50-91-9 Usage
Description
Floxuridine is a nucleoside analog that inhibits the enzyme ribonucleotide reductase, which is involved in the synthesis of DNA. Floxuridine has been shown to inhibit the growth of cancer cells and induce apoptosis in vivo. Floxuridine has also been shown to inhibit tumor growth in animal models by inhibiting the production of reactive oxygen species and upregulating tumor suppressor genes, such as p53. This drug also has inhibitory effects on enzymes that are involved in cell proliferation, such as protein kinase C and tyrosine kinases.
Chemical Properties
White Solid
Originator
FUDR,Roche,US ,1971
Uses
Different sources of media describe the Uses of 50-91-9 differently. You can refer to the following data:
1. Floxuridine USP is used in Palliative treatment of gastrointestinal adenocarcinoma with liver metastases.
2. Antiviral; antineoplastic.
3. renal function diagnosis
Definition
ChEBI: A pyrimidine 2'-deoxyribonucleoside compound having 5-fluorouracil as the nucleobase; used to treat hepatic metastases of gastrointestinal adenocarcinomas and for palliation in malignant neoplasms of the liver and gastrointestinal tract.
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.
Brand name
Fudr (Mayne).
Therapeutic Function
Antiviral, Cancer chemotherapy
General Description
Different sources of media describe the General Description of 50-91-9 differently. You can refer to the following data:
1. The drug is available as a 500-mg vial of lyophilized powder.The drug is used to treat metastatic GI adenocarcinoma.The mechanism of action of this fluoropyrimidine deoxynucleosideanalog involves metabolic conversion to 5-fluorouracil(5-FU) metabolites resulting in inhibition of TSthus disrupting DNA synthesis, function, and repair.Resistance can occur because of increased expression of TS,decreased levels of reduced folate 5,10-methylenetetrahydrofolate,increased activity of DNA repair enzymes, and increasedexpression of dihydropyrimidine dehydrogenase(the major catabolic enzyme). The drug is poorly absorbedfrom the GI tract and is extensive metabolized to 5-FU and5-FU metabolites. Dihydropyrimidine dehydrogenase is themain enzyme responsible for 5-FU catabolism, and it ispresent in liver, GI mucosa, white blood cells, and kidney.The drug interaction and toxicity profiles are equivalent tothose of 5-FU.
2. Inhibits DNA synthesis.
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.).
Bio-catalytic synthesis of unnatural nucleosides possessing a large functional group such as a fluorescent molecule by purine nucleoside phosphorylase
Hatano, Akihiko,Wakana, Hiroyuki,Terado, Nanae,Kojima, Aoi,Nishioka, Chisato,Iizuka, Yu,Imaizumi, Takuya,Uehara, Sanae
, p. 5122 - 5129 (2019/10/05)
Unnatural nucleosides are attracting interest as potential diagnostic tools, medicines, and functional molecules. However, it is difficult to couple unnatural nucleobases to the 1′-position of ribose in high yield and with β-regioselectivity. Purine nucleoside phosphorylase (PNP, EC2.4.2.1) is a metabolic enzyme that catalyses the conversion of inosine to ribose-1α-phosphate and free hypoxanthine in phosphate buffer with 100% α-selectivity. We explored whether PNP can be used to synthesize unnatural nucleosides. PNP catalysed the reaction of thymidine as a ribose donor with purine to produce 2′-deoxynebularine (3, β form) in high conversion (80%). It also catalysed the phosphorolysis of thymidine and introduced a pyrimidine base with a halogen atom substituted at the 5-position into the 1′-position of ribose in moderate yield (52-73%), suggesting that it exhibits loose selectivity. For a bulky purine substrate [e.g., 6-(N,N-di-propylamino)], the yield was lower, but addition of a polar solvent such as dimethyl sulfoxide (DMSO) increased the yield to 74%. PNP also catalysed the reaction between thymidine and uracil possessing a large functional fluorescent group, 5-(coumarin-7-oxyhex-5-yn) uracil (C4U). Conversion to 2′-deoxy-[5-(coumarin-7-oxyhex-5-yn)] uridine (dRC4U) was drastically enhanced by DMSO addition. Docking simulations between dRC4U and E. coli PNP (PDB 3UT6) showed the uracil moiety in the active-site pocket of PNP with the fluorescent moiety at the entrance of the pocket. Thus, the bulky fluorescent moiety has little influence on the coupling reaction. In summary, we have developed an efficient method for producing unnatural nucleosides, including purine derivatives and modified uracil, using PNP.
