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

• ChemBase ID: 70509
• Molecular Formular: C10H12FN5O4
• Molecular Mass: 285.2317832
• Monoisotopic Mass: 285.08733211
• SMILES: O1[C@H]([C@H]([C@@H]([C@H]1CO)O)O)n1cnc2c1nc(nc2N)F
• Canonical SMILES: OC[C@H]1O[C@H]([C@H]([C@@H]1O)O)n1cnc2c1nc(F)nc2N
• InChI: InChI=1S/C10H12FN5O4/c11-10-14-7(12)4-8(15-10)16(2-13-4)9-6(19)5(18)3(1-17)20-9/h2-3,5-6,9,17-19H,1H2,(H2,12,14,15)/t3-,5-,6+,9-/m1/s1
• InChIKey: HBUBKKRHXORPQB-FJFJXFQQSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: (2R,3S,4S,5R)-2-(6-amino-2-fluoro-9H-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol
• IUPAC Traditional name: fludarabine; @fludarabine
• Synonyms: (2R,3S,4S,5R)-2-(6-Amino-2-fluoro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol; 9-β-D-Arabinofuranosyl-2-fluoroadenine; F-ara-A; Fludarabine des-phosphate; 2-Fluoroadenine-9-β-D-arabinofuranoside; Fludara; Fludarabine(Fludara); (2R,3S,4S,5R)-2-(6-amino-2-fluoro-9H-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol

Database IDs

• CAS Number: 21679-14-1
• EC Number: 244-525-5
• MDL Number: MFCD00132942
• Beilstein Number: 1225932
• PubChem SID: 24894830; 162036224
• PubChem CID: 657237

CALCULATED PROPERTIES

• Acid pKa: 12.4539995
• H Acceptors: 8
• H Donor: 4
• LogD (pH = 5.5): -1.4700091
• LogD (pH = 7.4): -1.4700067
• Log P: -1.4700028
• Molar Refractivity: 64.0592 cm^3
• Polarizability: 24.368654 Å^3
• Polar Surface Area: 139.54 Å^2
• Rotatable Bonds: 2
• Lipinski's Rule of Five: true

PROPERTIES

Physical Property

• Solubility: DMF: soluble20 mg/mL, clear, faintly yellow; DMSO
• Melting Point: 265 - 267°C
• Hydrophobicity(logP): -2.005

Safety Information

• Storage Condition: -20°C
• Storage Warning: IRRITANT
• RTECS: AU6207000
• European Hazard Symbols: Harmful (Xn)
• German water hazard class: 3
• Risk Statements: 22
• TSCA Listed: false
• GHS Pictograms: GHS07
• GHS Signal Word: Warning
• GHS Hazard statements: H302
• Personal Protective Equipment: dust mask type N95 (US), Eyeshields, Faceshields, Gloves
• Storage Temperature: 2-8°C

Pharmacology Properties

• Target: Antimetabolites
• Gene Information: human ... ADORA3(140)rat ... Adora1(29290), Adora2a(25369), Adora3(25370)

Product Information

• Purity: ≥98.0% (HPLC); 95%; 95+%; 98%
• Salt Data: Free Base
• Empirical Formula (Hill Notation): C10H12FN5O4

DETAILS

Selleck Chemicals - S1491

Research Area

• Description: Cancer

Biological Activity

• Description: Fludarabine (Fludara, F-ara-A, NSC 118218) is a STAT1 activation inhibitor and a DNA synthesis inhibitor.
• In Vitro: Fludarabine efficiently inhibits the proliferation of RPMI 8226 cells with IC50 of 1.54 μg/mL. The IC50 of Fludarabine against MM.1S and MM.1R cells is 13.48 μg/mL and 33.79 μg/mL, respectively. In contrast, U266 cells are resistant to Fludarabine with IC50 of 222.2 μg/mL. Fludarabine treatment results in increased number of cells in the G1 phase of cell cycle, accompanied with a concomitant reduction of cells at the S phase of cell cycle in a time-dependent manner. Fludarabine induces a cell cycle block and triggers apoptosis in MM cells. Fludarabine triggers time-dependent cleavage of caspase-8, -9, and -3, -7, followed by PARP cleavage. Fludarabine increases expression of Bax in a time-dependent fashion, while the expression of Bak doesn’t change. After exposure to Fludarabine for 12 hours, RPMI 8226 cells shows a loss of membrane potential with 61.05% of the cells expressing low fluorescence of rhodamine 123 compared with 8.62% of cells in untreated control. ^[1] To enhance solubility, Fludarabine is formulated as the monophosphate (F-ara-AMP, fudarabine), which is instantaneously and quantitatively dephosphorylated to the parent nucleoside upon intravenous infusion. Inside the cells rephosphorylation occurs which leads to fuoroadenine arabinoside triphosphate (F-ara-ATP), the major cytotoxic metabolite of F-ara-A. ^[2] Fludarabine can also induce pro-inflammatory stimulation of monocytic cells, as evaluated by increased expression of ICAM-1 and IL-8 release. ^[3] Fludarabine does not affect the growth of ovarian cancer cell lines, whereas it induces marked and dose-dependent inhibition of proliferation in melanoma cell lines. ^[4] Fludarabine induces significant reduction of STAT-1 phosphorylation, whereas it does not change JAK2 activation. Interestingly, Fludarabine does not significantly affect the phosphorylation of these three STAT proteins. Fludarabine (1.5 mg) significantly prevents STAT-1 phosphorylation and also reduces the increased amount of this protein. No significant changes are demonstrated in JAK2 phosphorylation at 2 days, but Fludarabine inhibits JAK2-increased expression at 7 days. Fludarabine specifically inhibits STAT-1 activation without affecting other STAT proteins and consequently diminishes VSMC proliferation. ^[5]
• In Vivo: Tumors treated with PBS grow rapidly to approx-imately 10-fold their initial volume in 25 day, whereas, the tumors in the Fludarabine at 40 mg/kg increase less than 5-fold. A significant antitumor effect of 40 mg/kg Fludarabine on RPMI8226 tumor growth is demonstrated. RPMI8226 tumors treated with 40 mg/kg Fludarabine at day 10 increase apoptotic nuclei. Fludarabine is effective in suppressing RPMI8226 myeloma xenografts in SCID mice. ^[1]

Combination Therapy

• Description: Fludarabine phosphate plus cyclophosphamide and rituximab has entered in a Phase II clinical trial in the treatment of chronic lymphocytic leukemia.

Protocol

• Protocol: Cell Assay ^[1]
• Cell Lines: Dexamethasone-sensitive (MM.1S) and -resistant (MM.1R) human MM cell lines, RPMI8226 and U266 cell lines
• Concentrations: 2 μg/mL
• Incubation Time: 24 hours
• Methods: After treated with Fludarabine or control, dexamethasone-sensitive (MM.1S) and -resistant (MM.1R) human MM cell lines, RPMI8226 and U266 cell lines (5 × 10^5 cells) are washed twice in phosphate-buffered saline (PBS) and fixed with 70% ice-cold ethanol, then centrifuged and suspended in PBS containing 100 μg/mL RNase A. After incubated for 30 minutes at 37 oC, samples are resuspended in 25 μg/mL propidium iodide. Flow cytometry is performed on a FACSCalibur automated system. Apoptosis is determined by Annexin V-FITC apoptosis detection kit, according to the manufacturer’s instructions. For TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling) assay, cells are analyzed by flow cytometry using the in situ cell death detection kit.
• Protocol: Animal Study ^[1]
• Animal Models: Severe combined immunodeficient (SCID) mice bearing RPMI 8226 cells
• Formulation: PBS
• Doses: 40 mg/kg
• Administration: Administered via i.p.

References

• References: [1] Meng H, et al. Eur J Haematol. 2007, 79(6), 486-493.
• References: [2] Brachwitz H, et al. Bioorg Med Chem. 1999, 7(6), 1195-1200.
• References: [3] Fernández-Calotti P, et al. Int Immunopharmacol. 2006, 6(5), 715-723.
• References: [4] Zaffaroni N, et al. Eur J Cancer. 1996, 32A(10), 1766-1773.
• References: [5] Torella D, et al. Am J Physiol Heart Circ Physiol. 2007, 292(6), H2935-2943.

Sigma Aldrich - F2773

Warning
The name fludarabine refers to 9-β-D-arabinofuranosyl-2-fluoroadenine 5′-phosphate, but is sometimes erroneously used for this compound, which lacks the phosphate.
Biochem/physiol Actions
Fludarabine (the 5′-phosphate) is a prodrug that is converted to F-ara-A, which enters cells and accumulates primarily as the 5′-triphosphate. F-ara-A interferes with DNA synthesis and repair and induces apoptosis of cancer cells. F-ara-A also strongly inhibits DNA methylation, particularly methylation of cytosine in CpG dinucleotide sequences.1

Sigma Aldrich - 46455

Other Notes
Inhibitor of nucleic acid synthesis. Action on RNA metabolism2
Warning
The name fludarabine refers to 9-β-D-arabinofuranosyl-2-fluoroadenine 5′-phosphate, but is sometimes erroneously used for this compound, which lacks the phosphate.
Biochem/physiol Actions
Fludarabine (the 5′-phosphate) is a prodrug that is converted to F-ara-A, which enters cells and accumulates primarily as the 5′-triphosphate. F-ara-A interferes with DNA synthesis and repair and induces apoptosis of cancer cells. F-ara-A also strongly inhibits DNA methylation, particularly methylation of cytosine in CpG dinucleotide sequences.1

REFERENCES

• Meng H, et al. Eur J Haematol. 2007, 79(6), 486-493.
• Brachwitz H, et al. Bioorg Med Chem. 1999, 7(6), 1195-1200.
• Fernández-Calotti P, et al. Int Immunopharmacol. 2006, 6(5), 715-723.
• Zaffaroni N, et al. Eur J Cancer. 1996, 32A(10), 1766-1773.
• Torella D, et al. Am J Physiol Heart Circ Physiol. 2007, 292(6), H2935-2943.