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

20 January 2020, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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.


HIF 1 activation


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