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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism
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Cell Line, Tumor
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Cysteine / metabolism
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Drug Design
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Drug Screening Assays, Antitumor
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Gold / chemistry*
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Gold / pharmacokinetics
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Gold / pharmacology
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Heterocyclic Compounds / chemical synthesis
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Heterocyclic Compounds / chemistry
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Heterocyclic Compounds / pharmacokinetics
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Heterocyclic Compounds / pharmacology
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Humans
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Methane / analogs & derivatives
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Methane / chemical synthesis
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Methane / chemistry
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Methane / pharmacokinetics
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Methane / pharmacology
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Mitochondria / drug effects
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Mitochondria / enzymology
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Mitochondria / metabolism*
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Mitochondrial Proteins / metabolism*
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Organometallic Compounds / chemical synthesis
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Organometallic Compounds / chemistry*
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Organometallic Compounds / pharmacokinetics
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Organometallic Compounds / pharmacology*
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Selenocysteine / metabolism
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Thioredoxin-Disulfide Reductase / antagonists & inhibitors
Substances
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Antineoplastic Agents
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Heterocyclic Compounds
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Mitochondrial Proteins
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Organometallic Compounds
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Selenocysteine
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carbene
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Gold
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Thioredoxin-Disulfide Reductase
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Cysteine
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Methane