Document Detail

Gold(I) carbene complexes causing thioredoxin 1 and thioredoxin 2 oxidation as potential anticancer agents.
MedLine Citation:
PMID:  22621714     Owner:  NLM     Status:  Publisher    
Gold(I) complexes with 1,3-substituted imidazole-2-ylidene and benzimidazole-2-ylidene ligands of the type NHC-Au-L (NHC = N-hetero-cyclic carbene L = Cl or 2-mercapto-pyrimidine have been synthesized and structurally characterized. The compounds were evaluated for their antiproliferative properties in human ovarian cancer cells sensitive and resistant to cisplatin (A2780S/R), as well in the non-tumorigenic human embryonic kidney cell line (HEK-293T), showing in some cases important cytotoxic effects. Some of the complexes were comparatively tested as thioredoxin reductase (TrxR) and glutathione reductase (GR) inhibitors, directly against the purified proteins or in cell extracts from both cancerous and non-tumorigenic cell lines. Interestingly, the compounds showed potent and selective TrxR inhibition properties in particular in cancer cell lines, most likely due to the direct binding of Au(I) to the selenol moiety in the TrxR C-terminus active site. Remarkably, the most effective TrxR inhibitors induced extensive oxidation of thioredoxins (Trxs), which was more relevant in the cancerous cells with respect to the HEK-293T cells. Additional biochemical assays (eg. effect on the glutathione system, evaluation of enhancement of reactive oxygen species (ROS) formation) evidenced important differences with respect to the classical cytotoxic Au(I)-phosphine compound auranofin. The results have been discussed in relation to the possible mechanisms of action of Au(I) NHC complexes.
Esther Schuh; Carolin Pflueger; Anna Citta; Alessandra Folda; Maria Pia Rigobello; Alberto Bindoli; Angela Casini; Fabian Mohr
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-5-24
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  -     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-5-24     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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