Beyond Thiol-Enzyme Inhibition: Sterically Bulky NHC-Au(I) Complexes are Catalytically Active Anticancer Agents with...

Area of Science:

• Medicinal Chemistry
• Immunology
• Nanotechnology

Background:

• Metallodrugs, particularly gold compounds, show promise for cancer immunotherapy by inducing immunogenicity.
• However, some heavy metals can impair immune cell function, limiting their therapeutic potential.
• There is a need for metallodrugs that enhance immunogenicity without compromising immune integrity.

Purpose of the Study:

• To develop sterically bulky gold(I) complexes as catalytically active anticancer agents.
• To investigate the immunomodulatory effects of these novel gold compounds.
• To design gold-based therapeutics that enhance anticancer efficacy through immune system modulation.

Main Methods:

• Synthesis and characterization of sterically bulky Au(I) complexes, including IPr-Au-Cl and Au-8.
• Evaluation of catalytic activity, including alkyne probe activation and hydride transfer.
• Assessment of cytotoxicity against cancer cells and immunomodulatory effects in vitro, ex vivo, and in vivo.
• Analysis of proteomic responses, focusing on thioredoxin reductase 1 (TrxR1) inhibition.

Main Results:

• The novel gold compound Au-8 demonstrated enhanced catalytic activity and improved cytotoxicity compared to initial complexes.
• Au-8 induced immunogenic cell death markers (e.g., CRT exposure) and elevated ROS levels, similar to auranofin.
• Crucially, Au-8 minimally inhibited TrxR1, unlike auranofin, and maintained/enhanced immune cell function, including phagocytosis and cytotoxic effects.
• Auranofin's inhibition of TrxR1 led to immunosuppression at sub-cytotoxic concentrations.

Conclusions:

• Sterically bulky Au(I) complexes, exemplified by Au-8, can act as effective anticancer agents by reprogramming immunomodulatory function.
• The design strategy leveraging steric hindrance allows for potent anticancer activity without compromising immune cell function via TrxR1 inhibition.
• These findings present a novel class of gold compounds with desirable immunomodulatory effects, paving the way for advanced gold-based cancer therapeutics.