Clofarabine

Bezeichnung:Clofarabine

CAS-Nr123318-82-1

Englisch Name:Clofarabine

CBNumberCB2277491

SummenformelC10H11ClFN5O3

Molgewicht303.68

MOL-Datei123318-82-1.mol

Clofarabine physikalisch-chemischer Eigenschaften

Schmelzpunkt	228-2310C
Siedepunkt	550.0±60.0 °C(Predicted)
Dichte	1.4804 (estimate)
RTECS-Nr.	UD7473000
storage temp.	2-8°C
Löslichkeit	DMSO: >10mg/mL
Aggregatzustand	Powder
pka	12.56±0.70(Predicted)
Farbe	white
maximale Wellenlänge (λmax)	263nm(EtOH)(lit.)
Merck	14,2372
InChIKey	INHHKRVRRUIAPA-KJHIFWANSA-N
CAS Datenbank	123318-82-1(CAS DataBase Reference)

Sicherheit

Kennzeichnung gefährlicher	T
R-Sätze:	25
S-Sätze:	45
RIDADR	UN 2811 6.1 / PGIII
WGK Germany	2
HazardClass	6.1
HS Code	29349990

Gefahreninformationscode (GHS)

Clofarabine Chemische Eigenschaften,Einsatz,Produktion Methoden

Beschreibung
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.
Chemische Eigenschaften
White Solid
Originator
Southern Research Institute (US)
Verwenden
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.
Verwenden
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.
Trademarks
Clolar
Biologische Aktivität
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.
Synthese
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).
Lager
Store at +4°C

Clofarabine Upstream-Materialien And Downstream Produkte

Clofarabine Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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