5-Fluorouracil
[CAS# 51-21-8]

Identification

• Classification: Biochemical >> Nucleoside drugs >> Nucleotides and their analogues
• Name: 5-Fluorouracil
• Synonyms: 5-Fluoro-2,4(1H,3H)-pyrimidinedione; 5-Fluoro-2,4-pyrimidinedione; 5-Fluoropyrimidine-2,4-dione
• Molecular Formula: C₄H₃FN₂O₂
• Molecular Weight: 130.08
• CAS Registry Number: 51-21-8
• EC Number: 200-085-6
• SMILES: C1=C(C(=O)NC(=O)N1)F

Properties

• Density: 1.5±0.1 g/cm³ Calc.^*
• Melting point: 282 - 286 °C (Expl.)
• Solubility: DMSO: 100 mM, ethanol: 10 mM, water: 12.2 g/L 20 °C (Expl.)
• Index of refraction: 1.523 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS06;GHS07;GHS08 Danger
• Risk Statements: H301-H312-H315-H319-H335-H340-H360-H412
• Safety Statements: P203-P261-P264-P264+P265-P270-P271-P273-P280-P301+P316-P302+P352-P304+P340-P305+P351+P338-P317-P318-P319-P321-P330-P332+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	3	H301
Eye irritation	Eye Irrit.	2	H319
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335
Acute toxicity	Acute Tox.	4	H312
Germ cell mutagenicity	Muta.	1B	H340
Reproductive toxicity	Repr.	1B	H360
Chronic hazardous to the aquatic environment	Aquatic Chronic	3	H412
Acute toxicity	Acute Tox.	4	H332
Germ cell mutagenicity	Muta.	2	H341
Reproductive toxicity	Repr.	1A	H360
Specific target organ toxicity - repeated exposure	STOT RE	2	H373
Acute toxicity	Acute Tox.	3	H311
Carcinogenicity	Carc.	2	H351
Carcinogenicity	Carc.	1B	H350
Skin sensitization	Skin Sens.	1	H317
Acute toxicity	Acute Tox.	4	H302
Acute toxicity	Acute Tox.	3	H331
Reproductive toxicity	Repr.	2	H361d
Carcinogenicity	Carc.	1A	H350
Germ cell mutagenicity	Muta.	1A	H340
Acute hazardous to the aquatic environment	Aquatic Acute	1	H400
Respiratory sensitization	Resp. Sens.	1	H334

Discovery and Applications

5-Fluorouracil (5-FU) is a pyrimidine analog and chemotherapeutic agent widely used in the treatment of various cancers, including colorectal, breast, and gastrointestinal malignancies. Its molecular formula is C4H3FN2O2. Structurally, it is an analog of uracil, with a fluorine atom substituted at the 5-position of the pyrimidine ring, which significantly alters its biological activity by interfering with nucleic acid metabolism. 5-FU is a white crystalline solid that is soluble in water and polar organic solvents, making it suitable for both intravenous administration and formulation in topical preparations.

The discovery of 5-fluorouracil dates back to the 1950s, during research aimed at identifying nucleobase analogs that could selectively inhibit rapidly dividing cancer cells. Its activity is based on the incorporation of the fluorinated uracil analog into RNA and DNA, leading to faulty nucleic acid synthesis. Additionally, 5-FU inhibits the enzyme thymidylate synthase, which catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), a critical step in DNA synthesis. This dual mechanism results in cytotoxicity selectively targeting rapidly proliferating cells, such as cancer cells, while sparing most normal tissues.

Synthesis of 5-fluorouracil is typically achieved by halogenation of uracil derivatives. One common method involves treating uracil with a fluorinating agent under controlled conditions to selectively introduce the fluorine atom at the 5-position. Alternative approaches employ nucleophilic or electrophilic fluorination reactions using precursors such as 5-chlorouracil or 5-bromouracil, followed by substitution with a fluoride source. Reaction conditions are carefully optimized to achieve high regioselectivity and yield, and the final product is purified by recrystallization or chromatography to remove residual reagents and by-products.

Chemically, 5-FU retains the tautomeric and hydrogen-bonding properties of uracil but exhibits altered electronic distribution due to the electronegative fluorine atom. This modification enhances the compound’s ability to inhibit thymidylate synthase and to be incorporated into RNA and DNA, producing cytotoxic effects. Its solubility and stability allow it to be formulated in aqueous solutions for intravenous use or as creams for topical treatment of actinic keratosis and superficial skin cancers.

In practical applications, 5-fluorouracil is one of the most widely used chemotherapeutic agents. It is administered intravenously or as an oral prodrug (e.g., capecitabine) and is frequently combined with other chemotherapeutics or radiation therapy to enhance efficacy. Topically, it is used in dermatology for the treatment of precancerous lesions. The drug’s effectiveness depends on its ability to selectively target proliferating cells, while its toxicity profile necessitates careful dosing and monitoring of side effects, including myelosuppression, gastrointestinal disturbances, and mucositis.

Physically, 5-fluorouracil is stable under standard storage conditions when protected from moisture and light. Handling precautions include the use of gloves and protective clothing, as the compound is cytotoxic and can be harmful upon skin contact or inhalation.

Overall, 5-fluorouracil is a chemically and pharmacologically significant pyrimidine analog with broad applications in oncology and dermatology. Its fluorinated structure enables inhibition of thymidylate synthase and incorporation into nucleic acids, leading to cytotoxicity in rapidly dividing cells. The compound continues to be a cornerstone in cancer therapy, illustrating the importance of nucleobase analogs in medicinal chemistry and clinical practice.

References

2025. Chemoresistance mechanisms to 5-Fluorouracil and reversal strategies in lung and breast cancer. Scientific Reports.
DOI: 10.1038/s41598-025-12487-5