Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 59, Issue 29, Pages 12062-12068Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202002992
Keywords
cancer; chemoresistance; metallodrugs; gold; sorefanib
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Funding
- Centre National de la Recherche Scientifique (CNRS)
- Chinese Scholarship Council (CSC)
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A family of hybrid complexes combining two biologically active motifs, an artemisinin derivative and a cationic bis(NHC)-gold(I) unit, has been synthesized. One of these complexes, 2 a, has been analyzed by single-crystal X-ray diffraction. 2 a shows strong anticancer activities on a large panel of human cancer cell models (prostate, breast, lung, liver, bladder, bone, acute and chronic myeloid leukemias) with GI(50) values in the nm range, together with a high selectivity. An original and distinctive mechanism of action, that is, through inhibition of the redox antioxidant NRF2 transcription factor (strongly associated with aggressiveness and resistance to cancer therapies) has been evidenced. 2 a could remarkably sensitize to sorafenib in HepG2 liver cells, in which dysregulated NRF2 signaling is linked to primary and acquired drug resistance. 2 a also inhibited NF-kappa B and HIF transcriptional activities, which are also associated with progression and resistance in cancer. Our findings provide evidence that hybrid (NHC)gold(I) compounds represent a new class of organometallic hybrid molecules that may yield new therapeutic agents.
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