51-21-8 Usage
Antimetabolite
5-fluorouracil is short for fluorouracil, and is pyrimidine antimetabolites, 5-fluorouracil as fluorouracil for pyrimidine antimetabolites, is currently clinically commonly used a chemotherapy drug, having effect on proliferation, can prevent the thymine formation, inhibition of DNA biosynthesis, thereby inhibiting the growth of cancer cells. Clinically, it is used to treat gastrointestinal tumors, such as stomach cancer, colon cancer, liver cancer and so on. In breast cancer, ovarian cancer, lung cancer, bladder cancer, cervical cancer, pancreatic cancer and so on are also effective. The Swiss production of skin cancer treatment ointment containing 5% of the goods, mainly used for actinic keratoses and senile keratosis, precancerous dermatitis, single and multiple shallow table basal cell carcinoma, radioactive skin lesion of carcinoma and superficial basal cell carcinoma.
5-fluorouracil first changes for 5-Fluoro 2 deoxy urea pyrimidine nucleotides in vivo and inhibition of thymidylate synthase, blocking the transformation of urea pyrimidine deoxyribonucleotide thymidine, which affects DNA biosynthesis. At the same time, it can be incorporation into RNA by blocking urea ethyl pyridine and whey acid was incorporated into the RNA to direct inhibition of RNA synthesis.
This medicine is mainly in the liver metabolism, most of the decomposed into carbon dioxide discharged from breathing, rarely excreted from urine. After oral, absorption is different; vein after administration, concentrations in plasma quickly drop in two hours; static note within 30 minutes can arrive in cerebrospinal fluid (CSF) and maintain for 3 hours; continuous intravenous infusion toxicity is lighter than intravenous injection; vein to the drug's effect is compared with oral high. Toxicity of 5-fluorouracil on the proliferation is greater than non proliferating cells, but no obvious cell cycle specificity. Resistance to 5-FU can increase essential activity of enzyme missing or thymidylate synthetase activity.
The above information is edited by the lookchem Hayan.
Pharmacokinetics
Due to the instability of the absorption of 5-fluorouracil, the conventional the oral (in Europe can be obtained from oral preparation). General intravenous administration, We can also take transarterial Administration in order to directly reach the tumor (e.g. liver metastasis through hepatic artery) and injected directly into the body cavity infiltration liquid (such as ovarian cancer). Intravenous injection plasma half-life is 7.5~10 minutes, after 3 hours the drug in the plasma has not check did not change. Intracellular drug levels are last much longer.
Fluorouracil in the liver is used for metabolism; 60~80% in 8~12 hours as a respiratory carbon dioxide discharge and 15% in 6 hours technical unchanged from the urine discharge. The drug can enter into the exudate and cerebrospinal fluid (CSF). It has existed determination method for plasma fluorouracil.
Indications
Different sources of media describe the Indications of 51-21-8 differently. You can refer to the following data:
1. It is clinical for breast cancer, digestive tract cancer, ovarian cancer and primary bronchogenic lung adenocarcinoma adjuvant chemotherapy and palliative care; is also in the treatment of malignant hydatidiform mole, choriocarcinoma, serous cancer of effusion in bladder cancer and head and neck malignant tumor and liver cancer chemotherapy drugs.
Dermatological topical containing 5% 5-fluorouracil ointment is used in the treatment of actinic keratosis, actinic cheilitis, Bowen's disease, erythroplasia of Queyrat, Bowenoid papulosis, condyloma acuminatum, vitiligo, lichen amyloidosis, disseminated superficial porokeratosis, warts, flat warts, psoriasis, color of dry skin disease, superficial basal cell epithelioma table etc.; intralesional injection in the treatment of keratoacanthoma keloid.
2. Fluorouracil (5-fluorouracil, 5-fluorouracil, Efudex,
Adrucil) is a halogenated pyrimidine analogue that
must be activated metabolically. The active metabolite
that inhibits DNA synthesis is the deoxyribonucleotide
5-fluoro-2'deoxyuridine-S'-phosphate (FdUMP). 5-
Fluorouracil is selectively toxic to proliferating rather
than non-proliferating cells and is active in both the G1-
and S-phases. The target enzyme inhibited by 5-fluorouracilfluorouracil is thymidylate synthetase.
methylenetetrahydrofolate dihydrofolate
The carbon-donating cofactor for this reaction is
N5,N10 methylenetetrahydrofolate, which is converted
to dihydrofolate. The reduced folate cofactor occupies
an allosteric site on thymidylate synthetase, which allows
for the covalent binding of 5-FdUMP to the active
site of the enzyme.
Drug interaction
Before using this drug, first it is used methotrexate, 5-fluorouracil nucleotide formation is increased by increasing the content of intracellular phosphoribosyl pyrophosphate. Allopurinol can change the role of fluorouracil. Its metabolites, oxypurinol, can inhibit orotate phosphoribosyl transferase and thus reduce the toxicity and may improve the therapeutic index. Increase in thymidine and other nucleoside combination of fluorouracil and RNA and thymidine by dihydropyrimidine dehydrogenase can delay fluorouracil decomposition. However, the drug combination did not significantly improve the clinical effect so far.
Adverse reactions and precautions
The main toxic effect of fluorouracil is involving the gastrointestinal tract and blood cell generation system. Anorexia, nausea and vomiting were common. Stomatitis, pharyngo esophageal inflammation and diarrhea are withdrawal indication, otherwise there will be serious oropharyngeal and intestinal ulcers. Intravenous administration of gastrointestinal toxicity is often limiting dose. On the contrary, huge doses of intravenous injection, white cell reduction is the dose limiting toxicity. Low white cell counts often appear in medication for the first time after 7 to 14 days. Thrombocytopenia is not too obvious, appeared in 7~17. Monitoring of blood cell count is necessary.
Other adverse reactions are hair loss, dermatitis and pigment calm. There were acute and chronic conjunctivitis. Reversible cerebellar ataxia occurs in 1% of patients, possibly is related to the dose, occur at any time of the treatment process (often a few months later). After Cerebellar signs in the withdrawal can be last for a few of weeks. Myocardial ischemia occasionally appeared in the 5-FU intravenous drip. The drug in animals is caused by abnormal and may be carcinogenic.
Damage to the liver function of patients (e.g. extensive liver metastasis) fluorouracil should be reduced; The nutritional status of patients with poor medication should be cautious.
Using daily intermittent intravenous drip for 4~5d, can greatly reduce the toxic effects of blood. However, the results of clinical research mean rapid injection or intravenous drip method in the treatment of superiority. Long term intravenous drip infusion can be accompanied by pain, erythema and skin scaling of hand-foot comprehensive syndrome.
This medicine to FDA pregnancy category D.
Fluorofur
Fluorofur is fluorine urea pyrimidine derivatives, and effect is similar with fluorouracil, but chemotherapy index double higher than fluorouracil and toxicity is only the 1/4 to 1/6 of fluorouracil. It is suitable for gastrointestinal cancer and breast cancer. There are oral, intravenous and anal suppository three formulations.
Chemical property
It is white or white crystalline powder. Mp is 282-283℃ (decomposition), 0.1 mol/L hydrochloric acid solution has maximum absorption at 265nm wavelength. It is slightly soluble in water and ethanol, insoluble in chloroform and ether, soluble in dilute hydrochloric acid and sodium hydroxide solution. Medium toxicity, LD50 (mouse, i.p.) is 230mg/kg.
Uses
Different sources of media describe the Uses of 51-21-8 differently. You can refer to the following data:
1. 1. It is used for biochemical studies and antitumor drugs.
2. It is the anti tumor drug, also used for synthesis of flucytosine. 5-fluorouracil can be used in the study of rice in the biochemical studies, ear differentiation, genetic metabolic measurement, plant growth development research.
3. It is used for the digestive system cancer, head and neck cancer, gynecological cancer, lung cancer, liver cancer, treatment of bladder cancer and skin cancer.
4. Antimetabolite antitumor drugs.
5. Anti tumor drugs. There is a certain effect on a variety of tumors such as digestive tract cancer, breast cancer, ovarian cancer, chorionic epithelial cancer, cervical cancer, hepatocellular carcinoma, bladder cancer, skin cancer (topical), leukoplakia (topical) etc. Adverse reactions mainly are bone marrow transplantation, digestive tract reaction, serious person can have diarrhea, local injection site phlebitis, a few of which have nervous system reactions such as cerebellar degeneration and ataxia. The course of medication should strictly check the blood.
2. 5-Fluorouracil is used as an antitumor agent in the treatment of anal, breast, colorectal, oesophageal, stomach, pancreatic and skin cancers. It finds application as a suicide inhibitor due to its irreversible inhibition of thymidylate synthase. It is also used in the treatment of actinic keratoses and bowen's disease. Further, it serves as a potent antineoplastic agent in clinical use. In addition to this, it acts as a DNA synthesis inhibitor.
3. antineoplastic, pyrimidine antimetabolite
4. 5-Fluoro Uracil is an active metabolite of Doxifluridine (D556750).
5. A potent antineoplastic agent in clinical use. Also an inhibitor of DNA synthesis
Methods of production
1. It is obtained by fluoride ethyl acetate by condensation, cyclization and hydrolysis.
(1). Condensation, cyclization. Sodium methoxide is input dry stainless steel reaction pot, stirring under vacuum concentration to sodium methoxide into white powder, cooling to 50℃, adding toluene, then cold to below 10℃, dropping ethyl formate. After adding remained below 10℃, dripping ethyl fluoroacetate. Completely, at about 30℃ stirring reaction for 8 hours. Static, obtain pale yellow thick mixture. In the condensation product, adding methanol and methyl isobutyl urea sulfate, stirring and heating to 66-70℃, reflux reaction for 6h. Atmospheric recovering methanol to the reaction material showing a thin paste, then vacuum distilled to viscous so far. Heating, dissolving in water, adding activated charcoal, filtered, and the filtrate with concentrated hydrochloric acid to pH3-4, crystallization, cooling and filtering, use cold water to wash the filter cake, using boiling water to regulate plasma immersion to recognize, filtering, water washing, drying, to 5-fluorouracil (-4-hydroxy-2-four oxygen pyrimidine C5H5FN2O2. (2). The hydrolysis of the cyclization product 5-Fluoro-4-hydroxy-2-methoxy pyrimidine and adding 20% hydrochloric acid in 60℃are hydrolysis for 4h, after processing to obtain 5-fluorouracil.
2. 2-methylthio-5-fluorouracil is under acidic conditions and reflux system to obtain 5-fluorouracil.
Description
5-Fluorouracil (5-FU) is a prodrug form of the thymidylate synthase inhibitor fluorodeoxyuridylate (FdUMP). It is also converted to the active metabolites FUTP and FdUTP, which induce RNA and DNA damage, respectively. In vivo, 5-FU (15 mg/kg) when administered in combination with docetaxel reduces tumor growth in B88 and CAL 27 oral squamous cell carcinoma (OSCC) mouse xenograft models. Formulations containing 5-FU have been used in the treatment of colorectal, breast, gastric, and pancreatic cancers.
Chemical Properties
Different sources of media describe the Chemical Properties of 51-21-8 differently. You can refer to the following data:
1. White or almost white, crystalline powder
2. Fluorouracil is a white crystalline solid.
Practically odorless.
Originator
Efudex, Roche, US,1962
Manufacturing Process
A mixture of 200 grams (2 mols) of dry sodium fluoroacetate and 442 grams (2.86 mols) of diethyl sulfate was refluxed for 31? hours in an oil bath. The reaction mixture was then distilled through a fractionating column, yielding 177.3 grams of crude ethyl fluoroacetate, having a boiling range of 116° to 120°C. The material was redistilled through a fractionating column, yielding purified ethyl fluoroacetate boiling at 114° to 118°C.In a 2-liter, 3-neck, round bottom flask, provided with stirrer, dropping funnel and reflux condenser, was placed 880 ml of absolute diethyl ether, and 47.6 grams (1.22 mols) of potassium, cut into 5 mm pieces, was suspended therein. 220 ml of absolute ethanol was added dropwise, while stirring, whereby the heat of reaction produced refluxing. In order to obtain complete dissolution of the potassium, the mixture was finally refluxed on a steam bath. The reaction mixture was then cooled in an ice bath, and a mixture of 135 grams (1.22 mols) of ethyl fluoroacetate and 96.4 grams (1.3 mols) of freshly distilled ethyl formate was added dropwise, while stirring and cooling, over a period of 2? hours. Upon completion of the addition of the ethyl formate, the reaction mixture was stirred for an additional hour while cooling, and then was allowed to stand overnight at room temperature.At the end of this time the crystalline precipitate which had formed was filtered off with suction, washed with diethyl ether, and dried in a vacuum desiccator. The product comprised essentially the potassium enolate of ethyl fluoromalonaldehydate (alternative nomenclature, the potassium salt of fluoromalonaldehydic acid ethyl ester).A mixture of 103.6 grams (0.6 mol) of the freshly prepared potassium enolate of ethyl fluoromalonaldehydate, 83.4 grams (0.3 mol) of Smethylisothiouronium sulfate and 32.5 grams (0.6 mol) of sodium methoxide was refluxed with stirring in 1,500 ml of absolute methanol. At first the reactants dissolved to a great extent, but very shortly thereafter precipitation occurred. The reaction mixture was refluxed for 2 hours and at the end of this time was evaporated to dryness in vacuo. The residue was treated with 280 ml of water; incomplete dissolution was observed.The mixture obtained was clarified by filtering it through charcoal. The filtrate was acidified (to a slight Congo red acid reaction) by adding concentrated aqueous hydrochloric acid, containing 37% by weight HCl (48 ml required). The material which crystallized from the acidified solution was filtered off, washed free of sulfates with water and dried at 100°C, yielding crude Smethyl ether of 2-thio-5-fluorouracil, having a melting range from 202° to 221°C. The latter material was recrystallized by dissolving it in 2,035 ml of boiling ethylacetate and cooling to -20°C, yielding S-methyl ether of 2-thio-5fluorouracil, MP 230° to 237°C, in a sufficient state of purity that it could be used directly for the next step. A sample of the material was recrystallized from water (alternatively, from ethyl acetate) thereby raising the melting point to 241° to 243°C. For analysis the material was further purified by subliming it in vacuo at 140° to 150°/0.1 mmA solution of 10.0 grams of purified S-methyl ether of 2-thio-5-fluorouracil, MP 230° to 237°C, in 150 ml of concentrated aqueous hydrochloric acid (containing approximately 37% by weight HCl) was refluxed under nitrogen for 4 hours. The reaction mixture was then evaporated in vacuo. The crystalline brownish residue was recrystallized from water. The resulting recrystallized product was further purified by sublimation in vacuo at 190° to 200°C (bath temperature)/0.1 mm pressure. There was obtained 5fluorouracil, in the form of colorless or pinkish-tan crystals, MP 282° to 283°C (with decomposition).
Brand name
Adrucil (Pharmacia & Upjohn); Adrucil (Sicor); Carac (Sanofi Aventis); Efudex (Valeant); Fluoroplex (Allergan).
Therapeutic Function
Cancer chemotherapy
Synthesis Reference(s)
Journal of Heterocyclic Chemistry, 20, p. 457, 1983 DOI: 10.1002/jhet.5570200236Tetrahedron Letters, 21, p. 277, 1980 DOI: 10.1016/S0040-4039(00)71188-9
General Description
Different sources of media describe the General Description of 51-21-8 differently. You can refer to the following data:
1. The drug is available in a 500-mg or 10-mL vial for IV useand as a 1% and 5% topical cream. 5-FU is used in the treatmentof several carcinoma types including breast cancer,colorectal cancer, stomach cancer, pancreatic cancer, andtopical use in basal cell cancer of the skin. The mechanism ofaction includes inhibition of the enzyme TS by the deoxyribosemonophosphate metabolite, 5-FdUMP. The triphosphatemetabolite is incorporated into DNA and the ribosetriphosphate into RNA. These incorporations into growingchains result in inhibition of synthesis and function of DNAand RNA. Resistance can occur as a result of increased expressionof TS, decreased levels of reduced folate substrate5,10-methylenetetrahydrofolate, or increased levels of dihydropyrimidinedehydrogenase. Dihydropyrimidine dehydrogenaseis the main enzyme responsible for 5-FU catabolism.Bioavailability following oral absorption is erratic.Administration of 5-FU by IV yields high drug concentrationsin bone marrow and liver. The drug does distribute intothe central nervous system (CNS). Significant drug interactionsinclude enhanced toxicity and antitumor activity of5-FU following pretreatment with leucovorin. Toxicities includedose-limiting myelosuppression, mucositis, diarrhea,and hand–foot syndrome (numbness, pain, erythema, dryness,rash, swelling, increased pigmentation, nail changes,pruritus of the hands and feet).
2. White to nearly white crystalline powder; practically odorless. Used as an anti neoplastic drug, chemosterilant for insects.
Air & Water Reactions
Insoluble in water.
Reactivity Profile
5-Fluorouracil may be sensitive to prolonged exposure to light. Solutions discolor on storage. 5-Fluorouracil can react with oxidizing agents and strong bases. Incompatible with methotrexate sodium.
Hazard
Questionable carcinogen.
Health Hazard
Minimum toxic dose in humans is approximately 450 mg/kg (total dose) over 30 days for the ingested drug. Intravenous minimum toxic dose in humans is a total dose of 6 mg/kg over three days. Depression of white blood cells occurred after intravenous administrative of a total dose of 480 mg/kg over 32 days. Occasional neuropathy and cardiac toxicity have been reported. Do not use during pregnancy. Patients with impaired hepatic or renal function, with a history of high-dose pelvic irradiation or previous use of alkylating agents should be treated with extreme caution. Patients with nutritional deficiencies and protein depletion have a reduced tolerance to 5-Fluorouracil.
Fire Hazard
Emits very toxic fumes of flourides and nitrogen oxides when heated to decomposition. Avoid decomposing heat.
Biological Activity
Anticancer agent. Metabolized to form fluorodeoxyuridine monophosphate (FdUMP), fluorodeoxyuridine triphosphate (FdUTP) and fluorouridine (FUTP). FdUMP inhibits thymidylate reductase causing a reduction in dTMP synthesis. FUTP and FdUTP are misincorporated into RNA and DNA respectively.
Biochem/physiol Actions
A potent antitumor agent that affects pyrimidine synthesis by inhibiting thymidylate synthetase, thus depleting intracellular dTTP pools. It is metabolized to ribonucleotides and deoxyribonucleotides, which can be incorporated into RNA and DNA. Treatment of cells with 5-FU leads to an accumulation of cells in S-phase and has been shown to induce p53 dependent apoptosis.
Mechanism of action
Different sources of media describe the Mechanism of action of 51-21-8 differently. You can refer to the following data:
1. 5-Fluorouracil (FU) is converted intracellularly to several active metabolites: fluorodeoxyuridine monophosphate (FdUMP), fluorodeoxyuridine triphosphate (FdUTP), and fluorouridine triphosphate (FUTP). The active metabolites of 5-FU disrupt RNA synthesis (FUTP), inhibit the action of thymidylate synthase (TS)—a nucleotide synthetic enzyme (FdUMP)—and can also be directly misincorporated into DNA (FdUTP). The rate-limiting enzyme in 5-FU catabolism is dihydropyrimidine dehydrogenase (DPD), which converts 5-FU to dihydrofluorouracil (DHFU). Over 80% of administered 5-FU is normally catabolized primarily in the liver, where DPD is abundantly expressed.
5-Fluorouracil (5-FU) is converted to three major active metabolites: (1) fluorodeoxyuridine monophosphate (FdUMP), (2) fluorodeoxyuridine triphosphate (FdUTP), and (3) fluorouridine triphosphate (FUTP). The main mechanism of 5-FU activation is conversion to fluorouridine monophosphate (FUMP) either directly by orotate phosphoribosyl transferase (OPRT), or indirectly via fluorouridine (FUR) through the sequential action of uridine phosphorylase (UP) and uridine kinase (UK). FUMP is then phosporylated to fluorouridine diphosphate (FUDP), which can be either further phosphorylated to the active metabolite fluorouridine triphosphate (FUTP), or converted to fluorodeoxyuridine diphosphate (FdUDP) by ribonucleotide reductase (RR). In turn, FdUDP can either be phosphorylated or dephosphorylated to generate the active metabolites FdUTP and FdUMP respectively. An alternative activation pathway involves the thymidine phosphorylase catalyzed conversion of 5-FU to fluorodeoxyuridine (FUDR), which is then phosphorylated by thymidine kinase (TK) to the thymidylate synthase (TS) inhibitor, FdUMP. Dihydropyrimidine dehydrogenase (DPD)-mediated conversion of 5-FU to dihydrofluorouracil (DHFU) is the rate-limiting step of 5-FU catabolism in normal and tumor cells.
2. Another action proposed for 5-fluorouracil may involve
the incorporation of the nucleotide 5-fluorouridine
triphosphate (5-FUTP) into RNA. The cytotoxic
role of these “fraudulent” 5-fluorouracil-containing
RNAs is not well understood.
Several possible mechanisms of resistance to 5-fluorouracil
have been identified, including increased synthesis
of the target enzyme, altered affinity of thymidylate
synthetase for FdUMP, depletion of enzymes
(especially uridine kinase) that activate 5-fluorouracil
to nucleotides, an increase in the pool of the normal
metabolite deoxyuridylic acid (dUMP), and an increase
in the rate of catabolism of 5-fluorouracil.
The drug has been administered orally, but absorption
by this route is erratic. The plasma half-life of 5-
fluorouracil after intravenous injection is 10 to 20 minutes.
It readily enters CSF. Less than 20% of the parent
compound is excreted into the urine, the rest being
largely metabolized in the liver.
Pharmacology
Local inflammatory reactions characterized
by erythema, edema, crusting, burning, and pain are
common (and, some would argue, desirable) but may be
minimized by reduced frequency of application or use
in combination with a topical corticosteroid.
Clinical Use
Different sources of media describe the Clinical Use of 51-21-8 differently. You can refer to the following data:
1. 5-Fluorouracil (Efudex, Fluoroplex) is an antimetabolite
used for the topical treatment of actinic keratoses. It
is also useful for the treatment of superficial basal cell
carcinomas when conventional surgical modalities are
impractical.
2. 5-Fluorouracil (FU) is widely used in the treatment of a range of cancers including breast and cancers of the aerodigestive tract, but has had the greatest impact in colorectal cancer. 5-FU-based chemotherapy improves overall and disease-free survival of patients with resected stage III colorectal cancer. Nonetheless, response rates for 5-FU-based chemotherapy as a first-line treatment for advanced colorectal cancer are only between 10 and 15%. Combination of 5-FU with newer chemotherapies, such as irinotecan and oxaliplatin, has improved the response rates for advanced colorectal cancer to between 40 and 50%.
3. 5-Fluorouracil is used in several combination regimens
in the treatment of breast cancer. It also has palliative
activity in gastrointestinal adenocarcinomas, including
those originating in the stomach, pancreas, liver,
colon, and rectum. Other tumors in which some antitumor
effects have been reported include carcinomas of
the ovary, cervix, oropharynx, bladder, and prostate.
Topical 5-fluorouracil cream has been useful in the
treatment of premalignant keratoses of the skin and superficial
basal cell carcinomas, but it should not be used
in invasive skin cancer.
Side effects
Patients who are genetically deficient in this enzyme will experience a more pronounced effect from this drug and are at significant risk for use-limiting toxicity. In general, women clear fluorouracil faster than men do. Dosage adjustments usually are not required in hepatic or renal dysfunction. Major toxicities are related to bone marrow depression, stomatitis/esophagopharyngitis, and potential GI ulceration. Nausea and vomiting are common. Solutions of fluorouracil are light sensitive, but discolored products that have been properly stored and protected from light are still safe to use.
Safety Profile
Poison by ingestion,
intraperitoneal, subcutaneous, and
intravenous routes. Moderately toxic by
parented and rectal routes. Experimental
teratogenic and reproductive effects. Human
systemic effects: EKG changes, bone
marrow changes, cardiac, pulmonary, and
gastrointestinal effects. Human mutation
data reported. A human skin irritant.
Questionable carcinogen. When heated to decomposition it emits very toxic fumes of
Fand NOx.
Synthesis
Fluorouracil, 4-fluorouracil (30.1.3.3), is made by condensing the ethyl ester
of fluoroacetic acid with ethylformate in the presence of potassium ethoxide, forming
hydroxy-methylenfluoroacetic ester (30.3.1), which cyclizes by reacting it with S-methylisothiourea to 2-methylthio-4-hydroxy-5-fluoropyrimidine, which is subsequently hydrolyzed
by hydrochloric acid to fluorouracil (30.1.3.3). An alternative method of synthesizing5-fluorouracid is direct fluorination of uracil with fluorine or trifluoromethylhypofluoride.
Potential Exposure
This material is used as an antineo plastic drug for cancer treatment and as a chemosterilant
for insects.
Veterinary Drugs and Treatments
5-fluorouracil is a potent cytotoxic chemotherapeutic agent used
for the topical therapy of equine limbal and eyelid squamous cell
carcinoma. It is also used as an antimetabolite to limit fibrosis over
the body of gonioimplant devices used to artificially shunt aqueous
humor out of the eye in glaucoma as well as improve long-term
filtering performance of the implant.
1% solution applied to the affected eye three times daily.
Drug interactions
Potentially hazardous interactions with other drugs
Anticoagulants: possibly enhances effect of
coumarins.
Antipsychotics: avoid concomitant use with
clozapine, increased risk of agranulocytosis.
Cytotoxics: avoid with panitumumab.
Folic acid: toxicity of fluorouracil increased - avoid.
Metronidazole and cimetidine inhibit metabolism
(increased toxicity).
Temoporfin: increased skin photosensitivity with
topical fluorouracil
Metabolism
After intravenous injection fluorouracil is cleared rapidly
from plasma. It is distributed throughout body tissues
and fluids, and disappears from the plasma within about
3 hours. Within the target cell fluorouracil is converted
to 5-fluorouridine monophosphate and floxuridine
monophosphate (5-fluorodeoxyuridine monophosphate),
the former undergoing conversion to the triphosphate
which can be incorporated into RNA while the latter
inhibits thymidylate synthetase. About 15% of an
intravenous dose is excreted unchanged in the urine
within 6 hours. Approximately 80% is inactivated mainly
in the liver and is catabolised via dihydropyrimidine
dehydrogenase (DPD) similarly to endogenous uracil,
60-80% is excreted as respiratory carbon dioxide; urea
and other metabolites are also produced, and 2-3% by the
biliary system
Shipping
UN2811 Toxic solids, organic, n.o.s., Hazard
Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name
Required.
Incompatibilities
Incompatible with oxidizers (chlorates,
nitrates, peroxides, permanganates, perchlorates, chlorine,
bromine, fluorine, etc.); contact may cause fires or explo sions. Keep away from alkaline materials, strong bases,
strong acids, oxoacids, epoxides, methotrexrate sodium,
sources of heat.
References
1) Schlisky (1998), Biochemical and Clinical Pharmacology of 5-Fluorouracil; Oncology, 12 13
Check Digit Verification of cas no
The CAS Registry Mumber 51-21-8 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 5 and 1 respectively; the second part has 2 digits, 2 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 51-21:
(4*5)+(3*1)+(2*2)+(1*1)=28
28 % 10 = 8
So 51-21-8 is a valid CAS Registry Number.
InChI:InChI=1/C4H3FN2O2/c5-7-2-1-3(8)6-4(7)9/h1-2H,(H,6,8,9)
51-21-8Relevant articles and documents
Identification of proton-pump inhibitor drugs that inhibit Trichomonas vaginalis uridine nucleoside ribohydrolase
Shea, Tara A.,Burburan, Paola J.,Matubia, Vivian N.,Ramcharan, Sandy S.,Rosario Jr., Irving,Parkin, David W.,Stockman, Brian J.
, p. 1080 - 1084 (2014)
Trichomonas vaginalis continues to be a major health problem with drug-resistant strains increasing in prevalence. Novel antitrichomonal agents that are mechanistically distinct from current therapies are needed. The NIH Clinical Compound Collection was screened to find inhibitors of the uridine ribohydrolase enzyme required by the parasite to scavenge uracil for its growth. The proton-pump inhibitors omeprazole, pantoprazole, and rabeprazole were identified as inhibitors of this enzyme, with IC50 values ranging from 0.3 to 14.5 μM. This suggests a molecular mechanism for the in vitro antitrichomonal activity of these proton-pump inhibitors, and may provide important insights toward structure-based drug design.
Solid-phase synthesis of biocompatible N-heterocyclic carbene-Pd catalysts using a sub-monomer approach
Cherukaraveedu, Durgadas,Cowling, Paul T.,Birch, Gavin P.,Bradley, Mark,Lilienkampf, Annamaria
, p. 5533 - 5537 (2019)
Taking inspiration from the assembly of so-called peptoids (N-alkylglycine oligomers) we present a new synthetic methodology whereby N-heterocyclic carbene (NHC) based Pd ligands were assembled using a sub-monomer approach and loaded with Pd via solid-phase synthesis. This allowed the rapid generation a library of NHC-palladium catalysts that were readily functionalised to allow bioconjugation. These catalysts were able to rapidly activate a caged fluorophore and 'switch-on' an anticancer prodrug in 3D cell culture.
Stereoelectronic effect on one-electron reductive release of 5-Fluorouracil from 5-fluoro-1-(2'-oxocycloalkyl)uracils as a new class of radiation-activated antitumor prodrugs
Mori, Mayuko,Hatta, Hiroshi,Nishimoto, Sei-Ichi
, p. 4641 - 4647 (2000)
A series of 5-fluoro-1-(2'-oxocycloalkyl)uracils (3-11) that are potentially novel radiation-activated prodrugs for the radiotherapy of hypoxic tumor cells have been synthesized to evaluate a relationship between the molecular structure and the reactivity of one-electron reductive release of antitumor 5-fluorouracil (1) in anoxic aqueous solution. All the compounds 3-11 bearing the 2'-oxo group were one-electron reduced by hydrated electrons (e(aq)-) and thereby underwent C(1')-N(1) bond dissociation to release 5-fluorouracil 1 in 47-96% yields upon radiolysis of anoxic aqueous solution, while control compounds (12, 13) without the 2'-oxo substituent had no reactivity toward such a reductive C(1')-N(1) bond dissociation. The decomposition of 2-oxo compounds in the radiolytic one-electron reduction was more enhanced, as the one-electron reduction potential measured by cyclic voltammetry in N,N-dimethylformamide became more positive. The efficiency of 5-fluorouracil release was strongly dependent on the structural flexibility of 2-oxo compounds. X-ray crystallographic studies of representative compounds revealed that the C(1')-N(1) bond possesses normal geometry and bond length in the ground state. MO calculations by the AM1 method demonstrated that the LUMO is primarily localized at the π* orbital of C(5)-C(6) double bond of the 5-fluorouracil moiety, and that the LUMO + 1 is delocalized between the π* orbital of 2'-oxo substituent and the σ* orbital of adjacent C(1')-N(1) bond. The one-electron reductive release of 5-fluorouracil 1 in anoxic aqueous solution was presumed to occur from the LUMO + 1 of radical anion intermediates possessing a partial mixing of the antibonding C(2')=O π* and C(1')-N(1) σ(*) MO's, that may be facilitated by a dynamic conformational change to achieve higher degree of (π + σ) MO mixing.
Electron spin resonance of gamma- and X irradiated nucleic acid base pairs. 1 Methylcytosine: 5 fluorouracil co crystals at 77°K
Farley,Bernhard
, p. 47 - 54 (1975)
The predominant free radical trapped in single crystals of a hydrogen bonded complex of 1 methylcytosine and 5 fluorouracil x irradiated between 77°K and room temperature has been identified. It is characterized by hydrogen atom extraction from N(1) of the 5 fluorouracil moiety, the unpaired electron interacting with the N(1) and F nuclei of this molecule. The principal values of the hyperfine and g tensors are given. The radical is present at 77°K and decays upon warming to room temperature. There is at least one additional radical present at 77°K, but its structure has not been determined.
Inhibition of 5'-deoxy-5-fluorouridine phosphorolysis by acyclothymidine in tumor cell homogenates
Hamada, Akinobu,Nakano, Masahiro,Shimidzu, Satoshi,Hasegawa, Tetsuya,Kawaguchi, Takeo
, p. 935 - 938 (1997)
The inhibitory effect of acyclothymidine[AcyT, 5-methyl-1-(2'- hydroxyethoxymethyl) uracil], a potent pyrimidine nucleoside phosphorylase (PyNPase) inhibitor, on 5'-deoxy-5-fluorouridine (5'-DFUR) phosphorolysis in human and mouse tumor cell homogenates was measured. Competitive inhibition was observed in MKN-74 and Lewis lung carcinoma (LLC), whereas non- competitive inhibition was observed in HeLa. The strength of the inhibitory effect by AcyT showed the following pattern: HeLahuman normal intestinemouse normal intestineColon 26LLCMKN-74DLD-1. From the kinetic parameter obtained, we simulated the inhibitory effect of AcyT on 5'-DFUR phosphorolysis in tumor cells and the intestine. These data indicated that AcyT was more sensitive in normal mouse intestine than in Colon 26 find LLC, and that orally administered AcyT can reduce the intestinal toxicity of 5'- DFUR without reducing the antitumor effect in the mouse. The present finding may have an important implication for attempts to introduce AcyT, a potent PyNPase inhibitor, into the clinic.
Novel isoxazolidine analogues of homonucleosides and homonucleotides
Piotrowska, Dorota G.,Balzarini, Jan,Andrei, Graciela,Schols, Dominique,Snoeck, Robert,Wróblewski, Andrzej E.,Gotkowska, Joanna
, p. 8294 - 8308 (2016)
Isoxazolidine analogues of homonucleos(t)ides were synthesized from nucleobase-derived nitrones 20a-20e (uracil, 5-fluorouracil, 5-bromouracil, thymine, adenine) employing 1,3-dipolar cycloadditions with allyl alcohol as well as with alkenylphosphonates (allyl-, allyloxymethyl- and vinyloxymethyl- and vinylphosphonate). Besides reactions with vinylphosphonate the additions proceeded regioselectively to produce mixtures of major cis and minor trans 3,5-disubstituted isoxazolidines (d.e. 28–82%). From vinylphosphonate up to 10% of 3,4-disubstituted isoxazolidines was additionally produced. Vicinal couplings, shielding effects and 2D NOE correlations were employed in configurational assignments as well as in conformational analysis to find out preferred conformations for several isoxazolidines and to observe anomeric effects (pseudoaxial orientation of phosphonylmethoxy groups) for those obtained from vinyloxymethylphosphonate. None of the tested compounds were endowed in vitro with antiviral activity against a variety of DNA and RNA viruses at subtoxic concentrations (up to 250 μM) nor exhibited antiproliferative activity towards L1210, CEM, and HeLa cells (IC50= ≥100 μM).
Kinetic Study on the γ-Radiolysis of 5-Fluorouracil Derivatives
Kuroda, Tokuyuki,Hisamura, Koji,Nakamizo, Nobuhiro,Otsuji, Yoshio
, p. 707 - 710 (1989)
The reactivity of 5-fluoro-1-(2-phenylethenesulfonyl)uracil (1) and 5-fluoro-1-phenylthioureidouracil (2) in the γ-radiolysis of their aqueous solutions was studied by a competitive kinetic method using nitrobenzene and acetone as reference compounds.The rate constants for the reactions of 1 and 2 with eaq- were of the same order of magnitude as that for nitrobenzene.The efficiencies of the conversion of intermediates generated from 1 and 2 into 5-fluorouracil were also estimated.
Improvement of chemical instability of carmoful in β-cyclodextrin solid complex by utilizing some organic acids
Kikuchi,Hirayama,Uekama
, p. 315 - 319 (1987)
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Short oligonucleotide prodrug having 5-fluoro and 5-iodouracil inhibits the proliferation of cancer cells in a photo-responsive manner
Fujimoto, Kenzo,Takematsu, Yu-Ki,Shigeno, Atsuo,Furusawa, Mirei,Sakamoto, Takashi
, p. 3736 - 3738 (2014)
Photo-induced C1′ hydrogen abstraction of 5-fluoro-2′- deoxyuridine was adopted as the key reaction for releasing 5-fluorouracil (5-FU) anticancer drug from oligonucleotide strands. After photoirradiation following 5-FU release, anticancer activity was expected. We demonstrated that oligonucleotide tetramer, d(AFUIUA), can release 5-FU under physiological conditions in a photo-responsive manner thorough photo-induced C1′ hydrogen abstraction, and that the 5-FU released from d(AFUIUA) having a phosphorothioate backbone clearly suppresses the proliferation of HeLa cells in a photo-responsive manner.
Click Nucleic Acid Mediated Loading of Prodrug Activating Enzymes in PEG-PLGA Nanoparticles for Combination Chemotherapy
Harguindey, Albert,Roy, Shambojit,Harris, Alexander W.,Fairbanks, Benjamin D.,Goodwin, Andrew P.,Bowman, Christopher N.,Cha, Jennifer N.
, p. 1683 - 1690 (2019)
The simultaneous delivery of multiple therapeutics to a single site has shown promise for cancer targeting and treatment. However, because of the inherent differences in charge and size between drugs and biomolecules, new approaches are required for colocalization of unlike components in one delivery vehicle. In this work, we demonstrate that triblock copolymers containing click nucleic acids (CNAs) can be used to simultaneously load a prodrug enzyme (cytosine deaminase, CodA) and a chemotherapy drug (doxorubicin, DOX) in a single polymer nanoparticle. CNAs are synthetic analogs of DNA comprised of a thiolene backbone and nucleotide bases that can hybridize to complementary strands of DNA. In this study, CodA was appended with complementary DNA sequences and fluorescent dyes to allow its encapsulation in PEG-CNA-PLGA nanoparticles. The DNA-modified CodA was found to retain its enzyme activity for converting prodrug 5-fluorocytosine (5-FC) to active 5-fluorouracil (5-FU) using a modified fluorescent assay. The DNA-conjugated CodA was then loaded into the PEG-CNA-PLGA nanoparticles and tested for cell cytotoxicity in the presence of the 5-FC prodrug. To study the effect of coloading DOX and CodA within a single nanoparticle, cell toxicity assays were run to compare dually loaded nanoparticles with nanoparticles loaded only with either DOX or CodA. We show that the highest level of cell death occurred when both DOX and CodA were simultaneously entrapped and delivered to cells in the presence of 5-FC.
Green preparation process for preparing 5-fluorouracil
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Paragraph 0012-0015, (2021/07/17)
The invention relates to a green method for preparing 5-fluorouracil, which is characterized in that the preparation method comprises the following steps: stirring 2-methoxy-5-fluorouracil serving as a raw material and a methanol solution of hydrogen chloride serving as an acidifying reagent at a certain temperature for 5-6 hours, carrying out HPLC central control, cooling to 15 DEG C after the reaction is finished, carrying out suction filtration to obtain a solid, refining to obtain a 5-fluorouracil refined product, carrying out suction filtration, concentrating mother liquor, recovering methanol, introducing hydrogen chloride into the recovered methanol, and continuously taking the recovered methanol as an acidifying reagent of the reaction; and the specific reaction is shown in the specification. The green method has the advantages that hydrochloric acid is replaced by an organic solvent, the organic solvent can be recycled after the reaction is finished, the problem that a large amount of concentrated acid wastewater is generated is solved, and the resource utilization rate is increased while environmental pollution is prevented. In addition, the reaction is centrally controlled by a liquid chromatograph in the later stage of the reaction, the reaction efficiency is improved, the obtained 5-fluorouracil is qualified in purity and stable in yield, and the method is a green chemical synthesis method with good popularization and application prospects.
Platinum-Triggered Bond-Cleavage of Pentynoyl Amide and N-Propargyl Handles for Drug-Activation
Oliveira, Bruno L.,Stenton, Benjamin J.,Unnikrishnan,De Almeida, Cátia Rebelo,Conde, Jo?o,Negr?o, Magda,Schneider, Felipe S.S.,Cordeiro, Carlos,Ferreira, Miguel Godinho,Caramori, Giovanni F.,Domingos, Josiel B.,Fior, Rita,Bernardes, Gon?alo J. L.
supporting information, p. 10869 - 10880 (2020/07/04)
The ability to create ways to control drug activation at specific tissues while sparing healthy tissues remains a major challenge. The administration of exogenous target-specific triggers offers the potential for traceless release of active drugs on tumor sites from antibody-drug conjugates (ADCs) and caged prodrugs. We have developed a metal-mediated bond-cleavage reaction that uses platinum complexes [K2PtCl4 or Cisplatin (CisPt)] for drug activation. Key to the success of the reaction is a water-promoted activation process that triggers the reactivity of the platinum complexes. Under these conditions, the decaging of pentynoyl tertiary amides and N-propargyls occurs rapidly in aqueous systems. In cells, the protected analogues of cytotoxic drugs 5-fluorouracil (5-FU) and monomethyl auristatin E (MMAE) are partially activated by nontoxic amounts of platinum salts. Additionally, a noninternalizing ADC built with a pentynoyl traceless linker that features a tertiary amide protected MMAE was also decaged in the presence of platinum salts for extracellular drug release in cancer cells. Finally, CisPt-mediated prodrug activation of a propargyl derivative of 5-FU was shown in a colorectal zebrafish xenograft model that led to significant reductions in tumor size. Overall, our results reveal a new metal-based cleavable reaction that expands the application of platinum complexes beyond those in catalysis and cancer therapy.
