123318-82-1 Usage
Description
Clofarabine, also known by its brand name Clolar, is a second-generation purine nucleoside analog and an antimetabolite drug. It is a white solid toxic substance that belongs to the purine nucleoside antimetabolite class of drugs. Clofarabine is metabolized intracellularly to its active 5'-triphosphate metabolite, which inhibits DNA synthesis and stops the growth of cancer cells. 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.
Uses
Used in Oncology:
Clofarabine is used as an antimetabolite antineoplastic agent for the treatment of relapsed or refractory acute lymphoblastic leukemia. Its higher potency compared 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).
Used in Research:
Clofarabine has been used in cell viability assays to analyze the sensitivity of isogenic cell lines towards the drug. Additionally, it is used to study the interaction of the anticancer drug clofarabine with human serum albumin and human α-1 acid glycoprotein, which can provide insights into its pharmacokinetics and potential applications in cancer treatment.
Anti-cancer drugs
Clofarabine is a novel purine nucleoside anticancer drugs is first successfully developed by the Top10 biopharmaceutical company of the United States---Genzyme Corporation, NASDAQ: GENZ) with the trade names being “Clofarabine”. On December 28, 2004 the US food and Drug Administration (FDA) used fast-track for approval of clofarabine for application to children with refractory or relapsed acute lymphocytic leukemia. It is currently the only available drugs for the special treatment of children with acute myelogenous leukemia (ALL); it has an excellent efficacy on the treatment of leukemia with well tolerance and no unpredictable adverse reactions. It can be administrated through either administered intravenously or administered orally. This drug is the first product approved for being dedicated to the treatment of the children's leukemia in more than ten years.
Pharmacological effects
Clofarabine has also combined the advantages of fludarabine and cladribine that can inhibit both DNA polymerase as well as inhibit ribonucleotide reductase with strong anti-cancer activity against different cell lines and tumor models. Early studies have also shown that the product, when having a concentration of micromolar or less, can already effectively inhibit the proliferation of human CNS tumors, lung cancer, kidney cancer, and leukemia and melanoma cell lines. In vivo and in vitro experiments have showed that clofarabine can induce apoptosis of leukemia cells with the mechanism being the down-regulation of de-phosphorylation of BCL-2 family proteins BCL-X and MCL-1 as well as the AKT. Its inhibitory effect on the human leukemia cells K-562 is stronger than cladribine and fluorine with the IC50 being 5 nmol/L while the IC50 for cladribine and fluorine is 16 nmol/L and 460nmol/L, respectively. Preclinical and drug combination experiments have showed that clofarabine, similar as other deoxynucleotide analogs as well as other types of anti-cancer drugs such as Etoposide, can enhance the activity of the deoxycytidine kinase in normal or abnormal human lymphocytes, and therefore increasing the anti-cancer effect.
Dosage
Clofarabine belongs to the anticancer drug which affects tubulin and is mainly used for clinical treatment of the following diseases:
1. treatment of relapsed or refractory acute lymphocytic leukemia;
2. it also has efficacy in treating acute myeloid leukemia and myelodysplastic syndrome (MDS) in older patients and can be used in combination with cytarabine.
General adult dose:
1. relapsed or refractory acute lymphoblastic leukemia: suitable for the patient (1 to 21 years) should have previously received at least two kinds of treatment programs; take 52 mg/m2 daily X 5 days, have intravenous injection (more than 2 hours) until the organ get function recovery or return back to the baseline level, repeat 1 time every 2 to 6 weeks.
2. Acute myeloid leukemia and MDS: daily 52 mg/m2 × 5 days, have intravenous infusion for 1 hour; After 4 hours, administer cytarabine with 1 g(daily)/m2 X 5 days, perform intravenous infusion for 2 hours, it has positive effect for the newly diagnosed elderly patients with acute myelogenous leukemia and high-risk MDS.
Child:
It can be used for treating refractory and relapsed acute lymphocytic leukemia with the same amount for adults. For the treatment of the refractory and relapsed acute non-lymphocytic leukemia, use daily 52mg/m2 × 5 days, perform intravenous infusion (more than 2 hours) and repeat the treatment per 2-6 weeks depending on the reaction and toxicity in patients.
The above information is edited by the lookchem of Dai Xiongfeng.
Adverse reactions and precautions
Common adverse reactions about clofarabine are as follows:
Blood system: leukocytes and neutropenia, thrombocytopenia, anemia.
Digestive system: loss of appetite, nausea, vomiting, abdominal pain, constipation; stomatitis, gingival bleeding, sore throat.
Nervous System: fatigue, drowsiness, headache, dizziness; anxiety, depression; irritability, excitability.
Cardiovascular System: tachycardia, hypertension, hypotension, transient systolic dysfunction of the left ventricular; the drug should be discontinued upon any causes of hypotension; it was occasionally observed in pediatric patient of capillary leak syndrome and systemic inflammatory response syndrome (SIRS) which can be prevented by administration of hormone during the 1st to 3rd day of treatment. During the medication, once the above syndrome occurs, it should be discontinued immediately and combined with concurrent support treatment. Once the condition is stabilized and the organ gets function recovery, the patients can re-initiate the administration from low dosage.
Liver toxicity: reversible liver damage, increased level of aspartate aminotransferase, alanine aminotransferase and bilirubin; hepatomegaly and jaundice.
Respiratory system: respiratory distress, coughing, pleural effusions.
Urogenital: hematuria, secondary hyperuricemia, elevated level of serum creatinine and creatine.
Other: dermatitis, erythema; muscle pain, joint pain; fever and infection.
[Note] women of childbearing age should take care of contraception during medication, lactation women should stop breastfeeding. Patients of hypotension, dehydration, liver and kidney dysfunction as well as secondary infection of bone marrow suppression should take with caution. Clofarabine may cause tumor lysis syndrome and should drawn attention.
Flammability and hazard characteristics
It is combustible with fire decomposition releasing toxic nitrogen oxides; fluorides and chlorides fume.
Storage characteristics
warehouse: low-temperature, dry and ventilated.
Extinguishing media
Water, carbon dioxide, dry, sandy soil.
Originator
Southern Research Institute (US)
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-β-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 β-anomeric product
9 in 50:1 ratio. Deprotection of the benzoyl groups with sodium
methoxide then provided clofarabine (II).
Check Digit Verification of cas no
The CAS Registry Mumber 123318-82-1 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,2,3,3,1 and 8 respectively; the second part has 2 digits, 8 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 123318-82:
(8*1)+(7*2)+(6*3)+(5*3)+(4*1)+(3*8)+(2*8)+(1*2)=101
101 % 10 = 1
So 123318-82-1 is a valid CAS Registry Number.
InChI:InChI=1/C10H11ClFN5O3/c11-10-15-7(13)5-8(16-10)17(2-14-5)9-4(12)6(19)3(1-18)20-9/h2-4,6,9,18-19H,1H2,(H2,13,15,16)/t3-,4-,6?,9-/m1/s1
123318-82-1Relevant articles and documents
A new process for antineoplastic agent clofarabine
Bauta, William E.,Schulmeier, Brian E.,Burke, Brian,Puente, Jose F.,Cantrell Jr., William R.,Lovett, Dennis,Goebel, James,Anderson, Bruce,Ionescu, Dumitru,Guo, Ruichao
, p. 889 - 896 (2004)
Clofarabine is a promising DNA polymerase inhibitor currently in clinical trials for a variety of liquid and solid tumor indications. The efforts for development of a new manufacturing process for clofarabine are presented. This new process allows for the reliable and efficient production of drug substance in high anomeric excess and high overall purity, without using chromatography. The high anomeric selectivity is achieved by reacting 2-chloroadenine with 1-bromo-2-deoxy-2-fluoro-3,5-di-O-benzoyl-α-D-ribofuranose (4) and potassium tert-butoxide in a mixture of three solvents. Following crystallization, anomeric ratios exceeding 50 (β/α) are achieved. Deprotection and additional crystallization afford a clofarabine drug substance containing less than 0.1% of the α-anomer.
Green synthesizing technology of clofarabine
-
Paragraph 0004; 0028-0032, (2019/02/25)
The invention relates to a green synthesizing technology of clofarabine which comprises the following steps: (the structural formula is shown in the description), dissolving a compound which is shownin formula II into an organic solvent, adding 40% of hydrobromic acid and tetrabutylammonium fluoride in an ice bath, performing stirring reaction for 3 hours, adding triethylamine trihydrofluoride and continuing the stirring reaction for 2 to 3 hours to obtain a compound which is shown in formula I; (2) dissolving a compound which is shown in formula III into acetonitrile, adding potassium tert-butoxide, calcium hydride and tert-butyl alcohol, heating to 60 DEG C, reacting for 1 hour, adding the compound which is shown in the formula I, keeping at 60 DEG C and continuing reacting for 10 hoursto obtain a compound which is shown in formula IV; (3) removing Bz in the compound which is shown in the formula IV under an alkaline condition to obtain a compound which is shown in a formula V, namely the clofarabine.
Stereoselective synthesis of 2′-modified nucleosides by using ortho-alkynyl benzoate as a gold(i)-catalyzed removable neighboring participation group
Ding, Haixin,Li, Chuang,Zhou, Yirong,Hong, Sanguo,Zhang, Ning,Xiao, Qiang
, p. 1814 - 1817 (2017/01/21)
In the present paper, we report a novel strategy for highly efficient stereoselective synthesis of 2′-modified nucleosides by using ortho-alkynyl benzoate as neighboring participation group. Subsequently, ortho-alkynyl benzoate can be removed smoothly in the presence of 5 mol% Ph3PAuCl-AgOTf in dichloromethane with H2O (1 eq.) and ethanol (6 eq.) to afford 2′-OH nucleosides in high yields and selectivity.