Fludarabine Chemical Properties

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

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 Information

Hazard Codes 

Xn

Risk Statements 

23/24/25-36/37/38-39/23/24/25-39-22

Safety Statements 

26-36/37-45-36

WGK Germany 

3

RTECS 

AU6207000

F 

10

HS Code 

29349990

Hazardous Substances Data

21679-14-1(Hazardous Substances Data)

MSDS

• Language:English Provider:9-bata-D-Arabinofuranosyl-2-fluoroadenine
• Language:English Provider:SigmaAldrich

Fludarabine Usage And Synthesis

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

Fludarabine is not one of the most used drugs in pediatric oncology area. It is used in combination with other drugs to treat AML in children, mostly those who are receiving second-line therapy. It is commonly sold as 10 mg film-coated tablets and IV vial containing 50mg.

Uses

Fludarabine is used in the treatment of chroniclymphocytic leukaemia. It is a DNA synthesis and methylation inhibitor;A cell permeable agent that interferes with DNA synthesis and repair; also inhibits RNA transcription.

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.

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.

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.

Synthesis

Example 1 Synthesis of 2-fluoro-α-adenine Molecular weight (MW) = 41 1.35 g/mol Molecular Formula (MF) = C16H18FN5O7 Molecular weight (MW) = 285.24 g/mol Molecular formula (MF) = C10H12FN5O4 180 to 220 kg of ethanol and 8 to 12 kg of purified water were added to the mixing vessel. Subsequently, 15 kg of (2R,3R,4S,5R)-2-(acetoxymethyl)-5-(6-amino-2-fluoro-9H-purin-9-yl)tetrahydrofuran-3,4-diyl diacetate and 2.25 to 2.75 kg of potassium carbonate were added. The mixture was heated to 35 to 45°C and stirred at this temperature for 20 to 48 hours. Upon completion of the reaction, the mixture was cooled to 0 to 20°C and 190 to 230 kg of purified water was added. The pH was adjusted to 5 to 7 using organic or inorganic acid (preferably acetic acid). activated carbon was added to the reaction mixture and the mixture was refluxed. The activated carbon was removed by filtration while hot and the filtrate was inoculated with 0 to 1 kg of 2-fluoroadenosine crystals at temperatures in the range of 40 to 75°C. The resulting suspension was cooled to -12 to 10°C and stirring was continued for at least 60 minutes. The solid product was isolated by filtration, washed with a mixture of ethanol and purified water, and subsequently dried under vacuum using a carrier gas at a shell temperature of 80 to 100°C. The final yield was 82% of the theoretical value.

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

[1] S R ROSS  D F  D McTavish. Fludarabine. A review of its pharmacological properties and therapeutic potential in malignancy.[J]. Drugs, 1993, 45 5: 737-759. DOI:10.2165/00003495-199345050-00009
[2] V. GANDHI W P. Cellular and Clinical Pharmacology of Fludarabine[J]. Clinical Pharmacokinetics, 2002, 41 1: 93-103. DOI:10.2165/00003088-200241020-00002
[3] J. LANGENHORST. Fludarabine exposure in the conditioning prior to allogeneic hematopoietic cell transplantation predicts outcomes.[J]. Blood advances, 2019, 3 14 1: 2179-2187. DOI:10.1182/bloodadvances.2018029421
[4] C NISHIOKA. 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 κB[J]. Bone Marrow Transplantation, 2007, 41 3: 303-309. DOI:10.1038/sj.bmt.1705901
[5] KYLE JENSEN. Cytotoxic purine nucleoside analogues bind to A1, A2A, and A3 adenosine receptors.[J]. Naunyn-Schmiedeberg’s archives of pharmacology, 2012, 385 5: 519-525. DOI:10.1007/s00210-011-0719-6

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