Hickey James L, Ruhayel Rasha A, Barnard Peter J, Baker Murray V, Berners-Price Susan J, Filipovska Aleksandra
The University of Western Australia, School of Biomedical, Biomolecular and Chemical Sciences, 35 Stirling Highway, Crawley, Western Australia 6009, Australia.
J Am Chem Soc. 2008 Sep 24;130(38):12570-1. doi: 10.1021/ja804027j. Epub 2008 Aug 26.
A family of lipophilic, cationic Au(I) complexes of N-heterocyclic carbenes (NHCs) have been designed as new mitochondria-targeted antitumor agents that combine both selective mitochondrial accumulation and selective thioredoxin reductase inhibition properties within a single molecule. Two-step ligand exchange reactions with cysteine (Cys) and selenocysteine (Sec) occur with release of the NHC ligands. At physiological pH the rate constants for the reactions with Sec are 20- to 80-fold higher than those with Cys. The complexes are selectively toxic to two highly tumorigenic breast cancer cell lines and not to normal breast cells, and the degree of selectivity and potency are optimized by modification of the substituent on the simple imidazolium salt precursor. The lead compound is shown to accumulate in mitochondria of cancer cells, to cause cell death through a mitochondrial apoptotic pathway and to inhibit the activity of thioredoxin reductase (TrxR) but not the closely related and Se-free enzyme glutathione reductase.
已设计出一类亲脂性的、含氮杂环卡宾（NHC）的阳离子金（I）配合物，作为新型线粒体靶向抗肿瘤剂，其在单个分子中兼具选择性线粒体积累和选择性硫氧还蛋白还原酶抑制特性。与半胱氨酸（Cys）和硒代半胱氨酸（Sec）发生两步配体交换反应，同时释放出NHC配体。在生理pH值下，与Sec反应的速率常数比与Cys反应的速率常数高20至80倍。这些配合物对两种高致瘤性乳腺癌细胞系具有选择性毒性，而对正常乳腺细胞无毒性，并且通过修饰简单咪唑盐前体上的取代基可优化选择性和效力程度。先导化合物显示出积聚在癌细胞的线粒体中，通过线粒体凋亡途径导致细胞死亡，并抑制硫氧还蛋白还原酶（TrxR）的活性，但不抑制密切相关的无硒酶谷胱甘肽还原酶的活性。
