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An Artemisinin‐Derivative–(NHC)Gold(I) Hybrid with Enhanced Cytotoxicity through Inhibition of NRF2 Transcriptional Activity
Author(s) -
Zhang Chen,
Fortin PierreYves,
Barnoin Guillaume,
Qin Xue,
Wang Xing,
Fernandez Alvarez Alvaro,
Bijani Christian,
Maddelein MarieLise,
Hemmert Catherine,
Cuvillier Olivier,
Gornitzka Heinz
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202002992
Subject(s) - cytotoxicity , chemistry , artemisinin , cancer research , transcription factor , pharmacology , biochemistry , in vitro , medicine , gene , immunology , plasmodium falciparum , malaria
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 n m 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‐κB 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.