product name Clofarabine
Description: Clofarabine is an antimetabolite and a DNA synthesis inhibitor as well as a substrate of Deoxycytidine kinase (dCK). Clofarabine is phosphorylated to form clofarabine triphosphate, which competes with dATP for DNA polymerase-α and -ε. At the same time, clofarabine-monophosphate is incorporated into internal and terminal DNA sites, which impaired DNA elongation and repair. Clofarabine triphosphate inhibits ribonucleotide reductase with IC50 value of 65 nM, which then reduced dCTP and dATP. Clofarabine is efficiently transported into cells through nucleoside transporters hENT1, hENT2, and hCNT2.
References: Nat Rev Drug Discov. 2006 Oct;5(10):855-63; Clin Cancer Res. 2001 Nov;7(11):3580-9.
303.68
Formula
C10H11ClFN5O3
CAS No.
123318-82-1
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 60 mg/mL (197.6 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
Synonyms
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19412536
| In Vitro |
In vitro activity: Clofarabine is efficiently transported into cells via two facilitative or equilibrative nucleoside transporters, hENT1 and hENT2, and a concentrative nucleoside transporter, hCNT253. Clofarabine is phosphorylated in a stepwise manner by cytosolic kinases to the nucleotide analogues clofarabine 5′-mono-, di- and triphosphate following entry into cells, with Clofarabine triphosphate being the active form. Clofarabine 5′-mono-, di- and triphosphate are not substrates for nucleoside transporters and must be enzymatically converted by 5′-nucleotidase back to their dephosphorylated nucleoside form for transport out of the cell. Clofarabine triphosphate is a potent inhibitor of ribonucleotide reductase (IC50 = 65 nM), presumably by binding to the allosteric site on the regulatory subunit. Clofarabine has also been shown to act directly on mitochondria by altering the transmembrane potential with release of cytochrome c, apoptotic-inducing factor (AIF), apoptosis protease-activating factor 1 (APAF1) and caspase 9 into the cytosol. Clofarabine demonstrates strong in vitro growth inhibition and cytotoxic activity (IC50 values = 0.028–0.29 μM) in a wide variety of leukaemia and solid tumour cell lines. Clofarabine has been shown to increase the activity of dCK in HL60 cells, and increases the formation of the mono-, di-, and triphosphates of ara-C in K562 cells36. Clofarabine (10 μM) inhibits the repair initiated by 4-hydroperoxycyclophosphamide (4-HC), with inhibition peaking at the intracellular concentrations of 5 μM in chronic lymphocytic leukemia (CLL) lymphocytes. Clofarabine (10 μM) combined with 4-hydroperoxycyclophosphamide (4-HC) produces more than additive apoptotic cell death than the sum of each alone. Clofarabine (1 μM) combined with ara-C (10 μM) results in a biochemical modulation of ara-CTP and synergistic cell kill in K562 cells Kinase Assay: Cell Assay: |
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| In Vivo | Clofarabine administered intraperitoneally has significant activity against a wide variety of human tumour xenografts implanted subcutaneously in athymic nude or severe combined immune deficiency mice. |
| Animal model | |
| Formulation & Dosage | |
| References | Nat Rev Drug Discov. 2006 Oct;5(10):855-63; Clin Cancer Res. 2001 Nov;7(11):3580-9. |
