Chemistry and Biology of Two Novel Gold(I) Carbene Complexes as Prospective Anticancer Agents

Abstract

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.

First Crystal Structure for a Gold Carbene–Protein Adduct

“…Thanks to their favorable and peculiar chemical and biological properties, gold(I) Nheterocyclic carbene compounds have been tested extensively in recent years as antiarthritic 15 , antibacterial 16 and anticancer agents 2,[11][12][13][14][18][19][20][21][22][23][24][25][26] .…”

Structural evidences for a secondary gold binding site in the hydrophobic box of lysozyme

“…6) and at pH 4.5 (Fig. S1), according to previously reported protocols (Messori et al 2014c) (see ''Materials and Methods'' for details). The ESImass spectrum obtained at pH 6.8 is shown in Fig.…”

Current Researches and Applications of Azole-BasedSupermolecules as Medicinal Agents

“…金(I)桥联的双咪唑氮杂环卡宾 12 在生理 pH 下非常 稳定, 对卵巢癌 A2780 细胞的抑制能力非常强, 活性 是顺铂的两倍, 并且对耐顺铂的卵巢癌 A2780cisR 细胞 的 IC 50 值为 0.75 mol/L, 活性远优于顺铂, 其体外安全 性评估和进一步的抗癌活性研究正在进行中 [74] . [75,76] .…”