(2R,3S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-2-(hydroxymethyl)oxolan-3-ol

• ChemBase ID: 127
• Molecular Formular: C10H12ClN5O3
• Molecular Mass: 285.68698
• Monoisotopic Mass: 285.06286695
• SMILES: Clc1nc2n([C@@H]3O[C@@H]([C@@H](O)C3)CO)cnc2c(n1)N
• Canonical SMILES: OC[C@H]1O[C@H](C[C@@H]1O)n1cnc2c1nc(Cl)nc2N
• InChI: InChI=1S/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+/m0/s1
• InChIKey: PTOAARAWEBMLNO-KVQBGUIXSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: (2R,3S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-2-(hydroxymethyl)oxolan-3-ol
• IUPAC Traditional name: cladribine
• Brand Name: Leustatin; Mylinax
• Synonyms: CdA; 2-Chloro-2′-deoxyadenosine; 2-Chloro-2'-deoxy-beta-adenosine; 2-CdA; 2-Chloro-2'-deoxyadenosine; 2-Chlorodeoxyadenosine; Chlorodeoxyadenosine; cladribine; Cladribine; 2-Chloro-2'-deoxyadenosine; Leustatin

Database IDs

• CAS Number: 4291-63-8
• MDL Number: MFCD00153939
• PubChem SID: 46504588; 24892693; 160963590
• PubChem CID: 20279

CALCULATED PROPERTIES

JChem

• Acid pKa: 13.886716
• H Acceptors: 7
• H Donor: 3
• LogD (pH = 5.5): -0.2817818
• LogD (pH = 7.4): -0.28177568
• Log P: -0.28177547
• Molar Refractivity: 67.1835 cm^3
• Polarizability: 25.93346 Å^3
• Polar Surface Area: 119.31 Å^2
• Rotatable Bonds: 2
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: -0.12
• LOG S: -1.65
• Solubility (Water): 6.35e+00 g/l

PROPERTIES

Physical Property

• Solubility: DMSO
• Hydrophobicity(logP): -0.1

Safety Information

• Storage Condition: -20°C
• Storage Warning: IRRITANT
• RTECS: AU7357560
• European Hazard Symbols: Toxic (T)
• German water hazard class: 3
• Risk Statements: 23/24/25-36/37/38
• Safety Statements: 22-26-36-45
• TSCA Listed: false
• GHS Pictograms: GHS06
• GHS Signal Word: Danger
• GHS Hazard statements: H301-H311-H315-H319-H331-H335
• GHS Precautionary statements: P261-P280-P301 + P310-P305 + P351 + P338-P311
• Personal Protective Equipment: Eyeshields, Faceshields, Gloves, type P2 (EN 143) respirator cartridges
• Storage Temperature: 2-8°C

Pharmacology Properties

• Target: Antimetabolites
• Gene Information: human ... NP(4860)rat ... Adora1(29290), Adora2a(25369), Adora3(25370)

Product Information

• Purity: 95+%
• Salt Data: Free Base

DETAILS

DrugBank - DB00242

• Drug Groups: approved; investigational
• Description: An antineoplastic agent used in the treatment of lymphoproliferative diseases including hairy-cell leukemia. [PubChem]
• Indication: For the treatment of active hairy cell leukemia (leukemic reticuloendotheliosis) as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms. Also used as an alternative agent for the treatment of chronic lymphocytic leukemia (CLL), low-grade non-Hodgkin's lymphoma, and cutaneous T-cell lymphoma.
• Pharmacology: Cladribine is a synthetic purine nucleoside that acts as an antineoplastic agent with immunosuppressive effects. Cladribine differs structurally from deoxyadenosine only by the presence of a chlorine atom at position 2 of the purine ring, which results in resistance to enzymatic degradation by adenosine deaminase. Due to this resistance, cladribine exhibits a more prolonged cytotoxic effect than deoxyadenosine against resting and proliferating lymphocytes. Cladribine is one of a group of chemotherapy drugs known as the anti-metabolites. Anti-metabolites stop cells from making and repairing DNA, which are processes that are necessary for cancer cells to grow and multiply.
• Toxicity: Symptoms of overdose include irreversible neurologic toxicity (paraparesis/quadriparesis), acute nephrotoxicity, and severe bone marrow suppression resulting in neutropenia, anemia and thrombocytopenia.
• Affected Organisms: Humans and other mammals
• Biotransformation: Metabolized in all cells with deoxycytidine kinase activity to 2-chloro-2'-deoxyadenosine-5'-triphosphate
• Absorption: Oral bioavailability is 34 to 48%.
• Half Life: 5.4 hours
• Protein Binding: 20%
• Distribution: * 4.5 ± 2.8 L/kg [patients with hematologic malignancies]; * 9 L/kg
• Clearance: * 978 +/- 422 mL/h/kg
• References: Warnke C, Wiendl H, Hartung HP, Stuve O, Kieseier BC: Identification of targets and new developments in the treatment of multiple sclerosis - focus on cladribine. Drug Des Devel Ther. 2010 Jul 21;4:117-26. [Pubmed] ; Sigal DS, Miller HJ, Schram ED, Saven A: Beyond hairy cell: the activity of cladribine in other hematologic malignancies. Blood. 2010 Jul 15. [Pubmed] ; Khalid BA, Hamilton NT, Cauchi MN: Binding of thyroid microsomes by lymphocytes from patients with thyroid disease and normal subjects. Clin Exp Immunol. 1976 Jan;23(1):28-32. [Pubmed] ; Sampat K, Kantarjian H, Borthakur G: Clofarabine: emerging role in leukemias. Expert Opin Investig Drugs. 2009 Oct;18(10):1559-64. [Pubmed] ; Kantarjian HM, Jeha S, Gandhi V, Wess M, Faderl S: Clofarabine: past, present, and future. Leuk Lymphoma. 2007 Oct;48(10):1922-30. [Pubmed] ; Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. Epub 2009 Jul 1. [Pubmed] ; Larson ML, Venugopal P: Clofarabine: a new treatment option for patients with acute myeloid leukemia. Expert Opin Pharmacother. 2009 Jun;10(8):1353-7. [Pubmed]
• External Links: Wikipedia; RxList; Drugs.com

Selleck Chemicals - S1199

Research Area

• Description: Multiple sclerosis

Biological Activity

• Description: Cladribine (Leustatin, Litak, 2CDA) is an adenosine deaminase inhibitor for U266, RPMI8226, and MM1.S cells with IC50 of approximately 2.43 μM, 0.75 μM, and 0.18 μM, respectively.
• Targets: U266 cells; RPMI8226 cells; MM1.S cells
• IC50: 2.43 μM; 0.75 μM; 0.18 μM ^[1]
• In Vitro: Cladribine exerts remarkable activity in hairy cell leukemia (HCL), a chronic B-cell lymphoproliferative disorder, producing prolonged complete remissions. Cladribine induces accumulation of DNA strand breaks, and subsequently activates the tumor suppressor p53 in lymphocytes. Cladribine may modulate STAT3 activity in MM cells. Cladribine inhibits proliferation/survival of U266, RPMI8226 and MM1.S cells in a dose-dependent manner. While U266 is the least sensitive cell line, MM1.S is the most sensitive one to cladribine. Treatment with cladribine gradually increases the percentage of cells in the G1 phase of the cell cycle and reduces the percentage of cells in S phase. Cladribine appears to increase G2-M phase in U266 cells upon 24 hour-treatment. A dose-dependent increase in apoptosis induced by cladribine is seen in both RPMI8226 and MM1.S cells. Treatment with cladribine at 0.2 μM dramatically induces activation of caspase-3, -8, and -9 and PARP cleavage in a time-dependent manner in MM1.S. Cladribine significantly decreases the phospho-STAT3 (P-STAT3) levels in a dose-dependent manner, but has no effect on the total STAT3 protein levels. ^[1] Cladribine possesses concentration-dependent apoptosis-inducing potential in the HSB2 cells. ^[2] Cladribine inhibits growth of primary mast cell (MC) and the MC line HMC-1 in a dose-dependent manner, with lower IC50 values recorded in HMC-1.2 cells harboring KIT D816V compared to HMC-1.1 cells lacking KIT D816V. ^[3] Cladribine decreases the migratory capacity of CD14^+ monocytes, as well as of CD4^+ and CD8^+ T lymphocytes. ^[4]
• In Vivo: Cladribine (0.7-3.5 mM) and/or diltiazem (2.4 mM), is injected intraperitoneally into adult zebrafish and red blood cell (RBC) lysates are assayed by HPLC for levels of purine nucleotides (e.g. ATP), potential biomarkers of cardiovascular health. Diltiazem increased RBC ATP concentrations, which are inhibited by co-injection of cladribine. ^[5] Plasma concentrations of Cladribine decreases rapidly following a biphasic decline after both ia and s.c. administrations. The AUC and t _1/2 beta after a single 1 mg/kg ia and 2 mg/kg s.c. injection of Cladribine are 0.66 vs 1.2 μg × h/mL and 3.5 vs 4.5 hours, respectively. ^[6]
• Clinical Trials: Cladribine plus Rituximab has entered in a phase II clinical trial in the treatment of leukemia.
• Features: Cladribine is primarily active in lymphoid tissues.

Protocol

• Protocol: Cell Assay ^[1]
• Cell Lines: U266, RPMI8226 and MM1.S
• Concentrations: 0 μM - 32 μM
• Incubation Time: 72 hours
• Methods: The non-radioactive cell proliferation kit is used to determine cell viability. In brief, Human MM cell line U266, RPMI8226 and MM1.S are seeded onto 96-well plates with either 0.1 mL complete medium (5% FBS) as control, or 0.1 mL of the same medium containing a series of doses of cladribine, and incubated for 72 hours. After reading all wells at 490 nm with a micro-plate reader, the percentages of surviving cells from each group relative to controls, defined as 100% survival, are determined by reduction of MTS.
• Protocol: Animal Study ^[5]
• Animal Models: Adult wild-type (AB) zebrafish
• Formulation: Saline
• Doses: 0.7 mM - 3.5?mM
• Administration: Administered via i.p.

References

• References: [1] Ma J, et al. BMC Cancer. 2011, 11, 255.
• References: [2] Guchelaar HJ, et al. Cancer Chemother Pharmacol. 1998, 42(1), 77-83.
• References: [3] Böhm A, et al. Exp Hematol. 2010, 38(9), 744-755.
• References: [4] Kopadze T, et al. Eur J Neurol. 2009, 16(3), 409-412.
• References: [5] Klein LC, et al. Biomarkers. 2009, 14(8), 554-559.
• References: [6] Yeung PK, et al. Drug Metabol Drug Interact. 2008, 23(3-4), 291-298.
• References: [7] Szmigielska-Kaplon A, et al. Ann Hematol. 2002, 81(9), 508-513.

Sigma Aldrich - C4438

Biochem/physiol Actions
Deoxyadenosine analog resistant to adenosine deaminase; antileukemic with immunosuppressive activity
Application
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).
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). Clinically used for treatment of hairy cell leukemia, chronic lymphocytic leukemia and other indolent leukemias.

REFERENCES

• Warnke C, Wiendl H, Hartung HP, Stuve O, Kieseier BC: Identification of targets and new developments in the treatment of multiple sclerosis - focus on cladribine. Drug Des Devel Ther. 2010 Jul 21;4:117-26. Pubmed
• Sigal DS, Miller HJ, Schram ED, Saven A: Beyond hairy cell: the activity of cladribine in other hematologic malignancies. Blood. 2010 Jul 15. Pubmed
• Khalid BA, Hamilton NT, Cauchi MN: Binding of thyroid microsomes by lymphocytes from patients with thyroid disease and normal subjects. Clin Exp Immunol. 1976 Jan;23(1):28-32. Pubmed
• Sampat K, Kantarjian H, Borthakur G: Clofarabine: emerging role in leukemias. Expert Opin Investig Drugs. 2009 Oct;18(10):1559-64. Pubmed
• Kantarjian HM, Jeha S, Gandhi V, Wess M, Faderl S: Clofarabine: past, present, and future. Leuk Lymphoma. 2007 Oct;48(10):1922-30. Pubmed
• Zhenchuk A, Lotfi K, Juliusson G, Albertioni F: Mechanisms of anti-cancer action and pharmacology of clofarabine. Biochem Pharmacol. 2009 Dec 1;78(11):1351-9. Epub 2009 Jul 1. Pubmed
• Larson ML, Venugopal P: Clofarabine: a new treatment option for patients with acute myeloid leukemia. Expert Opin Pharmacother. 2009 Jun;10(8):1353-7. Pubmed
• Kopadze T, et al. Eur J Neurol. 2009, 16(3), 409-412.
• Klein LC, et al. Biomarkers. 2009, 14(8), 554-559.
• Yeung PK, et al. Drug Metabol Drug Interact. 2008, 23(3-4), 291-298.
• Szmigielska-Kaplon A, et al. Ann Hematol. 2002, 81(9), 508-513.
• Ma J, et al. BMC Cancer. 2011, 11, 255.
• Guchelaar HJ, et al. Cancer Chemother Pharmacol. 1998, 42(1), 77-83.
• Böhm A, et al. Exp Hematol. 2010, 38(9), 744-755.