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

J.L. Hickey, Rasha Ruhayel, Peter Barnard, Murray Baker, Susan Berners-Price, Aleksandra Filipovska

Research output: Contribution to journalArticlepeer-review

513 Citations (Scopus)

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 tumongenic breast cancer cell lines and not to normal breast cells, and the degree of selectivity and potency are optimized by modification 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.
Original languageEnglish
Pages (from-to)12570-12571
JournalJournal of the American Chemical Society
Volume130
Issue number38
DOIs
Publication statusPublished - 2008

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