: Cancer still continues as an important cause of death worldwide. Thus, several conventional anticancer treatments are widely used, however, most of them display low selectivity against malignant cells and induce many adverse side effects. Among these, the use of therapies based on 5-Fluorouracil (5-FU) has been one of the most efficient, with a broad-spectrum. Due to these circumstances, various modifications of 5-FU have been developed to improve drug delivery and reduce side effects. Among the optimization strategies, modifications of 5-FU at N1 or N3 position are made, usually including incorporation of pharmacological active compounds with anticancer activity (called hybrid molecule) and functionalization with other groups of compounds (called conjugates). Several studies have been conducted in the search for new alternative therapies against cancer, many of them have evidenced that hybrid compounds exhibit good anticancer activity, which has emerged as a promising strategy in this field of drug discovery and development. Furthermore, the binding of 5-FU to amino acids, peptides, phospholipids, polymers, among others, improves metabolic stability and absorption. This review highlights the potential of hybrids and derivatives based on 5-FU as a scaffold for the development of antitumor agents, besides, it also presents a detailed description of the different strategies employed to design and synthesized these compounds, together with their biological activities and Structure-Activity Relationship (SAR) analysis.

Eight hybrids based on genistein and aspirin were designed, synthesized, and elucidated by spectroscopic analysis. Chemopreventive potential of these compounds was evaluated against SW480 human colon adenocarcinoma cells, its metastatic derivative SW620 and normal cells (CHO-K1). According to the results, hybrids 4a and 4c displayed significant activity over SW480 cells causing a reduction of cell viability of 40.49% and 40.39%, respectively, when treated with 300 µM for 48 hours, being time-and concentration-dependent. None of the compounds exhibited activity at 24 hours; besides, these types of molecules were not active on human metastatic SW620 cells (data not shown). On the other hand, compounds 4d, 4e, 4f, and 4h did not display any activity on the cells at the conditions evaluated. Multitarget docking studies performed against six tumor-associated proteins targets in colorectal cancer, would reveal that hybrids 4a and 4c may inhibit function of Polo-like kinase 1 as primary mode of action with a binding affinity about −10 kcal/ mol. However, docking action would suggest these compounds may induce synergistic cytotoxic effects by regulation of B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein system and cyclooxygenase-2 in SW480 colorectal cancer cells with Vina scores in the range −10.1 to −9.3 kcal/mol. Additionally, in silico drug-likeness studies suggest that active hybrids 4a and 4c display favorable pharmacokinetics indices, good Absorption, Distribution, Metabolism and Excretion (ADME)/Tox profile, and a remarkable metabolic stability within recommended therapeutic ranges, making these compounds useful as promising medicinal scaffolds in the designing of novel orally active anticancer candidates.