N-heterocyclic carbene gold(I) derivatives with long aliphatic side chains as potential anticancer agents in colon cancer

Abstract

Mild hyperthermia has emerged as a powerful tool in cancer therapy, prompting the development of materials that respond to heat with enhanced therapeutic action. Gold(I)-NHC complexes are emerging as promising anticancer agents due to their stability, tunability, and ability to inhibit sulfur- and selenium-dependent enzymes overexpressed in tumors. In this study, we synthesised carbene–gold(I) derivatives bearing fluorous and hydrocarbon chains to assess the role of polyfluorinated groups and the impact of mild hyperthermia (41 °C) on their cytotoxic activity. The compounds exhibited significant antiproliferative effects against Caco-2/TC7 colon carcinoma cells at both 37 °C and 41 °C. This activity may be associated with alterations in the levels of ROS (reactive oxygen species) within the cells and the activity of TrxR (thioredoxin reductase), resulting in modifications to the intracellular redox state and subsequent disruptions to the cell cycle. Under hyperthermic conditions, cytotoxicity was further enhanced via mitochondrial depolarization and activation of caspase-3-mediated apoptosis. Notably, fluorinated complexes displayed superior cytotoxicity compared to their alkylated analogues, highlighting the relevance of polyfluorinated chains in boosting therapeutic efficacy under heat-triggered conditions.