4291-63-8 Usage
Description
Cladribine, also known as 2-chloro-2'-deoxyadenosine, is an adenosine deaminase-resistant analogue of deoxyadenosine. It is a chlorinated purine nucleoside with antileukemic activity and demonstrates a broad range of in vitro activity against both lymphoid and myeloid neoplasms. Cladribine is efficient in crossing lymphocyte and monocyte cell membranes and is metabolized in cells to the biologically active triphosphate, which inhibits DNA synthesis. It is unique in its ability to destroy both resting and proliferating cells.
Used in Pharmaceutical Industry:
Cladribine is used as an antineoplastic drug for its cytotoxic effect on lymphocytes and monocytes. It is particularly effective against hairy cell leukemia (HCL) and has potential uses in the treatment of autoimmune hemolytic anemia, multiple sclerosis, chronic lymphocytic leukemia, and various lymphomas.
Used in Oncology:
Cladribine is used as a treatment for hairy cell leukemia, systemic mastocytosis, and histiocytosis, including Erdheim-Chester disease and Langerhans cell histiocytosis. It is also used to treat chronic progressive multiple sclerosis.
Used in Research:
Cladribine may be used in studies involving the inhibition of DNA polymerase(s) and the induction of apoptosis through the incorporation of CdATP into DNA, which leads to strand breaks and activation of apoptosis.
Cladribine is administered through a 2-hour intravenous infusion at a dosage of 0.14 mg/kg/day, resulting in a mean maximum plasma drug concentration of 198 nmol/L. Intracellular concentrations of phosphorylated cladribine derivatives significantly exceed plasma concentrations. The drug penetrates into the cerebrospinal fluid (CSF), and its terminal elimination half-life of 6.7 hours suggests that it can be administered intermittently without loss of efficacy. The volume of distribution of cladribine is 9.2 L/kg.
References
[1] J.C Sipe,? J. S Romine, R. McMillan, E. Beutler, J. C. Sipe, J. S. Romine, J. Zyroff (1994) Cladribine in treatment of chronic progressive multiple sclerosis, 344, 9-13
[2] Alan Saven, Carol Burian (1999) Cladribine Activity in Adult Langerhans-Cell Histiocytosis, 93, 4125-4130
[3] https://en.wikipedia.org/wiki/Cladribine
[4] Harriet M. Bryson, Eugene M. Sorkin (1993) Cladribine: A Review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in haematological malignancies, 46, 872-894
Originator
Johnson & Johnson (U.S.A.)
Indications
Cladribine (Leustatin) is a synthetic purine nucleoside
that is converted to an active cytotoxic metabolite by
the enzyme deoxycytidine kinase. Like the other purine
antimetabolites, it is relatively selective for both normal
and malignant lymphoid cells and kills resting as well as
dividing cells by mechanisms that are not completely
understood.
The drug is highly active against hairy cell leukemia,
producing complete remissions in more than 60% of patients
treated with a single 7-day course. Activity has
also been noted in other low-grade lymphoid malignancies.
The major side effect is myelosuppression.
Manufacturing Process
Manufacturing process for Cladribine includes these steps as follows: Preparation of 2',3',5'-O-triacetyl guanosine;Preparation of 9-(2',3',5'-O-triacetyl-β-D-ribofuranosyl)-2-amino-6-
chloropurine;Preparation of 9-(2',3',5'-O-triacetyl-β-D-ribofuranosyl)-2,6-dichloropurine;Preparation of 2-chloroadenosine;Preparation of 2-chloro-(3',5'-O-tetraisopropyldisiloxyl)adenosine; Preparation of 2-chloro-2'-O-phenoxythiocarbonyl-(3',5'-O-tetraisopropyldisiloxyl)adenosine; Preparation of 2-chloro-2'-deoxy-(3',5'-O-tetraisopropyldisiloxyl)adenosine; Preparation of 2-chloro-2'-deoxy-adenosine.
Biochem/physiol Actions
Deoxyadenosine analog resistant to adenosine deaminase; antileukemic with immunosuppressive activity
Clinical Use
Antineoplastic agent:
Hairy cell leukaemia (HCL)
Chronic lymphocytic leukaemia (CLL) in patients
who have failed to respond to standard regimens.
Drug interactions
Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine - increased risk
of agranulocytosis.
Antivirals: avoid with lamivudine.
Caution when administering with any other
immunosuppressive or myelosuppressive therapy
Metabolism
Cladribine is extensively distributed and penetrates into
the CNS. Cladribine is phosphorylated within cells by
deoxycytidine kinase to form 2-chlorodeoxyadenosine-
5′-monophosphate which is further phosphorylated to
the diphosphate by nucleoside monophosphate kinase
and to the active metabolite 2-chlorodeoxyadenosine-5′-
triphosphate (CdATP) by nucleoside diphosphate kinase.
CdATP inhibits DNA synthesis and repair, particularly
in lymphocytes and monocytesThere is little information available on the route of
excretion of cladribine in man. An average of 18% of
the administered dose has been reported to be excreted
in urine of patients with solid tumours during a 5-day
continuous intravenous infusion.
Check Digit Verification of cas no
The CAS Registry Mumber 4291-63-8 includes 7 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 4 digits, 4,2,9 and 1 respectively; the second part has 2 digits, 6 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 4291-63:
(6*4)+(5*2)+(4*9)+(3*1)+(2*6)+(1*3)=88
88 % 10 = 8
So 4291-63-8 is a valid CAS Registry Number.
InChI:InChI=1/C10H12ClN5O3/c11-10-14-8(12)7-9(15-10)16(3-13-7)6-1-4(18)5(2-17)19-6/h3-6,17-18H,1-2H2,(H2,12,14,15)/t4-,5-,6-/m1/s1
4291-63-8Relevant articles and documents
Efficient synthesis of cladribine via the metal-free deoxygenation
Xia, Ran,Chen, Lei-Shan
, p. 729 - 735 (2015)
The efficient synthesis of cladribine via the metal-free deoxygenation was developed. Using (Bu4N)2S2O8/HCO2Na instead of Bu3SnH/AIBN as deoxygenation system, cladribine could be obtained with good yield and even on tens of grams scales. The intermediates and product could be purified by simple work-up process and chromatography was avoided, which showed the good future for industrial applications.
A concise synthesis of isoguanine 2'-deoxyriboside and its adenine-like triplex formation when incorporated into DNA
Walsh, Andrew J.,Schwalbe, Carl H.,Fraser, William
, p. 50 - 62 (2021/04/02)
A concise synthesis of 2'-deoxyisoguanosine is achieved whereby 2,6-dichloropurine is glycosylated using the Hoffer sugar to give a pair of beta-configured nucleoside N9/N7 regioisomers that are aminated using methanolic ammonia with concomitant deprotection of the sugar. Following chromatographic separation, pure 2-chloro-2'-deoxyadenosine was isolated as a single isomer. Displacement of the C2 chlorine atom using sodium benzyloxide, followed by hydrogenolysis of the benzyl group, gives 2'-deoxyisoguanosine. Isoguanine was incorporated into DNA by solid supported synthesis using the suitably protected 2-allyloxy-2'-deoxyadenosine phosphoramidite with the allyl group being removed post-oligomerisation under Noyori conditions. DNA melting studies showed isoguanine to exhibit adenine-like triplex formation.
Thermodynamic Reaction Control of Nucleoside Phosphorolysis
Kaspar, Felix,Giessmann, Robert T.,Neubauer, Peter,Wagner, Anke,Gimpel, Matthias
supporting information, 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.).
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.