Cladribine

Base Information

• Chemical Name: Cladribine
• CAS No.: 4291-63-8
• Deprecated CAS: 24757-90-2
• Molecular Formula: C10H12ClN5O3
• Molecular Weight: 285.69
• Hs Code.: 29349990
• European Community (EC) Number: 636-978-6
• UNII: 47M74X9YT5
• DSSTox Substance ID: DTXSID8022828
• Nikkaji Number: J446.344G
• Wikipedia: Cladribine
• Wikidata: Q414030
• NCI Thesaurus Code: C1336
• RXCUI: 44157
• Metabolomics Workbench ID: 42644
• ChEMBL ID: CHEMBL1619
• Mol file: 4291-63-8.mol

Synonyms:2'-Deoxy-2-chloroadenosine;2-Chloro-2'-deoxyadenosine;2-Chlorodeoxyadenosine;Cladribine;Leustatin

Chemical Property of Cladribine

Chemical Property:

• Appearance/Colour: White Crystalline Solid
• Melting Point: 181-185 °C(lit.)
• Boiling Point: 387.1 °C at 760 mmHg
• PKA: 13.75±0.60(Predicted)
• Flash Point: 187.9 °C
• PSA: 119.31000
• Density: 1.402 g/cm³
• LogP: 0.28380
• Storage Temp.: 2-8°C
• Solubility.: Slightly soluble in water, soluble in dimethyl sulfoxide, slightly soluble in methanol, practically insoluble in acetonitrile. It shows polymorphism (5.9).
• XLogP3: 0.8
• Hydrogen Bond Donor Count: 3
• Hydrogen Bond Acceptor Count: 7
• Rotatable Bond Count: 2
• Exact Mass: 285.0628670
• Heavy Atom Count: 19
• Complexity: 338

Purity/Quality:

99% ^*data from raw suppliers

Cladribine ^*data from reagent suppliers

Safty Information:

• Pictogram(s): T
• Hazard Codes: T
• Statements: 36/37/38-23/24/25
• Safety Statements: 26-37/39-45-36-22

MSDS Files:

SDS file from LookChem

Total 1 MSDS from other Authors

Useful:

• Drug Classes: Antineoplastic Agents
• Canonical SMILES: C1C(C(OC1N2C=NC3=C(N=C(N=C32)Cl)N)CO)O
• Isomeric SMILES: C1[C@@H]([C@H](O[C@H]1N2C=NC3=C(N=C(N=C32)Cl)N)CO)O
• Recent ClinicalTrials: Venetoclax and CLAG-M for the Treatment of Acute Myeloid Leukemia and High-Grade Myeloid Neoplasms
• Recent EU Clinical Trials: A phase 2 clinical trial assessing the efficacy and safety of adding cladribine for treatment modifying course of seropositive myasthenia gravis
• Recent NIPH Clinical Trials: Open labeled, single arm, multi centered, phase II trial to evaluate the efficacy and safety of combination therapy of rituximab and cladribine for previously untreated patients with advanced staged extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) and nodal marginal zone B-cell lymphoma
• Description: Cladribine (2-chloro-2′-deoxyadenosine) is an adenosine deaminase-resistant analogue of deoxyadenosine. The drug has a broad range of in vitro activity against both lymphoid and myeloid neoplasms [mean IC50values (drug concentration required to inhibit cell growth by 50% of control): 20 to 87 nmol/L]. But it possesses little activity against multiple myeloma specimens and many solid tumor cell lines. Monocytes are highly sensitive to cladribine in vitro. Cladribine demonstrates activity against both dividing and nondividing cells and this activity distinguishes it from many other agents. It has activity in murine models of leukaemia. Cladribine is used to treat chronic progressive multiple sclerosis, hairy cell leukemia, systemic mastocytosis, and histiocytosis (including Erdheim–Chester disease and Langerhans cell histiocytosis). After a 2-hour intravenous infusion of cladribine 0.14 mg/kg/day, the mean maximum plasma drug concentration was 198 nmol/L. Intracellular concentrations of phosphorylated cladribine derivatives exceed plasma concentrations 128- to 375-fold. Cladribine penetrates into the CSF. The terminal elimination half-life (6.7 hours) is long, which suggests that the drug may be administered intermittently without loss of efficacy. The volume of distribution of cladribine is 9.2 L/kg. Cladribine, an adenosine deaminase inhibitor, was introduced in the United States as a single intravenous treatment for hairy cell leukemia. The incorporation of a chlorine atom at the 2-position of deoxyadenosine renders cladribine more resistant to enzymatic attack by adenosine deaminase, resulting in a more prolonged cytotoxic effect. Cladribine efficiently crosses lymphocyte and monocyte cell membranes and is metabolized in cells to the biologically active triphosphate, which inhibits DNA synthesis. While most antineoplastic drugs are active primarily against dividing cells, cladribine destroys both resting and proliferating cells. Its potential uses in the treatment of autoimmune hemolytic anemia, multiple sclerosis, chronic lymphocytic leukemia and various lymphomas have also been evaluated.
• Uses: 2-Chloro-2′-deoxyadenosine (2-CdA) is a chlorinated purine nucleoside with activity against lymphoproliferative disorders, such as hairy cell leukemia (HCL) and multiple myeloma (MM). 2-CdA resists ADA degradation and is phosphorylated to CdATP in lymphocytes. CdATP incorporation into DNA induces strand breaks and the activation of apoptosis. 2-CdA may also be used in studies involving the inhibition of DNA polymerase(s).Cladribiane, like fludarabine, is a prodrug that is must be phosphorylated intracellularly to the monophosphate by the nuclear/cytosol enzyme deoxycytidine kinase (dCK) and possibly by the mitochondrial enzyme deoxyguanosine kinase (dGK). It is a substituted purine nucleoside with antileukemic activity
• 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.
• 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

Technology Process of Cladribine

There total 61 articles about Cladribine which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 100.0%

3-benzyl-1-{2-chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]-purin-6-yl}-2-propylimidazolium iodide → 2-chloro-2'-deoxyadenosine (4291-63-8)

Guidance literature:

With ammonia; In methanol; at 60 ℃; for 11h;

DOI:10.1021/jo061282+

Reference yield: 94.0%

9-(3,5-di-O-benzoyl-2-deoxy-β-D-erythro-pentofuranosyl)-2,6-dichloropurine (500225-62-7) → 2-chloro-2'-deoxyadenosine (4291-63-8)

Guidance literature:

With ammonia; In methanol; dichloromethane; at 80 ℃; for 7h;

DOI:10.1021/jo020644k

Reference yield: 93.0%

6-amino-2-chloro-9-(2'deoxy-3',5'-di-O-acetyl-β-D-erythro-pentofuranosyl)-9H-purine (146196-13-6) → 2-chloro-2'-deoxyadenosine (4291-63-8)

Guidance literature:

With sodium carbonate; In methanol; at 20 ℃; for 2h; pH=8 - 9;

DOI:10.1080/15257770.2015.1071848

upstream raw materials:

2,6-Dichloro-9-(2-deoxy-3,5-di-O-p-toluoyl-β-D-erythro-pentofuranosyl)-purine

2'-deoxyuridine

2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranosyl chloride

2,6-dichloro-7H-purine

Downstream raw materials:

2-deoxy–α-D-ribose 1-phosphate

2-chloroadenine

N-[9-{(2R,4S,5R)-5-[Bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-4-hydroxy-tetrahydro-furan-2-yl}-2-(3-imidazol-1-yl-propylamino)-9H-purin-6-yl]-isobutyramide

thymidine

Refernces

• 1、 Matyasovsky, Ján,Perlikova, Pavla,Malnuit, Vincent,Pohl, Radek,Hocek, Michal. "2-Substituted dATP Derivatives as Building Blocks for Polymerase-Catalyzed Synthesis of DNA Modified in the Minor Groove". . p. 15856 - 15859. Retrieved 2016.
• 2、 Artsemyeva, Julia N.,Buravskaya, Tatiana N.,Esipov, Roman S.,Konstantinova, Irina D.,Litvinko, Natalia M.,Mikhailopulo, Igor A.,Miroshnikov, Anatoly I.,Remeeva, Ekaterina A.. "Anion exchange resins in phosphate form as versatile carriers for the reactions catalyzed by nucleoside phosphorylases". . p. 2607 - 2622. Retrieved 2020/11/26.
• 3、 Kulikova, Irina V.,Drenichev, Mikhail S.,Solyev, Pavel N.,Alexeev, Cyril S.,Mikhailov, Sergey N.. "Enzymatic Synthesis of 2-Deoxyribose 1-Phosphate and Ribose 1 Phosphate and Subsequent Preparation of Nucleosides". supporting information. p. 6999 - 7004. Retrieved 2019/11/13.