State Key Laboratory of Synthetic Chemistry, Institute of Molecular Functional Materials, Chemical Biology Centre and Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, China.
HKU Shenzhen Institute of Research and Innovation, Shenzhen, 518053, China.
Angew Chem Int Ed Engl. 2017 Mar 27;56(14):3892-3896. doi: 10.1002/anie.201612583. Epub 2017 Mar 1.
Metal N-heterocyclic carbene (NHC) complexes are a promising class of anti-cancer agents displaying potent in vitro and in vivo activities. Taking a multi-faceted approach employing two clickable photoaffinity probes, herein we report the identification of multiple molecular targets for anti-cancer active pincer gold(III) NHC complexes. These complexes display potent and selective cytotoxicity against cultured cancer cells and in vivo anti-tumor activities in mice bearing xenografts of human cervical and lung cancers. Our experiments revealed the specific engagement of the gold(III) complexes with multiple cellular targets, including HSP60, vimentin, nucleophosmin, and YB-1, accompanied by expected downstream mechanisms of action. Additionally, Pt and Pd analogues can also bind the cellular proteins targeted by the gold(III) complexes, uncovering a distinct pincer cyclometalated metal-NHC scaffold in the design of anti-cancer metal medicines with multiple molecular targets.
金属氮杂环卡宾（NHC）配合物是一类很有前途的抗癌药物，具有很强的体外和体内活性。采用多方面的方法，使用两种可点击的光亲和探针，本文报道了抗癌活性的钳形金（III）NHC 配合物的多个分子靶标的鉴定。这些配合物对培养的癌细胞表现出很强的选择性细胞毒性，并且在携带人宫颈癌和肺癌异种移植物的小鼠体内具有抗肿瘤活性。我们的实验揭示了金（III）配合物与包括 HSP60、波形蛋白、核仁磷酸蛋白和 YB-1 在内的多种细胞靶标的特异性结合，同时伴随着预期的下游作用机制。此外，Pt 和 Pd 类似物也可以与金（III）配合物靶向的细胞蛋白结合，揭示了在设计具有多个分子靶标的抗癌金属药物时，独特的钳形环金属化金属-NHC 支架。
