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21679-14-1

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21679-14-1 Usage

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

Different sources of media describe the Uses of 21679-14-1 differently. You can refer to the following data:
1. 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.
2. 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.

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.

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.

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

Check Digit Verification of cas no

The CAS Registry Mumber 21679-14-1 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 2,1,6,7 and 9 respectively; the second part has 2 digits, 1 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 21679-14:
(7*2)+(6*1)+(5*6)+(4*7)+(3*9)+(2*1)+(1*4)=111
111 % 10 = 1
So 21679-14-1 is a valid CAS Registry Number.
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-/m1/s1

21679-14-1SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 17, 2017

Revision Date: Aug 17, 2017

1.Identification

1.1 GHS Product identifier

Product name (2R,3S,4S,5R)-2-(6-amino-2-fluoropurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol

1.2 Other means of identification

Product number -
Other names 2-Fluoroadenine-9-β-D-arabinofuranoside

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

More Details:21679-14-1 SDS

21679-14-1Relevant articles and documents

Practical Synthesis of Fludarabine and Nelarabine

Bai, Jiang,Ding, Haixin,Liu, Jiang,Ouyang, Wenliang,Shen, Chunyang,Xiao, Qiang

, p. 417 - 423 (2020/01/23)

A new practical synthesis strategy has been developed to access the β- d -arabinofuranosyl purine nucleosides fludarabine and nelarabine. In our approach, an ortho -alkyne benzoyl ester is transiently introduced as a neighbouring-participation group in Vorbrüggen glycosylation to afford the corresponding β-nucleoside exclusively. The latter was further removed efficiently by using freshly prepared Ph 3 PAuOTFA to give the corresponding 2′-OH nucleosides without transesterification. After reversion of the configuration of 2′-OH and deprotection, fludarabine and nelarabine were obtained in high yield and purity.

Synthesis method of fludarabine and nelarabine

-

, (2020/01/11)

The present invention discloses a synthesis method of fludarabine and nelarabine. The method is prepared from a ribofuranose derivative as a raw material, an o-alkynyl benzoate is introduced at a 2-position hydroxyl group to obtain a key glycosyl donor, the key glycosyl donor and purine bases are subjected to a coupling reaction using a Vorbruggen glycosylation reaction to highly efficiently construct beta-nucleoside bonds, under catalysis of a gold catalyst, 2'-position ester groups are selectively removed to obtain important furyl ribonucleotide, and a bare 2' hydroxyl group is then subjected to two-step reactions of hydroxyl inversion and deprotection to respectively obtain fludarabine and nelarabine. The synthesis strategy has characteristics of being simple in operation, simple and easy to obtain the raw materials, easy in separation of products, high in reaction yield, etc., and has relatively good prospects for popularization and application.

Enzymatic Synthesis of Therapeutic Nucleosides using a Highly Versatile Purine Nucleoside 2’-DeoxyribosylTransferase from Trypanosoma brucei

Pérez, Elena,Sánchez-Murcia, Pedro A.,Jordaan, Justin,Blanco, María Dolores,Manche?o, José Miguel,Gago, Federico,Fernández-Lucas, Jesús

, p. 4406 - 4416 (2018/09/14)

The use of enzymes for the synthesis of nucleoside analogues offers several advantages over multistep chemical methods, including chemo-, regio- and stereoselectivity as well as milder reaction conditions. Herein, the production, characterization and utilization of a purine nucleoside 2’-deoxyribosyltransferase (PDT) from Trypanosoma brucei are reported. TbPDT is a dimer which displays not only excellent activity and stability over a broad range of temperatures (50–70 °C), pH (4–7) and ionic strength (0–500 mM NaCl) but also an unusual high stability under alkaline conditions (pH 8–10). TbPDT is shown to be proficient in the biosynthesis of numerous therapeutic nucleosides, including didanosine, vidarabine, cladribine, fludarabine and nelarabine. The structure-guided replacement of Val11 with either Ala or Ser resulted in variants with 2.8-fold greater activity. TbPDT was also covalently immobilized on glutaraldehyde-activated magnetic microspheres. MTbPDT3 was selected as the best derivative (4200 IU/g, activity recovery of 22 %), and could be easily recaptured and recycled for >25 reactions with negligible loss of activity. Finally, MTbPDT3 was successfully employed in the expedient synthesis of several nucleoside analogues. Taken together, our results support the notion that TbPDT has good potential as an industrial biocatalyst for the synthesis of a wide range of therapeutic nucleosides through an efficient and environmentally friendly methodology.

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