Description
Clofarabine is a new member of the purine nucleoside antimetabolite class of
drugs, and it was launched as an intravenous infusion for treating pediatric
patients (1–21 years old) with relapsed or refractory acute lymphoblastic leukemia
(ALL) after at least two prior regimens. Adenosine-related antimetabolites, such
as cladribine and fludarabine have proven successful in treating low-grade lymphomas,
chronic lymphocytic leukemia, and hairy-cell leukemia. Although structurally
similar to cladribine and fludarabine, a key differentiator for clofarabine is the presence
of a fluorine in the C-2′ position, which renders it less susceptible to phosphorolytic
cleavage of the glycosydic bond and inactivation by purine nucleoside
phosphorylases. In addition, the C-2′ fluoro group improves the acid stability relative
to its predecessors. As seen with other purine nucleoside analogs, the mechanism
of action of clofarabine involves intracellular phosphorylation to active
triphosphate by 2′ -deoxycytidine kinase, and subsequent inhibition of RNA reductase
and DNA polymerase a. Clofarabine is cytotoxic to rapidly proliferating and
quiescent cancer cell types in vitro.The higher potency of clofarabine relative to other purine nucleoside analogs is
attributed to the higher efficiency of its phosphorylation by deoxycytidine kinase, and
the longer intracellular half-life of the triphosphate metabolite (＞24 h). The chemical
synthesis of clofarabine involves the conversion of 2-deoxy-2-β-fluoro-1,3,5-tri-O-benzoyl-
1-α-D-arabinofuranose to the corresponding bromosugar with hydrogen
bromide, subsequent coupling with 2-chloroadenine, and the removal of benzoyl
protecting groups with catalytic sodium methoxide in methanol. The recommended
pediatric dosage of clofarabine is 52mg/m2 daily, administered by i.v. infusion over
2 h, for 5 consecutive days. Treatment cycles are repeated following recovery or
return to baseline organ function, approximately every 2–6weeks.Clinical
efficacy of clofarabine was evaluated in a single-arm study involving 49 pediatric
patients, who had relapsed or failed two or more prior therapies. Fifteen patients
(30.6%) demonstrated either a complete remission, a complete remission minus
platelet recovery, or a partial response. For patients experiencing complete remission,
the response lasted from 43 days to ＞160 days. Adverse events associated with
clofarabine were similar to other chemotherapy agents, including vomiting, nausea,
febrile neutropenia, and diarrhea.
Chemical Properties
White Solid
Originator
Southern Research Institute (US)
Uses
Clofarabine has been used in a cell viability assay to analyze the sensitivity of the isogenic cell lines towards clofarabine. It is also used to study the interaction of anticancer drug clofarabine with human serum albumin and human α-1 acid glycoprotein.
Uses
ISecond generation purine nucleoside analog; antimetabolite that inhibits DNA synthesis and resists deamination by adenosine deaminase. Antineoplastic
Definition
ChEBI: A purine nucleoside analogue consisting of a 6-amino-2-chloropurin-9-yl group attached to the 1beta position of 2'-deoxy-2'-fluoro-D-arabinofuranose. It is metabolized intracellularly to the active 5'-triphosphate metaboli
e, which inhibits DNA synthesisis and so stops the growth of cancer cells. Clofarabine is used as an antimetabolite antineoplastic agent in the treatment of relapsed or refractory acute lymphoblastic leukaemia.
Biological Activity
Deoxycytidine kinase (dCK) substrate. Phosphorylated to form clofarabine triphosphate, which competes with dATP for DNA polymerase- α and - ε and potently inhibits ribonucleotide reductase (IC 50 = 65 nM). Induces apoptosis by directly altering mitochondrial transmembrane potential. Demonstrates growth inhibition and cytotoxic activity in a variety of leukemias and solid tumors.
Biochem/physiol Actions
Clofarabine is a second-generation nucleoside analog, used in cancer treatments. Clofarabine is metabolized to 5′-triphosphate and is known to block DNA synthesis. The human equilibrative nucleoside transporters (hENT1 and hENT2) and human concentrative nucleoside transporter (hCNT2 and hCNT3) mediates clofarabine transport into the cell. It also serves as a substrate for mitochondrial deoxyguanosine kinase. Clofarabine is an inhibitor of ribonucleotide reductase. It resists the phosphorolytic cleavage catalyzed by purine nucleoside phosphorylase of bacterias. Clofarabine also withstands deamination by adenosine deaminase.
Synthesis
The drug
was discovered by Ilex oncology (now Genzyme) and currently
marketed by Genzyme [3,6]. Several routes to the synthesis
of clofarabine have been published, including a process
scale-up chemistry as shown in the Scheme. Treatment
of commercially available 2-deoxy-2-|?-fluoro-1,3,5-tri-
O-benzoyl-1-R-D-arabinofuranose (6) with 33%HBr in acetic
acid provided the bromo sugar 7 in 88% yield. The bromide
7 was reacted with 2-chloroadenine (8) in optimized
mixed solvent system in the presence of calcium hydride and
potassium t-butoxide to give the desired |?-anomeric product
9 in 50:1 ratio. Deprotection of the benzoyl groups with sodium
methoxide then provided clofarabine (II).
References
[1] Patent: WO2011/3018, 2011, A2. Location in patent: Page/Page column 57
[2] Nucleosides, Nucleotides and Nucleic Acids, 2010, vol. 29, # 2, p. 113 - 122
