Beyond conventional 5-Fluorouracil: Recent medicinal chemistry strategies to enhance its anticancer efficacy

Antimetabolites are anticancer drugs designed to mimic endogenous substrates, thereby inducing irreversible damage that ultimately leads to tumor cell death. 5-Fluorouracil (5-FU) belongs to this class, as it is an uracil analog capable of interfering with both DNA and RNA. Despite its widespread use in the treatment of several solid tumors, such as pancreatic, stomach, lung, breast, esophageal, and colorectal cancers, 5-FU suffers from limitations such as poor bioavailability, a short half-life, and low selectivity. This review aims to discuss the main medicinal chemistry strategies developed to overcome these drawbacks, and to highlight emerging trends over the past five years. Unlike recently published reviews, which predominantly focus on single strategies, this work aims to offer a comparative analysis of structural modifications performed on 5-FU to develop its analogs, hybrid compounds, and prodrugs. Collectively, the available evidence identifies mutual prodrugs as a leading strategy to address the long-standing clinical challenges associated with 5-FU therapy, with future efforts likely to focus on improved tumor targeting and translational potential.