21679-14-1 Usage
Description
Fludarabine is a synthetic adenosine analog that functions as an antineoplastic agent, inhibiting DNA biosynthesis and displaying immunosuppressive effects. It is characterized by its white solid chemical properties and is clinically useful in the treatment of various cancers.
Used in Oncology:
Fludarabine is used as a treatment for chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma. It acts as a DNA synthesis and methylation inhibitor, interfering with DNA synthesis and repair, as well as inhibiting RNA transcription. The drug's mechanism of action involves the triphosphate metabolite and its inhibition of DNA chain elongation. Fludarabine is also a component of myeloablative conditioning regimens for allogeneic hematopoietic cell transplantation.
Used in Pediatric Oncology:
Although not one of the most used drugs in pediatric oncology, Fludarabine is utilized in combination with other drugs to treat Acute Myeloid Leukemia (AML) in children, particularly those receiving second-line therapy. It is commonly sold as 10 mg film-coated tablets and an IV vial containing 50 mg.
Used in Drug Metabolism:
Fludarabine is orally bioavailable and distributed throughout the body, reaching high levels in the liver, kidney, and spleen. The drug is metabolized to 2-fluoro-ara-adenosine (F-ara-A), which enters cells via the nucleoside transport system and is rephosphorylated by deoxycytidine kinase to fludarabine monophosphate and finally fludarabine triphosphate, the active species. About 25% of F-ara-A is excreted unchanged in urine.
Used in Drug Interactions:
Fludarabine may potentiate the effects of several other anticancer drugs, including cytarabine, cyclophosphamide, and cisplatin. Additionally, there is an increased incidence of fatal pulmonary toxicity when fludarabine is used in combination with pentostatin.
Toxicities:
The toxicities associated with Fludarabine include myelosuppression, immunosuppression, fever, nausea, and vomiting.
Originator
Fludarabine,Union Pharmaceutical
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
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
21679-14-1Relevant 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
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, (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.
Synthesis process of fludarabine base
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Paragraph 0012-0025, (2018/11/10)
The invention provides a synthesis process of fludarabine base. The synthesis process comprises selecting raw materials, synthesizing an intermediate, and synthesizing fludarabine base. The synthesisprocess has the beneficial effects that the source of the raw materials is widely available, the cost of the raw materials is low, the synthesis process is suitable for large-scale production and hassimple synthesis steps, fewer harmful substances are discharged in synthesis, and the synthesis process is safe and environment-friendly, has good use effect and can be promoted.
