Mutual Prodrugs of 5‐Fluorouracil: From a Classic Chemotherapeutic Agent to Novel Potential Anticancer Drugs

Abstract

The development of potent antitumor agents with a low toxicological profile against healthy cells is still one of the greatest challenges facing medicinal chemistry. In this context, the “mutual prodrug” approach has emerged as a potential tool to overcome undesirable physicochemical features and mitigate the side effects of approved drugs. Among broad‐spectrum chemotherapeutics available for clinical use today, 5‐fluorouracil (5‐FU) is one of the most representative, also included in the World Health Organization model list of essential medicines. Unfortunately, severe side effects and drug resistance phenomena are still the primary limits and drawbacks in its clinical use. This review describes the progress made over the last ten years in developing 5‐FU‐based mutual prodrugs to improve the therapeutic profile and achieve targeted delivery to cancer tissues.

The Promise of Nanotechnology in Personalized Medicine

“…5-Fluorouracil (5-FU) is a hydrophilic compound belonging to the chemical class of cytotoxic antimetabolites. Drug resistance phenomena have been encountered with this compound in colon cancer, and several strategies, such as the design of mutual prodrugs [ 152 , 153 ] or encapsulation in nanoparticles, are used to avoid this complication. For instance, 5-FU hydrophobicity and cytotoxicity can be alleviated by the production of prodrugs that can be efficiently loaded in xylan-stearic acid conjugates [ 154 ], liposomes [ 155 ] or exosomes [ 156 ].…”

Self-assembled coumarin- and 5-fluorouracil-PEG micelles as multifunctional drug delivery systems

“…In this work, 4-azidomethyl-7-methoxycoumarin (AMMC) and 1,3-bis(5-azidopentyl)-5fluorouracil (5-FUDA) were conjugated to methoxy PEG alkyne (mPEG-alkyne, molecular weight 2000 Da) via click chemistry to prepare two amphiphilic PDCs, CouPEG and 5-FUPEG, respectively. Both coumarin and 5-fluorouracil are privileged scaffolds well-known for their anticancer properties [19,20].…”

In Vitro Antioxidant and Pancreatic Anticancer Activity of Novel 5-Fluorouracil-Coumarin Conjugates

“…Unfortunately, 5-FU shows major drawbacks such as a short half-life, erratic bioavailability, and various undesired side effects [ 28 ]. Throughout its long history, different strategies have been developed to improve the clinical efficiency of 5-FU such as the synthesis of new derivatives, combination or conjugation with other types of drugs, and entrapment or binding to polymers [ 29 , 30 , 31 ]. On the other hand, coumarin is a privileged scaffold in medicinal chemistry due to its vast pharmacological attributes [ 32 ].…”