Messori Luigi, Marchetti Lorella, Massai Lara, Scaletti Federica, Guerri Annalisa, Landini Ida, Nobili Stefania, Perrone Gabriele, Mini Enrico, Leoni Piero, Pasquali Marco, Gabbiani Chiara
Laboratory of Metals in Medicine, Department of Chemistry, University of Florence , via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
Inorg Chem. 2014 Mar 3;53(5):2396-403. doi: 10.1021/ic401731a. Epub 2014 Feb 18.
Two novel gold carbene compounds, namely, chlorido (1-butyl-3-methyl-imidazole-2-ylidene) gold(I) (1) and bis(1-butyl-3-methyl-imidazole-2-ylidene) gold(I) (2), were prepared and characterized as prospective anticancer drug candidates. These compounds consist of a gold(I) center linearly coordinated either to one N-heterocyclic carbene (NHC) and one chloride ligand (1) or to two identical NHC ligands (2). Crystal structures were solved for both compounds, the resulting structural data being in good agreement with expectations. We wondered whether the presence of two tight carbene ligands in 2 might lead to biological properties distinct from those of the monocarbene complex 1. Notably, in spite of their appreciable structural differences, these two compounds manifested similarly potent cytotoxic actions in vitro when challenged against A2780 human ovarian carcinoma cells. In addition, both were able to overcome resistance to cisplatin in the A2780R line. Solution studies revealed that these gold carbene complexes are highly stable in aqueous buffers at physiological pH. Their reactivity with proteins was explored: no adduct formation was detected even upon a long incubation with the model proteins cytochrome c and lysozyme; in contrast, both compounds were able to metalate, to a large extent, the copper chaperone Atox-1, bearing a characteristic CXXC motif. The precise nature of the resulting gold-Atox-1 adducts was elucidated through ESI-MS analysis. On the basis of these findings, it is proposed that the investigated gold(I) carbene compounds are promising antiproliferative agents warranting a wider pharmacological evaluation. Most likely these gold compounds produce their potent biological effects through selective metalation and impairment of a few crucial cellular proteins.
制备了两种新型的金卡宾化合物，即氯（1-丁基-3-甲基咪唑-2-亚基）金（I）（1）和双（1-丁基-3-甲基咪唑-2-亚基）金（I）（2），并将其表征为有前景的抗癌药物候选物。这些化合物由一个金（I）中心组成，该中心与一个N-杂环卡宾（NHC）和一个氯配体（1）线性配位，或者与两个相同的NHC配体（2）线性配位。解析了这两种化合物的晶体结构，所得结构数据与预期结果吻合良好。我们想知道化合物2中两个紧密的卡宾配体的存在是否会导致其生物学性质与单卡宾配合物1不同。值得注意的是，尽管它们在结构上有明显差异，但这两种化合物在体外对A2780人卵巢癌细胞进行测试时表现出相似的强效细胞毒性作用。此外，两者都能够克服A2780R细胞系对顺铂的耐药性。溶液研究表明，这些金卡宾配合物在生理pH值的水性缓冲液中高度稳定。研究了它们与蛋白质的反应性：即使与模型蛋白质细胞色素c和溶菌酶长时间孵育，也未检测到加合物形成；相反，这两种化合物都能够在很大程度上使带有特征CXXC基序的铜伴侣蛋白Atox-1金属化。通过电喷雾电离质谱（ESI-MS）分析阐明了所得金-Atox-1加合物的确切性质。基于这些发现，有人提出所研究的金（I）卡宾化合物是有前途的抗增殖剂，值得进行更广泛的药理学评估。很可能这些金化合物通过选择性金属化和损害一些关键细胞蛋白而产生其强效生物学效应。
