3D Mol Similar

Fluorocytosine

: Iupac Name：6-amino-5-fluoro-1H-pyrimidin-2-one; CAS No.: 2022-85-7; Molecular Weight：129.094; Modify Date.: 2022-11-07 21:44; Introduction: A fluorinated pyrimidine, 5-flucytosine (fluorocytosine; 5-FC, Fig. 1), was initially developed as a potential anti-cancer agent but it was not sufficiently effective in the field of cancer chemotherapy[1]. Later, 5-FC proved to be active in experimental candidiasis and cryptococcosis in mice[2] and was used to treat human infections[3]. In addition to its activity against Candida and Cryptococcus, 5-FC also has an inhibitory activity against fungi causing chromobl View more+

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1. Names and Identifiers

: 1.1 Name; Fluorocytosine; 1.2 Synonyms; 4-amino-5-fluoro-1,2-dihydropyrimidin-2-one 4-Amino-5-Fluoro-2(1H)-pyrimidine, Flucytosine, 5-FC 4-amino-5-fluoro-2(1h)-pyrimidinon 4-Amino-5-fluoro-2(1H)-pyrimidinone 4-amino-5-fluoro-2(1H)-pyrimidinone,5-Fluorocytosine,Flucytosine 4-amino-5-fluoro-2(1H)-pyrimidinone,Flucytosine 4-Amino-5-fluoro-2(1H)-pyrmidinone 4-Amino-5-fluoro-2-hydroxypyrimidine 4-amino-5-fluoro-2-pyrimidone 5-fluorocystosine 5-fluorocytosin 5-fluoro-cytosin 5-Fluorocytosine 6-amino-5-fluoro-1H-pyrimidin-2-one Ancobon Ancotil EINECS 217-968-7 Flucytosin Flucytosine fluocytosine Fluorcytosine MFCD00006035; View all

1.3 CAS No.: 2022-85-7

1.4 CID: 3366

1.5 EINECS(EC#): 217-968-7

1.6 Molecular Formula: C4H4FN3O (isomer)

1.7 Inchi: InChI=1S/C4H4FN3O/c5-2-1-7-4(9)8-3(2)6/h1H,(H3,6,7,8,9)

1.8 InChIkey: XRECTZIEBJDKEO-UHFFFAOYSA-N

1.9 Canonical Smiles: C1=NC(=O)NC(=C1F)N

1.10 Isomers Smiles: C1=NC(=O)NC(=C1F)N

2. Properties

2.1 Density: 1.73

2.1 Melting point: 296℃

2.1 Boiling point: 298

2.1 Refractive index: 1.613

2.1 Flash Point: 296

2.1 Precise Quality: 129.03400

2.1 PSA: 71.77000

2.1 logP: 0.07240

2.1 Solubility: 1.5g/100mL (25 oC)

2.2 AnalyticLaboratory Methods: AOAC 988.21. Flucytosine; in Drug Capsules. Liquid Chromatographic Method.

2.3 Appearance: white crystalline solid

2.4 Storage: Light Sensitive. Ambient temperatures.

2.5 Chemical Properties: White Crystalline Solid

2.6 Color/Form: Powder

2.7 Decomposition: When heated to decomposition it emits very toxic fumes of F ion and nitroxides.

2.8 Odor: ODORLESS

2.9 Physical: Solid

2.10 pKa: 3.26(at 25℃)

2.11 Water Solubility: 1.5g/100mL (25 oC)

2.12 Spectral Properties: MAX ABSORPTION (0.1N HCL): 285 NM (E= 8900)

2.13 Stability: Light Sensitive

2.14 StorageTemp: 2-8°C

3. Use and Manufacturing

3.1 Definition: ChEBI: An organofluorine compound that is cytosine that is substituted at position 5 by a fluorine. A prodrug for the antifungal 5-fluorouracil, it is used for the treatment of systemic fungal infections.

3.2 GHS Classification: Signal: Warning
GHS Hazard Statements
Aggregated GHS information provided by 68 companies from 9 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Reported as not meeting GHS hazard criteria by 31 of 68 companies. For more detailed information, please visit ECHA C&L website

Of the 8 notification(s) provided by 37 of 68 companies with hazard statement code(s):

H341 (10.81%): Suspected of causing genetic defects [Warning Germ cell mutagenicity]
H361 (86.49%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

Precautionary Statement Codes
P201, P202, P281, P308+P313, P405, and P501; View all

3.3 Methods of Manufacturing: 5-FLUOROURACIL; IS REACTED WITH POCL3 TO GIVE 2, 4-DICHLORO-5-FLUOROPYRIMIDINE; WHICH IS REACTED WITH NH3 TO GIVE 2-CHLORO-4-AMINO-5-FLUOROPYRIMIDINE;. HEATING LATTER IN CONCN HCL YIELDS FLUCYTOSINE;.

3.4 Usage: antidiabetic

4. Safety and Handling

4.1 Symbol: GHS08;

4.1 Hazard Codes: Xn

4.1 Signal Word: Warning

4.1 Risk Statements: R40

4.1 Safety Statements: S36/37;S45

4.1 Exposure Standards and Regulations: Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

4.2 Hazard Class: IRRITANT, LIGHT SENSITIVE

4.2 Hazard Declaration: H361

4.2 DisposalMethods: SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

4.3 RIDADR: NONH for all modes of transport

4.3 Caution Statement: P280

4.3 Formulations/Preparations: FLUCYTOSINE, USP (ANCOBON), IS SUPPLIED IN CAPSULES CONTAINING EITHER 250 OR 500 MG FOR ORAL ADMIN. THERE ARE NO PARENTERAL PREPN.

4.4 WGK Germany: 2

4.4 RTECS: HA6040000

4.4 Safety: Hazard Codes:?Xn,Xi ;T
Risk Statements: 40-36/37/38?
R40:Limited evidence of a carcinogenic effect.?
R36/37/38:Irritating to eyes, respiratory system and skin.
Safety Statements: 22-24/25-45-36/37-36/37/39-27-26?
S22:Do not breathe dust.?
S24/25:Avoid contact with skin and eyes.?
S45:In case of accident or if you feel unwell, seek medical advice immediately (show the label whenever possible.)?
S36/37:Wear suitable protective clothing and gloves.?
S36/37/39:Wear suitable protective clothing, gloves and eye/face protection.?
S27:Take off immediately all contaminated clothing.?
S26: In case of contact with eyes, rinse immediately with plenty of water and seek medical advice.
WGK Germany: 2
RTECS: HA6040000
F: 10-23
Hazard Note: Toxic/Light Sensitive
HazardClass: IRRITANT, LIGHT SENSITIVE; View all

4.5 Sensitive: Light Sensitive

4.6 Specification: ?Fluorocytosine , its cas register number is 2022-85-7. It also can be called?2-Hydroxy-4-amino-5-fluoropyrimidine ; 4-Amino-5-fluoro-2(1H)-pyrimidinone ; 5-Fluorocytosine ; Alcobon ; Ancobon ; Ancotil .It is a?white crystalline solid.

4.7 Toxicity

Organism	Test Type	Route	Reported Dose (Normalized Dose)	Effect	Source
mouse	LD12	oral	500mg/kg (500mg/kg)	?	British UK Patent Application. Vol. #2067993,
mouse	LD50	intraperitoneal	1190mg/kg (1190mg/kg)	?	Antimicrobial Agents and Chemotherapy Vol. -, Pg. 566, 1963.
mouse	LD50	intravenous	500mg/kg (500mg/kg)	?	Antimicrobial Agents and Chemotherapy Vol. -, Pg. 566, 1963.
mouse	LD50	subcutaneous	1gm/kg (1000mg/kg)	?	Chemotherapy Vol. 25, Pg. 54, 1979.
rat	LD50	intraperitoneal	3811mg/kg (3811mg/kg)	?	Iyakuhin Kenkyu. Study of Medical Supplies. Vol. 10, Pg. 710, 1979.
rat	LD50	intravenous	> 600mg/kg (600mg/kg)	?	Iyakuhin Kenkyu. Study of Medical Supplies. Vol. 10, Pg. 710, 1979.
rat	LD50	oral	> 15gm/kg (15000mg/kg)	?	Drugs in Japan Vol. 6, Pg. 699, 1982.
rat	LD50	subcutaneous	3336mg/kg (3336mg/kg)	?	Gekkan Yakuji. Pharmaceuticals Monthly. Vol. 21, Pg. 935, 1979.
women	TDLo	oral	1080mg/kg/10D (1080mg/kg)	BRAIN AND COVERINGS: OTHER DEGENERATIVE CHANGES BEHAVIORAL: CHANGES IN MOTOR ACTIVITY (SPECIFIC ASSAY) BEHAVIORAL: ATAXIA	European Journal of Clinical Pharmacology. Vol. 51, 505.

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5. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

Not classified.

2.2 GHS label elements, including precautionary statements

Pictogram(s)	No symbol.
Signal word	No signal word.
Hazard statement(s)	none
Precautionary statement(s)
Prevention	none
Response	none
Storage	none
Disposal	none

2.3 Other hazards which do not result in classification

none

6. NMR Spectrum

7. Synthesis Route

2022-85-7Total: 3 Synthesis Route

701-87-1

2022-85-7 393 Suppliers

Literatures:
US2802005 , ; Journal of the American Chemical Society, , vol. 79, p. 4559
Yield: null

99429-06-8

2022-85-7 393 Suppliers

Literatures:
Bayer Aktiengesellschaft Patent: US4703121 A1, 1987 ;
Yield: ~96%

134379-77-4 7 Suppliers

98-00-0 306 Suppliers

2022-85-7 393 Suppliers

Literatures:
Shi, Junxing; Ray, Adrian S.; Mathew, Judy S.; Anderson, Karen S.; Chu, Chung K.; Schinazi, Raymond F. Bioorganic and Medicinal Chemistry Letters, 2004 , vol. 14, # 9 p. 2159 - 2162
Yield: null

8. Precursor and Product

precursor:

99429-06-8

701-87-1

134379-77-4

product :

2711-88-8

51-21-8

161599-46-8

111878-21-8

2022-78-8

9. Other Information

9.0 Usage: 5-Fluorocytosine acts as an antidiabetic, antifungal and antimicrobial agent. It is useful for the treatment of serious infections arises due to susceptible strains of Candida or Cryptococcus neoformans and chromomycosis. Further, it is employed in studies on TMP biosynthesis.

9.1 Merck: 14,4125

9.2 BRN: 127285

9.3 Overview: A fluorinated pyrimidine, 5-flucytosine (fluorocytosine; 5-FC, Fig. 1), was initially developed as a potential anti-cancer agent but it was not sufficiently effective in the field of cancer chemotherapy^[1]. Later, 5-FC proved to be active in experimental candidiasis and cryptococcosis in mice^[2] and was used to treat human infections^[3]. In addition to its activity against Candida and Cryptococcus, 5-FC also has an inhibitory activity against fungi causing chromoblastomycosis^[4]; however, it is ineffective against infections caused by filamentous fungi. 5-FC has a high prevalence of primary resistance in many fungal species. Due to this primary resistance, 5-FC is used mainly in combination with other antifungals (primarily amphotericin B, AmB) and more recently it has been investigated in combination with other agents including fluconazole (FLU), ketoconazole (KTZ), itraconazole (ITRA), voriconazole (VORI) and echinocandins (e.g., micafungin, MICA and caspofungin, CAS). It is used only rarely as a single agent.
Flucytosine (5-FC) is a synthetic antimycotic compound, first synthesized in 1957. It has no intrinsic antifungal capacity, but after it has been taken up by susceptible fungal cells, it is converted into 5-fluorouracil (5-FU), which is further converted to metabolites that inhibit fungal RNA and DNA synthesis. Monotherapy with 5-FC is limited because of the frequent development of resistance. In combination with amphotericin B, 5-FC can be used to treat severe systemic mycoses, such as cryptococcosis, candidosis, chromoblastomycosis and aspergillosis.

Figure 1 the chemical structure of Fluorocytosine ;; View all

9.4 Mechanism of action and resistance: 5-FC is most active against yeasts, including Candida, Torulopsis and Cryptococcus spp., and against the dematiaceous fungi causing chromomycosis (Phialophora and Cladosporium spp.) and Aspergillus spp.^[5] The MICs of 5-FC vary from 0.1 to 0.25 mg/L for these fungal species.
In Emmonsia crescens, Emmonsia parva, Madurella mycetomatis, Madurella grisea, Pyrenochaeta romeroi, Cephalosporium spp., Sporothrix schenckii and Blastomyces dermatitidis, MICs vary from 100 to 1000 mg/L.14 5-FC is also active against some protozoa, including Acanthamoeba culbertsoni both in vitro and in vivo and Leishmania spp. in patients.^[5]
Antimycotic activity of 5-FC results from its rapid conversion into 5-fluorouracil (5-FU) by the enzyme cytosine deaminase, within susceptible fungal cells. There are two mechanisms involved by which 5-fluorouracil exerts its antifungal activity. The first mechanism includes the conversion of 5-fluorouracil through 5-fluorouridine monophosphate (FUMP) and 5-fluorouridine diphosphate (FUDP) into 5-fluorouridine triphosphate (FUTP)^[6]. FUTP is further incorporated into fungal RNA in place of uridylic acid; this alters the aminoacylation of tRNA, disturbs the amino acid pool and inhibits protein synthesis^[6]. The second mechanism is the metabolism of 5-FU into 5-fluorodeoxyuridine monophosphate (FdUMP) by uridine monophosphate pyrophosphorylase^[6]. FdUMP is a potent inhibitor of thymidylate synthase, which is a key enzyme involved in DNA synthesis and nuclear division^[7]. Thus, 5-FC acts by interfering with pyrimidine metabolism and protein synthesis in the fungal cell. These activity results in cell lysis and death.
The occurrence of resistance with the use of 5-FC has been widely described and precludes use of 5-FC as a single agent^{[8, 10]} Two basic mechanisms of resistance can be distinguished: (i) certain mutations can result in a deficiency in the enzymes necessary for cellular transport and uptake of 5-FC or for its metabolism (i.e. cytosine permease, uridine monophosphate pyrophosphorylase or cytosine deaminase);^[9,11] (ii) resistance may result from increased synthesis of pyrimidines, which compete with the fluorinated antimetabolites of 5-FC and thus diminish its antimycotic activity.^[9] It has been shown that defective uridine monophosphate pyrophosphorylase is the most frequently occurring type of acquired 5-FC resistance in fungal cells.^[12] Normark & Sch?nebeck have reported that two different phenotypes of 5-FC-resistant strains can be recognized:^[10] strains of resistance phenotype class 1 are not affected by 5-FC at high concentrations (these are the totally (intrinsically) resistant strains), while those of class 2 are susceptible to 5-FC at low concentrations but, after long exposure to 5-FC (even at high concentrations) resistance develops (these are said to be partially resistant or to have acquired resistance). Development of resistance in the latter strains probably results from selection of non-susceptible mutants, leading to a secondary resistant population.^[9]
The incidence of resistance to 5-FC varies between species.20 Up to 7–8% of intrinsically resistant strains are found among pretreatment isolates of C. albicans, unspeciated candida and Torulopsis glabrata. In C. neoformans the incidence of resistance is lower (1–2%), but in Candida spp. other than C. albicans it is 22%, because of the prevalence of generally less sensitive species such as Candida tropicalis and Candida krusei^[13]. The exact incidence of primary 5-FC resistance is not clear. Different investigators report rates ranging between 8% and 44% for Candida spp^[14]. Possible factors contributing to this wide range include the susceptibility methods used, local factors involving use of antifungal agents and differences in the prevalence of various Candida spp^[14].; View all

9.5 Pharmacokinetic and dosage: 5-FC is absorbed very rapidly and almost completely: 76–89% is bioavailable after oral administration.^[16] In patients with normal renal function, peak concentrations are attained in serum and other body fluids within 1–2 h.^{[15, 16]}. 5-FC penetrates well into most body sites, including cerebrospinal, vitreous and peritoneal fluids, and into inflamed joints, because it is small and highly water-soluble and is not bound by serum proteins to a great extent^[15-17]. 5-FC is principally eliminated by the kidneys and the plasma clearance of the drug is closely related to creatinine clearance^{[15, 17]}. 5-FC is only minimally metabolized in the liver. Renal elimination is via glomerular filtration; no tubular resorption or secretion takes place. The half-life of 5-FC is c.3–4 h in patients with normal renal function, but can be extended up to 85 h in patients with severe renal insufficiency.^{[12, 16, 18]} Renal insufficiency alters 5-FC pharmacokinetics since it slows absorption, prolongs serum half-life and decreases clearance^[15]. The apparent volume of distribution of 5-FC approaches that of total body water and is not altered by renal failure.
Dosage must be adjusted in patients with renal impairment. Various recommendations have been made^[15-18]. Daneshmend & Warnock have suggested the following guidelines for the administration of 5-FC to patients with renal insufficiency.^[15]. In patients with a creatinine clearance of >40 mL/min, a standard dose of 37.5 mg/kg every 6 h should be used. If the creatinine clearance is between 20 and 40 mL/min, the recommended dose is 37.5 mg/kg every 12 h. In patients with a creatinine clearance of <20 mL/ minute, the dose of 5-FC should be 37.5 mg/kg once daily. Finally, if the creatinine clearance is <10 mL/min, frequent determinations of 5-FC concentration should be used as guidance for the frequency of dosing.; View all

9.6 Toxicity and side effects: 5-FC is known to have some relatively minor side effects, such as nausea, vomiting and diarrhoea, it also has more severe side effects, including hepatotoxicity and bonemarrow depression. Gastrointestinal side effects, the most common and least harmful side effects associated with 5-FC treatment, include nausea, diarrhoea and, occasionally, vomiting and diffuse abdominal pain. They occur in approximately 6% of patients treated with 5-FC^[18]. Although these side effects are usually not severe; two cases of ulcerative colitis and bowel perforation have been reported^[19]. Hepatotoxicity can occur during 5-FC treatment. In most cases it involves increases in serum concentrations of transaminases and alkaline phosphatase^[20]. The incidence of hepatotoxicity is between 0 and 25%^[20]. The most severe toxicity associated with 5-FC treatment are bone-marrow depression. There have been several reports of serious or life-threatening leucocytopenia, thrombocytopenia and/or pancytopenia^[21-23]. The mechanism of toxicity of 5-FC is still not fully understood. It is likely that some of the side effects caused by 5-FC, for example hepatotoxicity and bone-marrow depression, are dose-dependent, although not all reports support this theory. Furthermore, it has been postulated that conversion of 5-FC to certain metabolites, especially 5-FU, could be one of the mechanisms of development of 5-FC-associated toxicity.; View all

9.7 References

Heidelberg C, Chaudhuri NK, Danneberg P et al. Fluorinated pyrimidines, a new class of tumour-inhibitory compounds. Nature 1957; 179(4561): 663–666
Grunberg E, Titsworth E, Bennett M. Chemotherapeutic activity of 5-fluorocytosine. Antimicrob Agents Chemother 1963; 161:566–568
Tassel D, Madoff MA. Treatment of Candida sepsis and Cryptococcus meningitis with 5-fluorocytosine. A new antifungal agent. JAMA 1968; 206(4): 830–832
Benson JM, Nahata MC. Clinical use of systemic antifungal agents. Clin Pharm 1988; 7(6): 424–438
Scholer, H. J. (1980). Flucytosine. In Antifungal Chemotherapy, (Speller, D. C. E., Ed.), pp. 35–106. Wiley, Chichester.
Waldorf AR, Polak A. Mechanisms of action of 5-fluorocytosine. Antimicrob Agents Chemother 1983; 23(1):79–85
Diasio RB, Bennett JE, Myers CE. Mode of action of 5-fluorocytosine. Biochem Pharmacol 1978; 27(5):703–707
Polak, A. & Scholer, H. J. (1975). Mode of action of 5-fluorocytosine and mechanisms of resistance. Chemotherapy 21, 113–30.
Polak, A. (1977). 5-Fluorocytosine—current status with special references to mode of action and drug resistance. Contributions to Microbiology and Immunology 4, 158–67.
Normark, S. & Sch?nebeck, J. (1973). In vitro studies of 5-fluorocytosine resistance in Candida albicans and Torulopsis glabrata. Antimicrobial Agents and Chemotherapy 2, 114–21.
Fasoli, M. & Kerridge, D. (1988). Isolation and characterization of fluoropyrimidine-resistant mutants in two Candida species. Annals of the New York Academy of Sciences 544, 260–3.
Francis, P. & Walsh, T. J. (1992). Evolving role of flucytosine in immunocompromised patients: new insights into safety, pharmacokinetics, and antifungal therapy. Clinical Infectious Diseases 15, 1003–18.
Medoff, G. & Kobayashi, G. S. (1980). Strategies in the treatment of systemic fungal infections. New England Journal of Medicine 302, 145–55.
Armstrong, D. & Schmitt, H. J. (1990). Older drugs. In Chemotherapy for Fungal Diseases, (Ryley, J. F., Ed.), pp. 439–54. Springer-Verlag, Berlin.
Daneshmend, T. K. & Warnock, D. W. (1983). Clinical pharmacokinetics of systemic antifungal drugs. Clinical Pharmacokinetics 8, 17–42.
Cutler, R. E., Blair, A. D. & Kelly, M. R. (1978). Flucytosine kinetics in subjects with normal and impaired renal function. Clinical Pharmacology and Therapeutics 24, 333–42.
Block, E. R., Bennett, J. E., Livoti, L. G., Klein, W. J., MacGregor, R. R. & Henderson, L. (1974). Flucytosine and amphotericin B: hemodialysis effects on the plasma concentration and clearance. Studies in man. Annals of Internal Medicine 80, 613–7.
Sch?nebeck, J., Polak, A., Fernex, M. & Scholer, H. J. (1973). Pharmacokinetic studies on the oral antimycotic agent 5-fluorocytosine in individuals with normal and impaired kidney function. Chemotherapy 18, 321–36.
Benson, J. M. & Nahata, M. C. (1988). Clinical use of systemic antifungal agents. Clinical Pharmacy 7, 424–38.
Bennet, J. E. (1977). Flucytosine. Annals of Internal Medicine 86, 319–21.
Kauffman, C. A. & Frame, P. T. (1977). Bone marrow toxicity associated with 5-fluorocytosine therapy. Antimicrobial Agents and Chemotherapy 11, 244–7.
Schlegel, R. J., Bernier, G. M., Bellanti, J. A., Maybee, D. A., Osborne, G. B., Stewart, J. L. et al. (1970). Severe candidiasis associated with thymic dysplasia, IgA deficiency, and plasma antilymphocyte effects. Pediatrics 45, 926–36.
Meyer, R. & Axelrod, J. L. (1974). Fatal aplastic anemia resulting from flucytosine. Journal of the American Medical Association 228, 1573.

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9.8 Description: 5-Fluorocytosine (5-FC), a fluorinated pyrimidine analog, is a synthetic antimycotic prodrug that is converted by cytosine deaminase to 5-fluorouracil. 5-Fluorouracil, a widely used cytotoxic drug, is further metabolized to fluorinated ribo- and deoxyribonucleotides, resulting in the inhibition of DNA and protein synthesis, which has multiple effects including inhibition of Candida species and C. neoformans infections and cytotoxicity towards cancer cells. In combination with a retroviral replicating vector carrying a cytosine deaminase prodrug-activating gene, 5-FC has been shown to selectively eliminate CT26 and Tu-2449 tumor cells in vitro (IC₅₀s = 4.2 and 1.5 μM, respectively) and to significantly improve survival and reduce tumor size (at a dose of 500 mg/kg) in two different syngeneic mouse glioma models.; View all

9.9 Chemical Properties: White Crystalline Solid

9.10 Originator: Ancobon,Roche,US,1972

9.11 Uses: 5-FC is a toxic antifungal/antimicrobial agent

9.12 Definition: ChEBI: An organofluorine compound that is cytosine that is substituted at position 5 by a fluorine. A prodrug for the antifungal 5-fluorouracil, it is used for the treatment of systemic fungal infections.

9.13 Indications: Flucytosine (Ancobon) is a synthetic, fluorinated pyrimidine that is structurally related to fluorouracil (FU) and floxuridine. It can be fungistatic and fungicidal. Although it is used more frequently in the treatment of systemic infections caused by Candida and Cryptococcus, dermatologic indications may include infections due to chromomycosis, sporotrichosis, Cladosporium, and Sporothrix species. It is generally ineffective against Aspergillus species.

9.14 Manufacturing Process: The preparation of 5-fluorouracil is given under "Fluorouracil." As described in US Patent 3,040,026, 5-fluorouracil is then subjected to the following steps to give flucytosine.
Step 1: 2,4-Dichloro-5-Fluoropyrimidine - A mixture of 104 grams (0.8 mol) of 5-fluorouracil, 1,472 grams (9.6 mols) of phosphorus oxychloride and 166 grams (1.37 mols) of dimethylaniline was stirred under reflux for 2 hours. After cooling to room temperature, phosphorus oxychloride was removed by distillation at 18 to 22 mm and 22° to 37°C. The residue was then poured into a vigorously stirred mixture of 500 ml of ether and 500 gram of ice. After separating the ether layer, the aqueous layer was extracted with 500 ml, then 200 ml of ether. The combined ether fractions were dried over sodium sulfate, filtered, and the ether removed by vacuum distillation at 10° to 22°C. The residue, a yellow solid melting at 37° to 38°C, weighed 120 grams corresponding to a 90% yield. Vacuum distillation of 115 grams of this material at 74° to 80°C (16 mm) gave 108 grams of white solid melting at 38° to 39°C corresponding to an 84.5% yield.
Step 2: 2-Chloro-4-Amino-5-Fluoropyrimidine - To a solution of 10.0 grams (0.06 mol) of 2,4-dichloro-5-fluoropyrimidine in 100 ml of ethanol, 25 ml of concentrated aqueous ammonia were slowly added. A slightly opalescent solution resulted. The temperature gradually rose to 35°C. The solution was then cooled in ice to 18°C and thereafter remained below 30°C. After three hours, a Volhard titration showed that 0.0545 mol of chlorine was present in ionic form. Storage in a refrigerator overnight resulted in some crystallization of ammonium chloride. A white sludge, resulting from the evaporation of the reaction mixture at 40°C, was slurried with 75 ml of water, filtered and washed free of chloride. After drying in vacuo, the product melted at 196.5° to 197.5°C, yield 6.44 grams. Evaporation of the mother liquors yielded a second crop of 0.38 gram, raising the total yield to 6.82 grams (79.3%).
Step 3: 5-Fluorocytosine - A slurry of 34.0 grams (0.231 mol) of 2-chloro-4- amino-5-fluoropyrimidine in 231 ml of concentrated hydrochloric acid was heated in a water bath at 93° to 95°C for 125 minutes. The reaction was followed by means of ultraviolet spectrophotometry using the absorption at 245, 285, and 300 mμ as a guide. The absorption at 300 mμ rose to a maximum after 120 minutes and then dropped slightly. The clear solution was cooled to 25°C in an ice bath, then evaporated to dryness under vacuum at 40°C. After slurrying with water three times and reevaporating, the residue was dissolved in 100 milliliters of water. To this solution, cooled in ice, 29 ml of concentrated ammonia were added dropwise. The resulting precipitate was filtered, washed free of chloride with water, then with alcohol and ether. After drying in vacuo at 65°C, the product weighed 22.3 grams. An additional 6.35 grams was obtained by evaporation of the mother liquor, thus yielding a total of 28.65 grams (96.0%).; View all

9.15 Brand name: Ancobon (Valeant).

9.16 Therapeutic Function: Antifungal

9.17 Antimicrobial activity: The spectrum of activity is restricted to Candida spp., Cryptococcus spp. and some fungi causing chromoblastomycosis.

9.18 Acquired resistance: About 2–3 of Candida spp. isolates (more in some centers) are resistant before treatment starts, and resistance may develop during treatment. The most common cause of resistance appears to be loss of the enzyme uridine monophosphate pyrophosphorylase.

9.19 General Description: Chemical structure: nucleoside

10. Computational chemical data

Molecular Weight: 129.094g/mol
Molecular Formula: C₄H₄FN₃O
Compound Is Canonicalized: True
XLogP3-AA: -0.9
Exact Mass: 129.03383992
Monoisotopic Mass: 129.03383992
Complexity: 208
Rotatable Bond Count: 0
Hydrogen Bond Donor Count: 2
Hydrogen Bond Acceptor Count: 3
Topological Polar Surface Area: 67.5
Heavy Atom Count: 9
Defined Atom Stereocenter Count: 0
Undefined Atom Stereocenter Count: 0
Defined Bond Stereocenter Count: 0
Undefined Bond Stereocenter Count: 0
Isotope Atom Count: 0
Covalently-Bonded Unit Count: 1
CACTVS Substructure Key Fingerprint: AAADcYBjIQAAAAAAAAAAAAAAAAAAAAAAAAAgAAAAAAAAAAAAAAAAHwAQAAAACADBAAQBAALAAACoABBhVAAAAAAAAAAAAAAAABCAAAAAAAAAAAAAAQAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA==

11. Question & Answer

What is the Mechanism of Action and Indications of Fluorocytosine? Jan 23 2024
Originally synthesized at Hoffmann-La Roche Pharmaceuticals, fluorocytosine is an antimetabolite known as flucytosine. It has a limited antimycotic activity spectrum, targeting yeasts, Cryptococcus ne..
What are the Significant Advances in Antifungal Therapy and the Clinical Use of 5-Fluorocytosine? Oct 18 2023
Significant progress has been made in antifungal therapy over the past few decades. This includes the development of new generations of antifungal agents, improved fungal diagnostics, and standardize..
What is the Mechanism of Action of 5-Fluorocytosine and its Uses? Aug 16 2023
5-Fluorocytosine, also known as Capecitabine Intermediate 1, is a highly specific antifungal agent that can be taken orally. It is primarily used for treating severe systemic infections caused by susc..
What is the use of Fluorocytosine and its adverse effects? Dec 27 2022
Fluorocytosine, also known as 5-FC, is a white or off-white crystalline powder. It inhibits fungi by entering the sensitive fungal cells and forming a metabolite called 5-fluorouracil through the acti..

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