Mitochondria-targeted chemotherapeutics: the rational design of gold(I) N-heterocyclic carbene complexes that are selectively toxic to cancer cells and target protein selenols in preference to thiols

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Title Mitochondria-targeted chemotherapeutics: the rational design of gold(I) N-heterocyclic carbene complexes that are selectively toxic to cancer cells and target protein selenols in preference to thiols
Author Hickey, James L.; Ruhayel, Rasha A.; Barnard, Peter J.; Baker, Murray V.; Berners-Price, Sue; Filipovska, Aleksandra
Journal Name Journal of the American Chemical Society
Year Published 2008
Place of publication United States
Publisher American Chemical Society
Abstract 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.
Peer Reviewed Yes
Published Yes
Publisher URI http://pubs.acs.org/journal/jacsat
Copyright Statement Copyright 2008 American Chemical Society. Self-archiving of the author-manuscript version is not yet supported by this publisher. Please refer to the journal link for access to the definitive, published version or contact the authors for more information.
Volume 130
Issue Number 38
Page from 12570
Page to 12571
ISSN 0002-7863
Date Accessioned 2010-07-23
Date Available 2010-11-04T07:07:08Z
Language en_AU
Research Centre Institute for Glycomics
Faculty Faculty of Science, Environment, Engineering and Technology
Subject Bioinorganic Chemistry
URI http://hdl.handle.net/10072/33124
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1x

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