In silico and in vitro evaluation of drug-like properties and anticancer potential of novel 5-fluorouracil derivatives

Abstract

The development of more effective and safer anticancer agents remains a critical focus in cancer therapy. While biologics are gaining attention, small molecules continue to play a significant role due to their versatility and cost-effectiveness. This study investigates the potential of synthesized 5-fluorouracil derivatives to improve its drug-like properties, as well as anticancer activity in human lung cancer cells. Among the synthesized compounds, two (2c and 3a) demonstrated greater cytotoxicity and selectivity toward A549 lung cancer cells compared to 5-FU. These derivatives did not induce oxidative stress but instead affected antioxidant enzyme activity, suggesting interference with cellular metabolism. Additionally, these derivatives shifted cells toward hypodiploidy, suggesting the presence of apoptotic cells, while 5-FU significantly increased A549 cell ploidy, a trait linked to cancer progression and treatment resistance. In silico predictions revealed improved pharmacokinetic properties for the 2c derivative and a low probability of hepatotoxicity or neurotoxicity compared to 5-FU. These findings suggest that 2c and 3a derivatives warrant further research as potentially safer and more effective alternatives to 5-FU.