| Identification | More | [Name]
Fludarabine | [CAS]
21679-14-1 | [Synonyms]
2-F-ARAA
2-FLUORO-9-ARABINOADENINE
2-fluoroadenine-9-bata-d-arabinofuranoside
2-FLUOROADENINE 9-BETA-D-ARABINOFURANOSIDE
6-AMINO-9 BETA-D-ARABINOFURANOSYLFLUOROPURINE
9-bata-d-arabinofuranosyl-2-fluoroadenine
9-BETA-D-ARABINOFURANOSYL-2-FLUORO-9H-PURIN-6-AMINE
9-BETA-D-ARABINOFURANOSYL-2-FLUOROADENINE
9-D-ARUBINOFURANOSYL-2-FLUORO-9H-PURIN-6-AMINE
FLUDARABINE
FLUDARABINE BASE
FLUDARABINE DES-PHOSPHATE
FLUDARUBINE
2-Fluoroadeninearabinoside
9-beta-d-arabinofuranosyl-2-fluoro-9h-purin-6-amin
9-beta-d-arabinofuranosyl-2-fluoro-adenin
f-ara-a
2-FLUOROADENINE 9-B-D-ARABINOFURANOSIDE
2-FLUOROADENINE-9-BETA-D-ARABINOFURANO-&
Fludarabine&Int. | [EINECS(EC#)]
244-525-5 | [Molecular Formula]
C10H12FN5O4 | [MDL Number]
MFCD00132942 | [Molecular Weight]
285.23 | [MOL File]
21679-14-1.mol |
| Chemical Properties | Back Directory | [Appearance]
White Solid | [Melting point ]
265-268°C | [alpha ]
D25 +17 ±2.5° (c = 0.1 in ethanol) | [Boiling point ]
747.3±70.0 °C(Predicted) | [density ]
2.17±0.1 g/cm3(Predicted) | [storage temp. ]
2-8°C
| [solubility ]
DMF: 20 mg/mL, clear, faintly yellow
| [form ]
Powder | [pka]
13.05±0.70(Predicted) | [color ]
White to Pale Yellow | [Water Solubility ]
Soluble in DMF, DMSO, methanol or ethanol. Sparingly soluble in water | [Usage]
Used as an antineoplastic | [Merck ]
13,4152 | [BRN ]
1225932 | [Stability:]
Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months. | [InChI]
InChI=1/C10H12FN5O4/c11-10-14-7(12)4-8(15-10)16(2-13-4)9-6(19)5(18)3(1-17)20-9/h2-3,5-6,9,17-19H,1H2,(H2,12,14,15)/t3-,5-,6+,9-/s3 | [InChIKey]
HBUBKKRHXORPQB-VOSPVXAENA-N | [SMILES]
C12N=C(N=C(N)C=1N=CN2[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1)F |&1:10,11,13,15,r| | [CAS DataBase Reference]
21679-14-1(CAS DataBase Reference) |
| Safety Data | Back Directory | [Hazard Codes ]
Xn | [Risk Statements ]
R23/24/25:Toxic by inhalation, in contact with skin and if swallowed .
R36/37/38:Irritating to eyes, respiratory system and skin .
R39/23/24/25:Toxic: danger of very serious irreversible effects through inhalation, in contact with skin and if swallowed .
R39:Danger of very serious irreversible effects. | [Safety Statements ]
S26:In case of contact with eyes, rinse immediately with plenty of water and seek medical advice .
S36/37:Wear suitable protective clothing and gloves .
S45:In case of accident or if you feel unwell, seek medical advice immediately (show label where possible) . | [WGK Germany ]
3
| [RTECS ]
AU6207000
| [F ]
10 | [HS Code ]
29349900 | [Hazardous Substances Data]
21679-14-1(Hazardous Substances Data) |
| Hazard Information | Back Directory | [Description]
Fludarabine (21679-14-1) is a synthetic adenosine analog that inhibits DNA biosynthesis and is a clinically useful antineoplastic agent.1 In cells fludarabine accumulates as its 5’-triphosphate (F-ara-ATP) for which the rate-limiting step in formation is the conversion of fludarabine to its monophosphate.2 F-ara-ATP has multiple mechanisms of action including inhibition of ribonucleotide reductase, DNA polymerase, ligase and primase.2 A frequently used agent in myeloablative conditioning regimens for allogeneic hematopoietic cell transplantation.3 Immunosuppressive effects are mediated via inhibition of TNFa-stimulated production of IL-2 and IFN-g through inactivation of NFkB.4 Antagonist at adenosine A1 receptors.5 | [Chemical Properties]
White Solid | [Originator]
Fludarabine,Union Pharmaceutical | [Uses]
A STAT-1 activation inhibitor and a DNA synthesis inhibitor.? | [Uses]
DNA synthesis and methylation inhibitor;A cell permeable agent that interferes with DNA synthesis and repair; also inhibits RNA transcription | [Uses]
Irreversible muscarinic agonist | [Uses]
phosphate as antineoplastic;inhibits DNA synthesis by interfering with ribonucleotide reductase and DNA polymerase | [Uses]
Used as an antineoplastic | [Definition]
ChEBI: (2R,3S,4S,5R)-2-(6-amino-2-fluoro-9-purinyl)-5-(hydroxymethyl)oxolane-3,4-diol is a purine nucleoside. | [Indications]
Fludarabine (Fludara) is a fluorinated purine analogue
of the antiviral agent vidarabine.The active metabolite,
2-fluoro-ara-adenosine triphosphate, inhibits various
enzymes involved in DNA synthesis, including DNA
polymerase-α, ribonucleotide reductase, and DNA primase.
Unlike most antimetabolites, it is toxic to nonproliferating
as well as dividing cells, primarily lymphocytes
and lymphoid cancer cells.
The drug is highly active in the treatment of chronic
lymphocytic leukemia, with approximately 40% of patients
achieving remissions after previous therapy with
alkylating agents has failed. Activity is also seen in the
low-grade lymphomas.
The major side effect is myelosuppression, which
contributes to fevers and infections in as many as half of
treated patients. Nausea and vomiting are mild.
Occasional neurotoxicity has been noted at higher
doses, with agitation, confusion, and visual disturbances. | [Preparation]
Synthesis of fludarabine 1: 2-Fluoroadenine is reacted with 9-β-D-arabinosyl-uracile, taking water as a solvent. The reaction will take place in the presence of Enterobacter aerogenes. Fludarabine so formed is then treated with acetic anhydride to form the acetylderivative.The acetyl derivative is then crystallize to get back the pure Fludarabine.
Synthesis of fludarabine 2: 2,4,5,6-tetraaminopyrimidine and formamide were cyclized together by heating to give 2,6-diaminopurine. acylation with acetic anhydride-pyridine complex gave 2,6-diacetamidopurine. then reacted with 2,3,5-tri-o-benzyl-d-arabinofuranosyl chloride to give compound (i). (i) was deacetylated to give compound (ii). (ii) in fluoroboronic acid-tetrahydrofuran, first nitrosated and then substituted to give compound (ili). in the presence of boron trichloride, the benzyl group was removed to give fludarabine. the yield was 17.5% in terms of 2,3,5-tri-o-benzyl-d-arabinofuranosyl chloride. | [Manufacturing Process]
Guanosine (87 g, 0.31 mL, predried for two days under vacuum at 100°C over
P2O5) was combined with acetic anhydride (180 mL, 1.9 mol), pyridine (90
mL, 1.11 mol) and DMF (245 mL) and heated in oil bath at 75°C. The reaction
was monitored by TLC on silica gel plates eluted with mixture of ethyl
acetate:DMF:1-butanol (6:3:1). After 2 hours, the guanosine was consumed
and the 2',3',5'-tri-O-acetylguanosine was observed to be the major product.
The mixture was concentrated under vacuum. The residue was suspended in
ethyl ether:2-propanol (1:1) and the solid collected by filtration was
recrystallized from absolute ethanol. The product was dried at 80°C under
vacuum to obtain 106.9 g (84%) of 2',3',5'-tri-O-acetylguanosine as a fluffy
white solid; M.P. 229-233°C.
Distilled phosphorous oxychloride (47.7 mL, 510 mmol) was added to a
solution of dried 2',3',5'-tri-O-acetylguanosine (36.1 g, 88 mmol),
benzyltriethylammonium chloride (40.2 g, 176 mmol), and N,Ndimethylaniline
(11.2 mL, 88 mmol, distilled from CaH2 in anhydrous
acetonitrile (200 mL, distilled from P2O5). The flask was fitted with a reflux
condenser and placed in an oil bath preheated at 100°C. The mixture was
heated to reflux, and heating was continued for 10 min. The mixture was
concentrated under vacuum, and the residue was dissolved in
dichloromethane (800 mL). The solution was stirred with ice for 15 min before
the layers were separated. The aqueous layer was then washed with several
portions of dichloromethane. The combined organic extracts were washed with
water and then with portions of saturated sodium bicarbonate until neutral.
Finally, it was dried over MgSO4, filtered, and concentrated under vacuum.
The residue was recrystallized twice from 300 mL of 2-propanol to obtain the
purified 2',3',5'-tri-O-acetyl-6-chloroguanosine; 32.2 g (85%); M.P. 146-
148°C.
A round bottom flask fitted with a mechanical stirrer and cold finger
condenser was charged with potassium fluoride (140 g, 2.4 mole), 2',3',5'-tri-
O-acetyl-6-chloroguanosine (70 g, 0. 16 mol) and anhydrous DMF (1.5 L).
About 5-7 mL of trimethylamine was condensed into the flask. The suspensionwas stirred at ambient temperature for 24 hours and then the mixture was
concentrated under vacuum. The residue was suspended in chloroform and
filtered and the insoluble material was washed thoroughly with chloroform
(1.5 L total). The filtrate was concentrated under vacuum and the residue was
recrystallized from 2-propanol to obtain 61.7 g (92%) of the 6-fluoro-2',3',5'-
tri-O-acetylguanosine, M.P. 143-144°C.
The protecting groups in 6-fluoro-2',3',5'-tri-O-acetylguanosine was then
deleted (alcaline saponification by action lithium hydroxide or NH3) and the
product was transformed into 9-beta-D-arabinofuranosyl-2-fluoro-adenine. | [Therapeutic Function]
Antineoplastic | [General Description]
The drug is available as the phosphate salt in a 50-mg vialfor IV use. Fludarabine is used to treat chronic lymphocyticleukemia and non-Hodgkin’s lymphoma. The mechanism ofaction involves the triphosphate metabolite and its inhibitionof DNA chain elongation. The 2-fluoro group on the adeninering renders fludarabine resistant to breakdown byadenosine deaminase. The drug is rapidly dephosphorylatedto 2-fluoro-ara-adenosine (F-ara-A) after administration. Fara-A is taken into the cell and subsequently re-phosphorylatedto yield the triphosphate (F-ara-ATP), the active drugspecies. Resistance can occur via decreased expression ofthe activating enzymes and decreased drug transport.Fludarabine is orally bioavailable and is distributed throughoutthe body reaching high levels in liver, kidney, andspleen. The drug is metabolized to F-ara-A, which enterscells via the nucleoside transport system and is rephosphorylatedby deoxycytidine kinase to fludarabine monophosphateand finally fludarabine triphosphate, the activespecies. About 25% of F-ara-A is excreted unchanged inurine. Drug interactions include an increased incidence offatal pulmonary toxicity when fludarabine is used in combinationwith pentostatin. Additionally, fludarabine may potentiate the effects of several other anticancer drugs includingcytarabine, cyclophosphamide, and cisplatin.Toxicities include myelosuppression, immunosuppression,fever, nausea, and vomiting. | [Biological Activity]
Purine analog that inhibits DNA synthesis. Exhibits antiproliferative activity (IC 50 = 1.54 μ M in RPMI cells) and triggers apoptosis through increasing Bax and decreasing Bid, XIAP and survivin expression. Displays anticancer activity against hematological malignancies in vivo . | [Biochem/physiol Actions]
Fludarabine (the 5′-phosphate) is a prodrug that is converted to F-ara-A, which enters cells and accumulates primarily as the 5′-triphosphate. F-ara-A interferes with DNA synthesis and repair and induces apoptosis of cancer cells. F-ara-A also strongly inhibits DNA methylation, particularly methylation of cytosine in CpG dinucleotide sequences. | [storage]
Desiccate at +4°C | [Mode of action]
Fludarabine is a fluorinated analogue of adenine that is relatively resistant to deamination by adenosine deaminase. Fludarabine phosphate is a prodrug that is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active metabolite triphosphate 2-fluoro-ara-ATP. Fludarabine inhibits the DNA synthesis via inhibition of ribonucleotide reductase, DNA polymerase (α, δ, and ε), DNA primase, and DNA ligase. The action mechanism also is by partial inhibition of RNA polymerase II, causing reduction in protein synthesis. It is believed that effects on DNA, RNA, and protein synthesis contribute to the inhibition of cell growth, mostly by inhibition of DNA synthesis. Lymphocytes of CLL when exposed, in vitro, to the compound 2-fluoro-ara-A lead to extensive DNA fragmentation and apoptosis. | [References]
Ross et al. (1993), A review of its pharmacological properties and therapeutic potential in malignancy; Drugs, 45 737
Gandhi and Plunkett (2002), Cellular and clinical pharmacology of fludarabine; Pharmacokinet. 41 93
Langenhorst et al. (2019), Fludarabine exposure in the conditioning prior to allogeneic hematopoietic cell transplantation predicts outcomes; Blood Adv., 3 2179
Nishioka et al. (2008), Fludarabine induces growth arrest and apoptosis of cytokine- or alloantigen-stimulated peripheral blood mononuclear cells and decreases production of Th1 cytokines via inhibition of nuclear factor kappaB; Bone Marrow Transplant., 41 303
Jensen et al. (2012), Cytotoxic purine nucleoside analogues bind to A1, A2A and A3 adenosine receptors; Naunyn Schmiedebergs Arch. Pharmacol., 385 519 |
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