Dual-Action NSAID-Gold(I) Alkynyl Hybrids for Synergistic Anti-Inflammatory and Anticancer Therapy of Colorectal Cancer

Colorectal cancer (CRC) remains a major global health challenge, in which chronic inflammation and redox dysregulation are key drivers of tumor progression. Here, we report a rationally designed family of NSAID-derived alkyne ligands coordinated to JohnPhos-gold(I) fragments, affording eight new alkynyl gold(I) derivatives. Complexes based on naproxen, ibuprofen, and salicylic acid derivatives display potent antiproliferative activity against Caco-2/TC7 colon cancer cells, outperforming oxaliplatin and being comparable to auranofin, while showing markedly reduced cytotoxicity in breast cancer lines and nonmalignant cells, thus indicating promising selectivity. Mechanistic studies revealed that the most active complex, [Au(L1)JP] (<b>1</b>), which contains a naproxen-derived alkyne, inhibits thioredoxin reductase (TrxR), triggers ROS overproduction, disrupts mitochondrial membrane potential, and induces G1-phase arrest while only marginally increasing apoptosis. This suggests the involvement of additional forms of cell death or cytostatic effects. Additionally, complex <b>1</b> selectively inhibits the enzyme cyclooxygenase-2 (COX-2) over COX-1 and reduces <i>IL-8</i> expression without affecting <i>PTGS2</i> transcription, highlighting a post-transcriptional anti-inflammatory action. These results support NSAID-derived alkynyl gold(I) complexes as promising multitarget agents for colorectal cancer intervention, combining disruption and COX-2 modulation.