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Artemisinin NHC.pdf (6.96 MB)

Artemisinin-Derivative-NHC-gold(I)-Hybrid with Enhanced Cytotoxic Activity Through Inhibiting NRF2 Transcriptional Activity

submitted on 17.01.2020, 09:27 and posted on 20.01.2020, 12:54 by Chen Zhang, Pierre-Yves Fortin, Guillaume Barnoin, Xue Qin, Xing Wang, Alvaro Fernandez Alvarez, Christian Bijani, Marie-Lise Maddelein, Catherine Hemmert, Olivier CUVILLIER, Heinz Gornitzka

A family of original bis(artemisinin-NHC)gold(I) complexes have been synthesized. These hybrid molecules combine two biological active motifs, an artemisinin derivative (DHA) and a cationic bis(NHC)gold(I) unit. One of these complexes, complex 2a, has been analyzed by single-crystal X-ray diffraction and tested in depth for its anticancer properties. Complex 2a shows strong anticancer activities on a representative panel of human cancer cell models from 8 different localizations (prostate, breast, lung, liver, bladder, bone, acute and chronic myeloid leukemias). Complex 2a shows anticancer activity to a much better degree than Auranofin and DHA standards with GI50 values in nM range, together with a superior selectivity in regard to non-cancer cell models. Next to expected ROS formation and TrxR inhibition, an original and distinctive mechanism of action through inhibition of NRF2 - a transcription factor strongly associated with aggressiveness and resistance to cancer therapies - with an IC50 value at nM range has been evidenced. Importantly, the NRF2 inhibitory effect of complex 2a could remarkably sensitize to sorafenib in HepG2 liver cells, in which dysregulated NRF2 signaling is known to be associated with primary and acquired drug resistance. Moreover, complex 2a also inhibited NF-κB and HIF transcriptional activities, which are also linked to progression and resistance in cancer. Our findings provide experimental evidence that hybrid (NHC)gold(I) molecules - such as complex 2a - represent a new class of organometallic hybrid molecules that may yield new therapeutic agents.


Email Address of Submitting Author


Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS



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Declaration of Conflict of Interest


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manuscript version 1