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Review
. 2021 Dec 6;16(23):3496-3512.
doi: 10.1002/cmdc.202100473. Epub 2021 Sep 7.

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

Valeria Ciaffaglione  1 , Maria N Modica  1 , Valeria Pittalà  1 , Giuseppe Romeo  1 , Loredana Salerno  1 , Sebastiano Intagliata  1
Affiliations
Review

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

Valeria Ciaffaglione et al. ChemMedChem. .

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.

Keywords: 5-FU conjugates; 5-FU hybrids; 5-Fluorouracil; Anticancer agents; Mutual prodrugs.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
A simplified illustration of the mutual prodrugs approach.
Figure 2
Figure 2
Schematic representation of 5‐FU metabolism leading to active metabolites FdUMP, FdUTP, and FUTP which cause DNA and RNA damage.
Figure 3
Figure 3
Chemical structures of 5‐FU, MS‐275, 1 a,b and hydrolysis of the carbamate linker.
Figure 4
Figure 4
Chemical structures of DDPT‐5‐FU conjugates 6 a–g.
Figure 5
Figure 5
Chemical structure of codrugs 11 a–d, 12 a–d, their precursors 8–10, their linkers, and hydrophobic chains.
Figure 6
Figure 6
Chemical structure of conjugates 14 a–d, 15 a–d, 16 a,b, and 17 a,b.
Figure 7
Figure 7
Chemical structure of 5‐FU/HO‐1 mutual prodrug 19, its precursors 5‐FU and HO‐1 inhibitor 18, and the proposed biotransformation process.
Figure 8
Figure 8
Chemical structure of codrugs 22 a–c and 24 a–c and their precursors 20, 21 a–c and 23.
Figure 9
Figure 9
Chemical structure of the first developed 5‐FU/F16 mutual codrug 25 and its derivatives 26 a–c.
Figure 10
Figure 10
Development of c(RGDyK)‐based 5‐FU codrugs 27 and 28.
See this image and copyright information in PMC

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