Artemisinin‐Derivative‐NHC‐gold(I)‐Hybrid with enhanced cytotoxic activity through inhibiting NRF2 transcriptional activity

A family of original hybrid complexes combining two biological active motifs, an artemisinin derivative and a cationic bis(NHC)gold(I) unit, has been synthesized. One of these complexes, 2a , has been analyzed by single-crystal X-ray diffraction. 2a shows strong anticancer activities on a large panel of representative human cancer cell models (prostate, breast, lung, liver, bladder, bone, acute and chronic myeloid leukemias) with GI 50 values in nM range, together with a high selectivity. An original and distinctive mechanism of action, through inhibition of the redox antioxidant NRF2 transcription factor - strongly associated with aggressiveness and resistance to cancer therapies - has been evidenced. 2a could remarkably sensitize to sorafenib in HepG2 liver cells, in which dysregulated NRF2 signaling is linked to primary and acquired drug resistance. 2a also inhibited NF-kappaB and HIF transcriptional activities, which are also associated with progression and resistance in cancer. Our findings provide evidence that hybrid (NHC)gold(I) molecules represent a new class of organometallic hybrid molecules that may yield new therapeutic agents.