配体亚胺鎓盐和PTA配合物无毒。相比之下，CAAC配合物显示出高细胞毒性，IC值在亚微摩尔至约100纳摩尔范围内，即使对顺铂不敏感的MCF-7和A549细胞也是如此。阳离子双卡宾配合物[(CAAC)M]（6 - 8，M = Cu、Ag和Au）被证明特别有效。尽管可以排除一些可能的作用模式，如抑制硫氧还蛋白还原酶（TrxR）（这是金NHC化合物的常见途径）或通过氧化还原过程形成活性氧（ROS）作为主要途径，但这些配合物控制细胞生长的机制仍有待确定。
