50-91-9 Usage
Description
Floxuridine, also known as Fudr, is a nucleoside analog that functions as an antiviral and antineoplastic agent. It is a white solid available in a 500-mg vial of lyophilized powder. Floxuridine works by inhibiting the enzyme ribonucleotide reductase, which is involved in the synthesis of DNA. This action disrupts DNA synthesis, function, and repair, leading to the inhibition of cancer cell growth and induction of apoptosis. The drug has also demonstrated inhibitory effects on enzymes involved in cell proliferation, such as protein kinase C and tyrosine kinases.
Uses
Used in Antiviral Applications:
Floxuridine is used as an antiviral agent, targeting and inhibiting the replication of certain viruses within the host cells.
Used in Antineoplastic Applications:
Floxuridine is employed as an antineoplastic agent, particularly for the treatment of metastatic gastrointestinal adenocarcinoma. It is also used for palliative treatment of gastrointestinal adenocarcinoma with liver metastases.
Used in Renal Function Diagnosis:
Floxuridine is utilized in the diagnosis of renal function, aiding in the assessment of kidney health and functionality.
Used in the Pharmaceutical Industry:
Floxuridine is used as an active pharmaceutical ingredient for the development of drugs targeting cancer and viral infections.
Used in Research and Development:
Floxuridine is used as a research tool for studying the mechanisms of DNA synthesis, cancer cell growth, and apoptosis, as well as for the development of novel drug delivery systems and therapies.
Originator
FUDR,Roche,US ,1971
Manufacturing Process
Cells of Streptococcus fecalis (ATCC-8043) were grown in the AOAC folic acid
assay medium [Lepper, Official and Tentative Methods of the Association of Official Agricultural Chemists, Washington, D.C., 7th edition, 784 (1950)],
supplemented with 2 mg per liter of thymine; following the teachings of
Prusoff, Proc. Soc. Exp. Biol. & Med. 85, 564 (1954). After 20 hours of
incubation at 37°C, the cells were harvested by centrifugation. The collected
cells were washed three times with four volumes of potassium phosphate
buffer solution (M/15 aqueous KH2PO4 solution, adjusted to pH 8.0 by addition
of 2 N aqueous KOH) and the wet cells were weighed. The cells were finally
suspended in the above potassium phosphate buffer solution and ground in a
glass tissue homogenizer.An amount of enzyme preparation equivalent to 900 mg of wet cells was
made up to 25 ml with the above potassium phosphate buffer solution. 150
mg (1.15 mmol) of 5-fluorouracil and 1.0 gram of thymidine (4.12 mmol)
were dissolved in 15 ml of the above potassium phosphate buffer solution.
The mixture was incubated at 37°C for 18 hours. After this time, enzyme
action was stopped by the addition of four volumes of acetone and one
volume of peroxide-free diethyl ether. The precipitated solids were removed by
filtration, and the filtrate was evaporated under nitrogen at reduced pressure
until substantially all volatile organic solvent had been removed. About 20 ml
of aqueous solution, essentially free of organic solvent, remained. This
solution was diluted to 100 ml with distilled water.Ten microliters of this solution were submitted to descending chromatography
on a paper buffered with 0.2 N KH2PO4 (pH 7.8), using a solvent mixture of
tertiary amyl alcohol:water:n-butyl ether (80:13:7 by volume). A spot visible
under ultraviolet light and having Rf = 0.55 was leached with 0.1 N HCl and
assayed for deoxyribose by the method of Stumpf, J. Biol. Chem. 169, 367
(1947). This analysis indicated the presence of a minimum of 85.5 mg (0.35
mmol) of 2'-deoxy-5-fluorouridine in the protein-free reaction mixture
according to US Patent 2,885,396. An alternate route from 5-fluorouracil via
the mercury derivative, through toluoyl deoxyuridines and then toluoyl
removal to give floxuridine is described in US Patent 3,041,335.
Therapeutic Function
Antiviral, Cancer chemotherapy
Health Hazard
ACUTE/CHRONIC HAZARDS: Floxuridine is highly toxic by ingestion.
Fire Hazard
Flash point data for Floxuridine are not available, but Floxuridine is probably combustible.
Biochem/physiol Actions
Antineoplastic drug that acts as a potent inhibitor of thymidylate synthetase Resistance to FUdR can develop in cancer cell cultures, among other means, by low-level Mycoplasma infection.
Safety Profile
Poison by ingestion.
Moderately toxic by intraperitoneal route.
An experimental teratogen. Other
experimental reproductive effects. Human
systemic effects: hypermotitity, diarrhea,
nausea, vomiting and other gastrointestinal
effects, allergic dermatitis, and bone marrow
changes. Human mutation data reported.
When heated to decomposition it emits very
toxic fumes of Fand NOx.
Synthesis
Fluoxuridine, 5-fluoro-1-(2-deoxyribofuranosyl)-pyrimidin-2,4-(1H,3H)-
dione (30.1.3.5), is a pyrimidine nucleotide made by reacting fluorouracil (30.1.3.3) with
2-deoxyribofuranosylbromide in the presence of silver or mercury salts.
Check Digit Verification of cas no
The CAS Registry Mumber 50-91-9 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 5 and 0 respectively; the second part has 2 digits, 9 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 50-91:
(4*5)+(3*0)+(2*9)+(1*1)=39
39 % 10 = 9
So 50-91-9 is a valid CAS Registry Number.
50-91-9Relevant articles and documents
Activation of antibacterial prodrugs by peptide deformylase
Wei, Yaoming,Pei, Dehua
, p. 1073 - 1076 (2000)
5'-Dipeptidyl derivatives of 5-fluorodeoxyuridine (FdU) (1a-d) were synthesized. These compounds are biologically inactive but can be activated by peptide deformylase, which removes the N-terminal formyl group of the dipeptide, to release the active drug FdU via an intramolecular cyclization reaction. Because the deformylase is ubiquitous among bacteria but absent in mammalian cells, 1a-d provide a novel class of potential antibacterial agents. (C) 2000 Elsevier Science Ltd. All rights reserved.
Floxuridine Oligomers Activated under Hypoxic Environment
Morihiro, Kunihiko,Ishinabe, Takuro,Takatsu, Masako,Osumi, Hiraki,Osawa, Tsuyoshi,Okamoto, Akimitsu
, p. 3340 - 3347 (2021)
Floxuridine oligomers are anticancer oligonucleotide drugs composed of a number of floxuridine residues. They show enhanced cytotoxicity per floxuridine monomer because the nuclease degradation of floxuridine oligomers directly releases highly active floxuridine monophosphate in cells. However, their clinical use is limited by the low selectivity against cancer cells. To address this limitation, we herein report floxuridine oligomer prodrugs that are active under hypoxia conditions, which is one of the distinguishing features of the microenvironment of all solid tumors. We designed and synthesized two types of floxuridine oligomer prodrugs that possess hypoxia-responsive moieties on nucleobases. The floxuridine oligomer prodrugs showed lower cytotoxicity under normoxia conditions (O2 = 20%), while the parent floxuridine oligomer showed similar anticancer effects under hypoxia conditions (O2 = 1%). The floxuridine oligomer prodrug enabled tumor growth suppression in live mice. This would be the first example demonstrating the conditional control of the medicinal efficacy of oligomerized nucleoside anticancer drugs.
Thermodynamic Reaction Control of Nucleoside Phosphorolysis
Kaspar, Felix,Giessmann, Robert T.,Neubauer, Peter,Wagner, Anke,Gimpel, Matthias
, p. 867 - 876 (2020/01/24)
Nucleoside analogs represent a class of important drugs for cancer and antiviral treatments. Nucleoside phosphorylases (NPases) catalyze the phosphorolysis of nucleosides and are widely employed for the synthesis of pentose-1-phosphates and nucleoside analogs, which are difficult to access via conventional synthetic methods. However, for the vast majority of nucleosides, it has been observed that either no or incomplete conversion of the starting materials is achieved in NPase-catalyzed reactions. For some substrates, it has been shown that these reactions are reversible equilibrium reactions that adhere to the law of mass action. In this contribution, we broadly demonstrate that nucleoside phosphorolysis is a thermodynamically controlled endothermic reaction that proceeds to a reaction equilibrium dictated by the substrate-specific equilibrium constant of phosphorolysis, irrespective of the type or amount of NPase used, as shown by several examples. Furthermore, we explored the temperature-dependency of nucleoside phosphorolysis equilibrium states and provide the apparent transformed reaction enthalpy and apparent transformed reaction entropy for 24 nucleosides, confirming that these conversions are thermodynamically controlled endothermic reactions. This data allows calculation of the Gibbs free energy and, consequently, the equilibrium constant of phosphorolysis at any given reaction temperature. Overall, our investigations revealed that pyrimidine nucleosides are generally more susceptible to phosphorolysis than purine nucleosides. The data disclosed in this work allow the accurate prediction of phosphorolysis or transglycosylation yields for a range of pyrimidine and purine nucleosides and thus serve to empower further research in the field of nucleoside biocatalysis. (Figure presented.).
FLOXURIDINE SYNTHESIS
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Page/Page column 33-34, (2019/04/11)
The present invention relates to a process for the preparation of floxuridine, said process comprising reacting a compound of Formula la with a compound of Formula lla in the presence of an acid Al to provide a compound of Formula Ilia in substantially diastereomerically pure form. Floxuridine may be useful as an anti-cancer drug. Floxuridine may also be useful in the preparation of other anti-cancer drugs, e.g. NUC-3373.