(2R,3S,4S,5R)-2-(2-amino-6-methoxy-9H-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol

• ChemBase ID: 1139
• Molecular Formular: C11H15N5O5
• Molecular Mass: 297.2673
• Monoisotopic Mass: 297.10731861
• SMILES: O1[C@@H](n2c3nc(nc(OC)c3nc2)N)[C@@H](O)[C@H](O)[C@H]1CO
• Canonical SMILES: OC[C@H]1O[C@H]([C@H]([C@@H]1O)O)n1cnc2c1nc(N)nc2OC
• InChI: InChI=1S/C11H15N5O5/c1-20-9-5-8(14-11(12)15-9)16(3-13-5)10-7(19)6(18)4(2-17)21-10/h3-4,6-7,10,17-19H,2H2,1H3,(H2,12,14,15)/t4-,6-,7+,10-/m1/s1
• InChIKey: IXOXBSCIXZEQEQ-UHTZMRCNSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: (2R,3S,4S,5R)-2-(2-amino-6-methoxy-9H-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol
• IUPAC Traditional name: nelarabine; (2R,3S,4S,5R)-2-(2-amino-6-methoxy-9H-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol
• Brand Name: Arranon (GlaxoSmithKline); Arranon; Atriance
• Synonyms: Nelzarabine; nelarabine; GW-506U78; Nelarabine; 9-β-D-Arabinofuranosyl-6-methoxy-9H-purin-2-amine; 506u; GW 506U78; MAY; Arranon; Nelzarabine

Database IDs

• CAS Number: 121032-29-9
• MDL Number: MFCD00871078
• PubChem SID: 160964602; 46506325
• PubChem CID: 3011155

CALCULATED PROPERTIES

JChem

• Acid pKa: 12.453927
• H Acceptors: 9
• H Donor: 4
• LogD (pH = 5.5): -1.5700827
• LogD (pH = 7.4): -1.5698559
• Log P: -1.5698491
• Molar Refractivity: 69.6048 cm^3
• Polarizability: 27.112698 Å^3
• Polar Surface Area: 148.77 Å^2
• Rotatable Bonds: 3
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: -0.81
• LOG S: -1.33
• Solubility (Water): 1.39e+01 g/l

PROPERTIES

Physical Property

• Solubility: DMSO; Slightly soluble to soluble in water
• Hydrophobicity(logP): -1

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: DNA/RNA synthesis

Product Information

• Purity: 95+%
• Salt Data: Free Base

DETAILS

DrugBank - DB01280

• Drug Groups: approved; investigational
• Description: Nelarabine is a chemotherapy drug used in T-cell acute lymphoblastic leukemia. Nelarabine is a purine nucleoside analog converted to its corresponding arabinosylguanine nucleotide triphosphate (araGTP), resulting in inhibition of DNA synthesis and cytotoxicity.
• Indication: For the treatment of pediatric and adult patients with acute T-cell lymphoblastic leukemia and T-cell lymphoblastic lymphoma whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens.
• Pharmacology: Nelarabine is a prodrug of the cytotoxic deoxyguanosine analogue 9-ß-D-arabinofuranosylguanine (ara-G). Nelarabine is demethylated by adenosine deaminase (ADA) to ara-G. Ara-G is then transported into cells, where it undergoes three phosphorylation steps, resulting in the formation of ara-G triphosphate (ara-GTP). In the first phosphorylation step, ara-G is converted to ara-G monophosphate (ara-GMP). Ara-GMP is then monophosphorylated by deoxyguanosine kinase and deoxycytidine kinase to ara-G diphosphate, and then subsequently to the active ara-G triphosphate (ara-GTP). Ara-GTP is the one that exerts the pharmacological effect. Pre-clinical studies suggest that T-cells are particularly sensitive to nelarabine.
• Toxicity: A single IV dose of 4,800 mg/m^2 was lethal in monkeys, and was associated with CNS signs including reduced/shallow respiration, reduced reflexes, and flaccid muscle tone. It is anticipated that overdosage would result in severe neurotoxicity (possibly including paralysis, coma), myelosuppression, and potentially death.
• Affected Organisms: Humans and other mammals
• Biotransformation: The principal route of metabolism for nelarabine is O-demethylation by adenosine deaminase to form ara-G, which undergoes hydrolysis to form guanine. In addition, some nelarabine is hydrolyzed to form methylguanine, which is O-demethylated to form guanine. Guanine is N-deaminated to form xanthine, which is further oxidized to yield uric acid. Ring opening of uric acid followed by further oxidation results in the formation of allantoin.
• Half Life: Nelarabine and ara-G are rapidly eliminated from plasma with a half-life of approximately 30 minutes and 3 hours.
• Protein Binding: Nelarabine and ara-G are not substantially bound to human plasma proteins (<25%) in vitro, and binding is independent of nelarabine or ara-G concentrations up to 600 mM.
• Elimination: Excretion: Nelarabine and ara-G are partially eliminated by the kidneys.
• Clearance: * 197? +/- ?189 L/h/m2 [Adult patients with refractory leukemia or lymphoma receiving doses of 199 to 2,900 mg/m2]; * 259? +/- ?409 L/h/m2 [Pediatric patients with refractory leukemia or lymphoma receiving doses of 104 to 2,900 mg/m2]
• References: Buie LW, Epstein SS, Lindley CM: Nelarabine: a novel purine antimetabolite antineoplastic agent. Clin Ther. 2007 Sep;29(9):1887-99. [Pubmed] ; DeAngelo DJ: Nelarabine for the treatment of patients with relapsed or refractory T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma. Hematol Oncol Clin North Am. 2009 Oct;23(5):1121-35, vii-viii. [Pubmed] ; Roecker AM, Allison JC, Kisor DF: Nelarabine: efficacy in the treatment of clinical malignancies. Future Oncol. 2006 Aug;2(4):441-8. [Pubmed] ; Sanford M, Lyseng-Williamson KA: Nelarabine. Drugs. 2008;68(4):439-47. [Pubmed] ; Reilly KM, Kisor DF: Profile of nelarabine: use in the treatment of T-cell acute lymphoblastic leukemia. Onco Targets Ther. 2009 Feb 18;2:219-28. [Pubmed] ; Cooper TM: Role of nelarabine in the treatment of T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Ther Clin Risk Manag. 2007 Dec;3(6):1135-41. [Pubmed] ; Curbo S, Karlsson A: Nelarabine: a new purine analog in the treatment of hematologic malignancies. Rev Recent Clin Trials. 2006 Sep;1(3):185-92. [Pubmed] ; Sigalas P, Tourvas AD, Moulakakis A, Pangalis G, Kontopidou F: Nelarabine induced complete remission in an adult with refractory T-lineage acute lymphoblastic leukemia: A case report and review of the literature. Leuk Res. 2009 Jul;33(7):e61-3. Epub 2009 Jan 21. [Pubmed] ; Gandhi V, Keating MJ, Bate G, Kirkpatrick P: Nelarabine. Nat Rev Drug Discov. 2006 Jan;5(1):17-8. [Pubmed]
• External Links: Wikipedia; RxList; Drugs.com

Selleck Chemicals - S1213

Research Area

• Description: Cancer

Biological Activity

• Description: Nelarabine (Arranon, 506U78) is a purine nucleoside analog and DNA synthesis inhibitor for HSB2 cell lines and ALL-SIL cell lines with IC50 of 0.13 μg/mL and 0.37 μg/mL, respectively.
• Targets: HSB2 cell lines; ALL-SIL cell lines; JURKAT cell lines; PER-255 cell lines
• IC50: 0.13 μg/mL; 0.37 μg/mL; 0.64 μg/mL; 0.02 μg/mL ^[1]
• In Vitro: The IC50 of Nelarabine is 25-fold and 113-fold higher than ARAC in T- and B-lineage, respectively. T-ALL cells are eightfold more sensitive to Nelarabine than B-lineage but there is considerable overlap. The efficacy of NEL in T-lineage and B-lineage cell lines is 25-fold and 113-fold less than ARAC, respectively. ^[1] Nelarabine acts by inhibiting DNA synthesis and inducing apoptosis in susceptible cells. ^[2]Nelarabine demonstrated significant antineoplastic activity with acceptable toxicity. ^[3]
• In Vivo: The Nelarabine plasma AUC is 2.82 mM minutes and the ara-G plasma AUC is 20 mM minutes. The terminal half-life of Nelarabine in plasma is 25 min, clearance is 42 mL/minutes/kg, and central volume of distribution is 1.1 L/kg. The terminal half-life of ara-G in plasma is 182 minutes and the central volume of distribution is 1.4 L/kg. In CSF the terminal half-life of Nelarabine is 77 minutes and of ara-G is 232 minutes. The AUCcsf:AUCplasma is 29 % for Nelarabine and 23 % for ara-G. Nelarabine and ara-G do not accumulate with daily infusions because of their relatively short half-lives. ^[4]
• Clinical Trials: Nelarabine plus Doxorubicin, Cyclophosphamide,Cytarabine, Dexamethasone, Methotrexate or Vincristine has entered in a phase II clinical trial in the treatment of leukemia, acute lymphoblastic leukemia, and lymphoblastic lymphoma.
• Features: Nelarabine is rapidly converted into ara-G through demethoxylation by adenosine deaminase.

Protocol

• Protocol: Cell Assay ^[1]
• Cell Lines: HSB2, ALL-SIL, JURKAT and PER-255 cell lines
• Concentrations: 0.125 μg/mL - 8 μg/mL
• Incubation Time: 96 hours
• Methods: HSB2, ALL-SIL, JURKAT and PER-255 cell lines are tested for drug resistance using the MTT assay. Nelarabine are incubated over 4 days, with concentration tested in triplicate. The IC50 (drug concentration that inhibits cell growth by 50%) is used as the measure of drug resistance. Data represent the average of 2–6 experiments performed on separate occasions. In cases where 50% cytotoxicity is not achieved by even the highest dose in a particular experiment, the IC50 is recorded as double the highest concentration tested.
• Protocol: Animal Study ^[4]
• Animal Models: Healthy adult male rhesus monkeys
• Formulation: Control
• Doses: 35 mg/kg
• Administration: Administered via i.v.

References

• References: [1] Beesley AH, et al. Br J Haematol. 2007, 137(2), 109-116.
• References: [2] Kline J, et al. Expert Opin Pharmacother. 2006, 7(13), 1791-1799.
• References: [3] DeAngelo DJ, et al. Blood. 2007, 109(12), 5136-5142.
• References: [4] Berg SL, et al. Cancer Chemother Pharmacol. 2007, 59(6), 743-747.

Toronto Research Chemicals - N389650

A chemotherapy drug used in the treatment of relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL).

REFERENCES

• Sanford M, Lyseng-Williamson KA: Nelarabine. Drugs. 2008;68(4):439-47. Pubmed
• Gandhi V, Keating MJ, Bate G, Kirkpatrick P: Nelarabine. Nat Rev Drug Discov. 2006 Jan;5(1):17-8. Pubmed
• Curbo S, Karlsson A: Nelarabine: a new purine analog in the treatment of hematologic malignancies. Rev Recent Clin Trials. 2006 Sep;1(3):185-92. Pubmed
• Sigalas P, Tourvas AD, Moulakakis A, Pangalis G, Kontopidou F: Nelarabine induced complete remission in an adult with refractory T-lineage acute lymphoblastic leukemia: A case report and review of the literature. Leuk Res. 2009 Jul;33(7):e61-3. Epub 2009 Jan 21. Pubmed
• Buie LW, Epstein SS, Lindley CM: Nelarabine: a novel purine antimetabolite antineoplastic agent. Clin Ther. 2007 Sep;29(9):1887-99. Pubmed
• DeAngelo DJ: Nelarabine for the treatment of patients with relapsed or refractory T-cell acute lymphoblastic leukemia or lymphoblastic lymphoma. Hematol Oncol Clin North Am. 2009 Oct;23(5):1121-35, vii-viii. Pubmed
• Roecker AM, Allison JC, Kisor DF: Nelarabine: efficacy in the treatment of clinical malignancies. Future Oncol. 2006 Aug;2(4):441-8. Pubmed
• Reilly KM, Kisor DF: Profile of nelarabine: use in the treatment of T-cell acute lymphoblastic leukemia. Onco Targets Ther. 2009 Feb 18;2:219-28. Pubmed
• Cooper TM: Role of nelarabine in the treatment of T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Ther Clin Risk Manag. 2007 Dec;3(6):1135-41. Pubmed
• Berg SL, et al. Cancer Chemother Pharmacol. 2007, 59(6), 743-747.
• DeAngelo DJ, et al. Blood. 2007, 109(12), 5136-5142.
• Beesley AH, et al. Br J Haematol. 2007, 137(2), 109-116.
• Kline J, et al. Expert Opin Pharmacother. 2006, 7(13), 1791-1799.
• Cohen, M.H. et al.: Oncologist, 13, 709 (2008)
• Hernandez-Ilizaliturri, F.J. et al.: Clin. Med. Therap., 1, 505 (2008)
• Sigalas, P. et al.: Leuk. Res., 33, e61 (2008)