Anticancer Activity of Imidazolyl Gold(I/III) Compounds in Non-Small Cell Lung Cancer Cell Lines

Area of Science:

• Medicinal Chemistry
• Oncology
• Nanotechnology

Background:

• Lung cancer remains a major global health challenge, necessitating novel therapeutic strategies to overcome drug resistance and severe side effects.
• Existing treatments for non-small cell lung cancer (NSCLC) often face limitations, driving the search for more effective and targeted therapies.

Purpose of the Study:

• To investigate the efficacy of novel gold(I) and gold(III) complexes as inhibitors of non-small cell lung cancer (NSCLC) cell growth.
• To identify specific gold compounds with enhanced cytotoxic activity and understand their molecular mechanisms of action.

Main Methods:

• Synthesis and characterization of eight structurally related gold(I) and gold(III) complexes featuring NHC, halide, and triphenylphosphane ligands.
• Evaluation of the cytotoxic effects of these gold complexes on a panel of NSCLC cell lines.
• Assessment of the inhibition of thioredoxin reductase (TrxR) activity and human dihydrofolate reductase (DHFR) by the most potent gold compounds.

Main Results:

• Gold complexes incorporating triphenylphosphane (PPh3) ligands exhibited greater cytotoxicity compared to homoleptic or heteroleptic NHC-gold complexes.
• Mixed-ligand gold(I) compounds, specifically NHC-AuPPh3 (compound 7) and NHC-Au(Cl)PPh3 (compound 8), demonstrated the highest efficacy in inhibiting NSCLC cell growth.
• Compound 8 significantly inhibited TrxR activity (over 80% reduction) and also showed inhibitory effects on human DHFR, suggesting a dual mechanism of action.

Conclusions:

• Novel gold(I) and gold(III) complexes, particularly those with mixed NHC and PPh3 ligands, represent promising candidates for NSCLC therapy.
• The identified gold compounds effectively inhibit TrxR and DHFR, key targets in cancer therapy, offering a potential strategy to overcome drug resistance.
• Compound 8's ability to inhibit both TrxR and DHFR, potentially through an allosteric mechanism on DHFR, warrants further investigation for clinical applications in lung cancer treatment.