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Record Information
Version2.0
Creation Date2014-09-11 05:14:03 UTC
Update Date2014-12-24 20:26:56 UTC
Accession NumberT3D4736
Identification
Common NameFludarabine
ClassSmall Molecule
DescriptionFludarabine (marketed as fludarabine phosphate under the trade name Fludara) is a chemotherapy drug used in the treatment of hematological malignancies.
Compound Type
  • Amine
  • Antineoplastic Agent
  • Drug
  • Ether
  • Organic Compound
  • Organofluoride
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
2-Fluoro-ara AMP
2-Fluoroadenine arabinoside 5'-monophosphate
2F-Ara-AMP
9-beta-Arabinofuranosyl-2-fluoroadenine-5'-phosphate
9-beta-D-Arabinofuranosyl-2-fluoroadenine 5'-(dihydrogen phosphate)
9-beta-D-Arabinofuranosyl-2-fluoroadenine 5'-monophosphate
FAMP
Fludara
Fludarabine 5'-monophosphate
Fludarabine monophosphate
Fludarabine phosphate
Fludura
Chemical FormulaC10H13FN5O7P
Average Molecular Mass365.212 g/mol
Monoisotopic Mass365.054 g/mol
CAS Registry Number75607-67-9
IUPAC Name{[(2R,3S,4S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}phosphonic acid
Traditional Namefludarabine
SMILES[H][C@]1(COP(O)(O)=O)O[C@@]([H])(N2C=NC3=C(N)N=C(F)N=C23)[C@@]([H])(O)[C@]1([H])O
InChI IdentifierInChI=1S/C10H13FN5O7P/c11-10-14-7(12)4-8(15-10)16(2-13-4)9-6(18)5(17)3(23-9)1-22-24(19,20)21/h2-3,5-6,9,17-18H,1H2,(H2,12,14,15)(H2,19,20,21)/t3-,5-,6+,9-/m1/s1
InChI KeyInChIKey=GIUYCYHIANZCFB-FJFJXFQQSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as purine ribonucleoside monophosphates. These are nucleotides consisting of a purine base linked to a ribose to which one monophosphate group is attached.
KingdomOrganic compounds
Super ClassNucleosides, nucleotides, and analogues
ClassPurine nucleotides
Sub ClassPurine ribonucleotides
Direct ParentPurine ribonucleoside monophosphates
Alternative Parents
Substituents
  • Purine ribonucleoside monophosphate
  • Pentose phosphate
  • Pentose-5-phosphate
  • Glycosyl compound
  • N-glycosyl compound
  • 6-aminopurine
  • Monosaccharide phosphate
  • Pentose monosaccharide
  • Imidazopyrimidine
  • Purine
  • Aminopyrimidine
  • Halopyrimidine
  • 2-halopyrimidine
  • Monoalkyl phosphate
  • Imidolactam
  • Alkyl phosphate
  • Aryl fluoride
  • Aryl halide
  • Monosaccharide
  • N-substituted imidazole
  • Organic phosphoric acid derivative
  • Phosphoric acid ester
  • Pyrimidine
  • Azole
  • Tetrahydrofuran
  • Heteroaromatic compound
  • Imidazole
  • Secondary alcohol
  • 1,2-diol
  • Organoheterocyclic compound
  • Azacycle
  • Oxacycle
  • Organooxygen compound
  • Alcohol
  • Organic nitrogen compound
  • Organopnictogen compound
  • Organic oxygen compound
  • Hydrocarbon derivative
  • Organic oxide
  • Organohalogen compound
  • Primary amine
  • Amine
  • Organofluoride
  • Organonitrogen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point260°C
Boiling PointNot Available
Solubility3.53 mg/ml
LogP-2.8
Predicted Properties
PropertyValueSource
Water Solubility2.97 g/LALOGPS
logP-2.5ALOGPS
logP-3.6ChemAxon
logS-2.1ALOGPS
pKa (Strongest Acidic)1.34ChemAxon
pKa (Strongest Basic)0.6ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area186.07 ŲChemAxon
Rotatable Bond Count4ChemAxon
Refractivity74.93 m³·mol⁻¹ChemAxon
Polarizability28.88 ųChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0002-9623000000-df7fef014b7ed6f138caJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positivesplash10-01vk-9412300000-a8e2be4c7ab19ccd3280JSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0udi-0913000000-80f61b17aa4ad7d3fce9JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0udi-0900000000-e0aa5e8a08f61ff3d3b7JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0ue9-0900000000-0bba10c09fa50579ea86JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0i29-4409000000-1d1175238eed452b53c2JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0fb9-8900000000-b0d8f9f14834a2ff1f97JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-004i-9200000000-b33283ba6688bd6f3e24JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0gb9-0946000000-3a07161a0ba92c58de3bJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0udi-0900000000-aa1b46adc5cdd97f9294JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0ue9-0900000000-19d5fbe69fb7f606a97aJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-03di-2009000000-acf04284a548ec80568eJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-004i-9102000000-d93a2baa104d5742de76JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-004i-9300000000-c74fcde8d9f9eae4249bJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
Toxicity Profile
Route of ExposureBioavailability is 55% following oral administration.
Mechanism of ToxicityFludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis. The mechanism of action of this antimetabolite is not completely characterized and may be multi-faceted.
MetabolismHalf Life: 20 hours
Toxicity ValuesNot Available
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor the treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) who have not responded to or whose disease has progressed during treatment with at least one standard alkylating-agent containing regimen
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01073
HMDB IDNot Available
PubChem Compound ID30751
ChEMBL IDCHEMBL1568
ChemSpider ID28532
KEGG IDNot Available
UniProt IDNot Available
OMIM ID
ChEBI IDNot Available
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNot Available
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkFludarabine
References
Synthesis Reference

John G. Bauman, Randolph C. Wirsching, “Process for the preparation of fludarabine or fludarabine phosphate from guanosine.” U.S. Patent US5602246, issued January, 1992.

MSDST3D4736.pdf
General References
  1. Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, Hines J, Threatte GA, Larson RA, Cheson BD, Schiffer CA: Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 14;343(24):1750-7. [11114313 ]
  2. Gonzalez H, Leblond V, Azar N, Sutton L, Gabarre J, Binet JL, Vernant JP, Dighiero G: Severe autoimmune hemolytic anemia in eight patients treated with fludarabine. Hematol Cell Ther. 1998 Jun;40(3):113-8. [9698219 ]
  3. Tournilhac O, Cazin B, Lepretre S, Divine M, Maloum K, Delmer A, Grosbois B, Feugier P, Maloisel F, Villard F, Villemagne B, Bastit D, Belhadj K, Azar N, Michallet M, Manhes G, Travade P: Impact of frontline fludarabine and cyclophosphamide combined treatment on peripheral blood stem cell mobilization in B-cell chronic lymphocytic leukemia. Blood. 2004 Jan 1;103(1):363-5. Epub 2003 Sep 11. [12969985 ]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Protein kinase binding
Specific Function:
Plays an essential role in the initiation of DNA replication. During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1/p180, a regulatory subunit POLA2/p70 and two primase subunits PRIM1/p49 and PRIM2/p58) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1. The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands. These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively. The reason this transfer occurs is because the polymerase alpha has limited processivity and lacks intrinsic 3' exonuclease activity for proofreading error, and therefore is not well suited for replicating long complexes.
Gene Name:
POLA1
Uniprot ID:
P09884
Molecular Weight:
165911.405 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]
  3. Lech-Maranda E, Korycka A, Robak T: Clofarabine as a novel nucleoside analogue approved to treat patients with haematological malignancies: mechanism of action and clinical activity. Mini Rev Med Chem. 2009 Jun;9(7):805-12. [19519505 ]
  4. Robak T, Korycka A, Lech-Maranda E, Robak P: Current status of older and new purine nucleoside analogues in the treatment of lymphoproliferative diseases. Molecules. 2009 Mar 23;14(3):1183-226. doi: 10.3390/molecules14031183. [19325518 ]
  5. Robak T, Lech-Maranda E, Korycka A, Robak E: Purine nucleoside analogs as immunosuppressive and antineoplastic agents: mechanism of action and clinical activity. Curr Med Chem. 2006;13(26):3165-89. [17168705 ]
General Function:
Ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor
Specific Function:
Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides.
Gene Name:
RRM1
Uniprot ID:
P23921
Molecular Weight:
90069.375 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]
  3. Lech-Maranda E, Korycka A, Robak T: Clofarabine as a novel nucleoside analogue approved to treat patients with haematological malignancies: mechanism of action and clinical activity. Mini Rev Med Chem. 2009 Jun;9(7):805-12. [19519505 ]
  4. Robak T, Korycka A, Lech-Maranda E, Robak P: Current status of older and new purine nucleoside analogues in the treatment of lymphoproliferative diseases. Molecules. 2009 Mar 23;14(3):1183-226. doi: 10.3390/molecules14031183. [19325518 ]
General Function:
Protein homodimerization activity
Specific Function:
Required for the phosphorylation of the deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and deoxyadenosine (dA). Has broad substrate specificity, and does not display selectivity based on the chirality of the substrate. It is also an essential enzyme for the phosphorylation of numerous nucleoside analogs widely employed as antiviral and chemotherapeutic agents.
Gene Name:
DCK
Uniprot ID:
P27707
Molecular Weight:
30518.315 Da
References
  1. Jordheim LP, Galmarini CM, Dumontet C: [Metabolism, mechanism of action and resistance to cytotoxic nucleoside analogues]. Bull Cancer. 2005 Mar;92(3):239-48. [15820918 ]
  2. Yao L, Xu W, Fan L, Miao KR, Wu YJ, Qiao C, Zhu DX, Zhu HY, Liu P, Li JY: [Correlation of deoxycytidine kinase gene expression with fludarabine resistance in patients with chronic lymphocytic leukemia]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2010 Feb;18(1):36-9. [20137114 ]
  3. Zhang Y, Secrist JA 3rd, Ealick SE: The structure of human deoxycytidine kinase in complex with clofarabine reveals key interactions for prodrug activation. Acta Crystallogr D Biol Crystallogr. 2006 Feb;62(Pt 2):133-9. Epub 2006 Jan 18. [16421443 ]
4. DNA
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da
References
  1. Robak T, Lech-Maranda E, Korycka A, Robak E: Purine nucleoside analogs as immunosuppressive and antineoplastic agents: mechanism of action and clinical activity. Curr Med Chem. 2006;13(26):3165-89. [17168705 ]