4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-2-one

• ChemBase ID: 861
• Molecular Formular: C9H13N3O5
• Molecular Mass: 243.21662
• Monoisotopic Mass: 243.08552053
• SMILES: O1[C@@H](n2ccc(nc2=O)N)[C@@H](O)[C@H](O)[C@H]1CO
• Canonical SMILES: OC[C@H]1O[C@H]([C@H]([C@@H]1O)O)n1ccc(nc1=O)N
• InChI: InChI=1S/C9H13N3O5/c10-5-1-2-12(9(16)11-5)8-7(15)6(14)4(3-13)17-8/h1-2,4,6-8,13-15H,3H2,(H2,10,11,16)/t4-,6-,7+,8-/m1/s1
• InChIKey: UHDGCWIWMRVCDJ-CCXZUQQUSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 4-amino-1-[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-2-one
• IUPAC Traditional name: cytarabine
• Brand Name: AR3; Alexan; Arabitin; Arafcyt; Cytarbel; Cytosar; Cytosar-U; Depocyt; Depocyt (liposomal); Erpalfa; Iretin; Spongocytidine; Tarabine; Udicil
• Synonyms: (β-D-Arabinofuranosyl)cytosine; Cytarabine; Cytosine β-D-arabinofuranoside; Ara-C; Arabinocytidine; Arabinofuranosylcytosine; Arabinosylcytosine; AraC; Aracytidine; Aracytin; Aracytine; beta-Arabinosylcytosine; Beta-cytosine arabinoside; beta-D-Arabinosylcytosine; Citarabina [INN-Spanish]; Cytarabina; Cytarabin; Cytarabinoside; Cytarabinum [INN-Latin]; Cytosine 1-beta-D-arabinofuranoside; Cytosine beta-D-arabinoside; Cytosine arabinoside; Cytosine arabinose; Cytosine arabinofuranoside; Cytosine, beta-D-arabinoside; Cytosine-1-beta-D-arabinofuranoside; Cytosine-beta-arabinoside; Cytosine-beta-D-arabinofuranoside; cytarabine liposome injection; Cytarabine; Cytosar-U; 4-AMino-1-((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxyMethyl)tetrahydrofuran-2-yl)pyriMidin-2(1H)-one; (β-D-阿拉伯呋喃糖基)胞嘧啶; 胞嘧啶阿拉伯糖苷; 阿拉伯糖胞嘧啶; 阿糖胞嘧啶; 阿糖胞苷; 胞嘧啶 β-D-呋喃阿拉伯糖苷

Database IDs

• CAS Number: 147-94-4
• EC Number: 205-705-9
• MDL Number: MFCD00066487
• Beilstein Number: 89175
• PubChem SID: 160964324; 24858315; 46505879; 24892435
• PubChem CID: 6253

CALCULATED PROPERTIES

JChem

• Acid pKa: 12.553241
• H Acceptors: 7
• H Donor: 4
• LogD (pH = 5.5): -2.7975185
• LogD (pH = 7.4): -2.7975204
• Log P: -2.7975173
• Molar Refractivity: 54.5448 cm^3
• Polarizability: 21.48729 Å^3
• Polar Surface Area: 128.61 Å^2
• Rotatable Bonds: 2
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: -2.18
• LOG S: -0.74
• Solubility (Water): 4.38e+01 g/l

PROPERTIES

Physical Property

• Solubility: DMSO; Freely soluble; H2O: soluble50 mg/mL, clear, colorless
• Apperance: crystalline
• Optical Rotation: [α]20/D +158±2°, c = 1% in H2O
• Hydrophobicity(logP): -2.8

Safety Information

• Storage Condition: -20°C
• RTECS: HA5425000
• European Hazard Symbols: Harmful (Xn)
• German water hazard class: 3
• Risk Statements: 63-43
• Safety Statements: 36/37
• GHS Pictograms: GHS07; GHS08
• GHS Signal Word: Warning
• GHS Hazard statements: H317-H361
• GHS Precautionary statements: P280
• Personal Protective Equipment: Eyeshields, Faceshields, full-face particle respirator type N100 (US), Gloves, respirator cartridge type N100 (US), type P1 (EN143) respirator filter, type P3 (EN 143) respirator cartridges
• Storage Temperature: 2-8°C

Pharmacology Properties

• Gene Information: human ... POLB(5423)mouse ... Cda(72269)

Product Information

• Purity: ≥90% (HPLC); ≥99.0% (HPLC); 98%
• Salt Data: Free Base
• Empirical Formula (Hill Notation): C9H13N3O5

DETAILS

DrugBank - DB00987

• Drug Groups: approved; investigational
• Description: A pyrimidine nucleoside analog that is used mainly in the treatment of leukemia, especially acute non-lymphoblastic leukemia. Cytarabine is an antimetabolite antineoplastic agent that inhibits the synthesis of DNA. Its actions are specific for the S phase of the cell cycle. It also has antiviral and immunosuppressant properties. (From Martindale, The Extra Pharmacopoeia, 30th ed, p472)
• Indication: For the treatment of acute non-lymphocytic leukemia, acute lymphocytic leukemia and blast phase of chronic myelocytic leukemia.
• Pharmacology: Cytarabine is an antineoplastic anti-metabolite used in the treatment of several forms of leukemia including acute myelogenous leukemia and meningeal leukemia. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Cytarabine is metabolized intracellularly into its active triphosphate form (cytosine arabinoside triphosphate). This metabolite then damages DNA by multiple mechanisms, including the inhibition of alpha-DNA polymerase, inhibition of DNA repair through an effect on beta-DNA polymerase, and incorporation into DNA. The latter mechanism is probably the most important. Cytotoxicity is highly specific for the S phase of the cell cycle.
• Toxicity: Cytarabine syndrome may develop - it is characterized by fever, myalgia, bone pain, occasionally chest pain, maculopapular rash, conjunctivitis, and malaise.
• Affected Organisms: Humans and other mammals
• Biotransformation: Hepatic.
• Absorption: Less than 20% of the orally administered dose is absorbed from the gastrointestinal tract.
• Half Life: 10 minutes
• Protein Binding: 13%
• Elimination: The primary route of elimination of cytarabine is metabolism to the inactive compound ara-U, followed by urinary excretion of ara-U.
• External Links: Wikipedia; RxList; Drugs.com

Selleck Chemicals - S1648

Research Area

• Description: Cancer

Biological Activity

• Description: Cytarabine (Cytosine arabinoside, AraC) is an antimetabolic agent and DNA synthesis inhibitor with IC50 of 16 nM in wild-type CCRF-CEM cells.
• Targets: DNA synthesis
• IC50: 16 nM ^[1] in wild-
• In Vitro: Cytarabine (AraC) is phosphorylated into a triphosphate form (Ara-CTP) involving deoxycytidine kinase (dCK), which competes with dCTP for incorporation into DNA, and then blocks DNA synthesis by inhibiting the function of DNA and RNA polymerases. Cytarabine displays a higher growth inhibitory activity towards wild-type CCRF-CEM cells compared to other acute myelogenous leukemia (AML) cells with IC50 of 16 nM. ^[1] Increasing concentrations of Cytarabine (IC50 of 0.69 μM) results in decreased metabolic activity of sensitive rat leukemic cell line RO/1, and the cell toxity can be highly enhanced by transfection with human wt dCK (IC50 of 0.037 μM) but not the inactive, alternatively spliced dCK forms. ^[2] Cytarabine apparently induces apoptosis of rat sympathetic neurons at 10 μM, of which 100 μM shows the highest toxicity and kills over 80% of the neurons by 84 hours, involving the release of mitochondrial cytochrome-c and the activation of caspase-3, and the toxicity can be attenuated by p53 knockdown and delayed by bax deletion. ^[3]
• In Vivo: Cytarabine is highly effective against acute leukaemias, which causes the characteristic G1/S blockage and synchronization, and increases the survival time for leukaemic Brown Norway rats in a weak dose-related fashion indicating that the use of higher dosages of Cytarabine does not contribute to its antileukaemic effectiveness in man. ^[4] Cytarabine (250 mg/kg) also causes placental growth retardation and increases placental trophoblastic cells apoptosis in the placental labyrinth zone of the pregnant Slc:Wistar rats, which increases from 3 hour after the treatment and peaks at 6 hour before returning to control levels at 48 hour, with remarkably enhanced p53 protein, p53 trancriptional target genes such as p21, cyclinG1 and fas and caspase-3 activity. ^[5]
• Clinical Trials: Phase I-II has been completed in the study of Oxaliplatin, Fludarabine, Cytarabine and Rituximab in patients with Richter's transformation, prolymphocytic leukemia or refractory/relapsed B-cell chronic lymphocytic leukemia.
• Features: Cytarabine is the first of a series of cancer drugs that altered the sugar component of nucleosides.

Protocol

• Protocol: Kinase Assay ^[1]
• In Vitro Growth Inhibition Assay: Stock solution of Cytarabine is prepared in absolute ethanol, and serial dilutions of Cytarabine are prepared. CCRF-CEM cells are suspended in RPMI medium supplemented with 10% FBS, 0.1% gentamicin, and 1% sodium pyruvate. The cells are suspended in their respective media to give 10 mL volumes of cell suspension at a final density of 3-6 × 10^4 cells/mL. Appropriate volumes of Cytarabine solution are transferred to the cell suspensions, and incubation is continued for 72 hours. The cells are spun down and resuspended in fresh Cytarabine -free medium, and final cell counts are determined. The data are analyzed by sigmoidal curve fitting of the cell count versus Cytarabine concentration, and the results are expressed as the IC50 (Cytarabine concentration that inhibits cell growth to 50% of the control value).
• Protocol: Cell Assay ^[2]
• Cell Lines: Rat leukemic cell lines RCL/0, RO/1 and K7 and human myelomonocytic leukemic U937
• Concentrations: ~100 μM
• Incubation Time: 24, 48 and 72 hours
• Methods: Cells are incubated in the presence of different concentrations of Cytarabine at 37 °C for 24, 48, and 72 hours. At the time of 20-, 44-, or 68-hour incubation in the presence of Cytarabine, 10 mL of cell proliferation reagent WST-1 solution is added. After 2- and 4-hour incubation with WST-1, cell metabolic activity is assessed with colorimetric changes quantified by measuring the absorbance in a spectrophotometer at 450 nm. And cell division times are calculated from eosin counting in parallel with viability assays.
• Protocol: Animal Study ^[4]
• Animal Models: Brown Norway rat with myelocytic leukaemia
• Formulation: Dissolved in phosphate-buffered saline (pH 7.0) just before use.
• Doses: 5 - 1000 mg/kg
• Administration: Injection i.v.

References

• References: [1] Tobias SC, et al. Mol Pharm, 2004, 1(2), 112-116.
• References: [2] Veuger MJ, et al. Blood, 2002, 99(4), 1373-1380.
• References: [3] Besirli CG, et al. Cell Death Differ, 2003, 10(9), 1045-1058.
• References: [4] Richel DJ, Br J Cancer, 1988, 58(6), 730-733.
• References: [5] Yamauchi H, et al. Biol Reprod, 2004, 70(6), 1762-1767.

Sigma Aldrich - C1768

Biochem/physiol Actions
阿糖胞苷复合到 DNA 中后，可通过与导致 DNA 断裂的拓扑异构酶 I 形成可裂解复合物而抑制 DNA 的复制，但不会抑制 RNA 的合成。抗白血病制剂。

Sigma Aldrich - 30399

Biochem/physiol Actions
Ara-C incorporates into DNA and inhibits DNA replication by forming cleavage complexes with topoisomerase I resulting in DNA fragmentation; does not inhibit RNA synthesis. Anti-leukemia agent.

REFERENCES

• Besirli CG, et al. Cell Death Differ, 2003, 10(9), 1045-1058.
• Richel DJ, Br J Cancer, 1988, 58(6), 730-733.
• Yamauchi H, et al. Biol Reprod, 2004, 70(6), 1762-1767.
• Tobias SC, et al. Mol Pharm, 2004, 1(2), 112-116.
• Veuger MJ, et al. Blood, 2002, 99(4), 1373-1380.