Clofarabine

Iupac Name：(2R,3R,4S,5R)-5-(6-amino-2-chloropurin-9-yl)-4-fluoro-2-(hydroxymethyl)oxolan-3-ol

Molecular Weight：303.678

Modify Date.: 2022-11-10 22:38

Introduction: ISecond generation purine nucleoside analog; antimetabolite that inhibits DNA synthesis and resists deamination by adenosine deaminase. Antineoplastic View more+

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1. Names and Identifiers

1.1 Name: Clofarabine
1.2 Synonyms: (2R,3R,4S,5R)-5-(6-Amino-2-chlor-9H-purin-9-yl)-4-fluor-2-(hydroxymethyl)tetrahydrofuran-3-ol (2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-2-(hydroxyméthyl)tétrahydrofuran-3-ol (2R,3R,4S,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol (2R,3R,4S,5R)-5-(6-amino-2-chloropurin-9-yl)-4-fluoro-2-(hydroxymethyl)oxolan-3-ol 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine 2-CHLORO-2'-ARABINOFLUORO-2'-DEOXYADENOSINE 2-chloro-9-(2-deoxy-2-fluoroarabinofuranosyl)adenine 2-chloro-9-(2-deoxy-2-fluoro-beta-d-arabinofuranosyl)-9h-purin-6-amin 2-chloro-9-(2-deoxy-2-fluoro-beta-d-arabinofuranosyl)adenine 2-Chloro-9-(2-deoxy-2-fluoro-Β-D-arabinofuranosyl)-9H-purin-6-amine 2-Chloro-9-(2-deoxy-2-fluoro-Β-D-arabinofuranosyl)adenine 5-(6-amino-2-chloro-purin-9-yl)-4-fluoro-2-(hydroxymethyl)oxolan-3-ol 9H-Purin-6-amine, 2-chloro-9-(2-deoxy-2-fluoro-Β-D-arabinofuranosyl)- CAFDA Cl-F-Ara-A Clofarabine [USAN] Clofarex Clolar MFCD00871077

1.3 CAS No.: 123318-82-1

1.4 CID: 119182

1.5 EINECS(EC#): 2017-001-1

1.6 Molecular Formula: C10H11ClFN5O3 (isomer)

1.7 Inchi: InChI=1S/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

1.8 InChkey: WDDPHFBMKLOVOX-AYQXTPAHSA-N

1.9 Canonical Smiles: C1=NC2=C(N=C(N=C2N1C3C(C(C(O3)CO)O)F)Cl)N

1.10 Isomers Smiles: C1=NC2=C(N=C(N=C2N1[C@H]3[C@H]([C@@H]([C@H](O3)CO)O)F)Cl)N

2. Properties

2.1 Density: 2.12

2.1 Melting point: 228-2310C

2.1 Boiling point: 550 °C at 760 mmHg

2.1 Refractive index: 1.843

2.1 Flash Point: 286.4 °C

2.1 Precise Quality: 303.05300

2.1 PSA: 119.31000

2.1 logP: 0.23180

2.1 Solubility: DMSO: >10mg/mL

2.2 Λmax: 263nm(EtOH)(lit.)

2.3 Appearance: White Solid

2.4 Storage: Keep Cold.

2.5 Chemical Properties: White Solid

2.6 Color/Form: white

2.7 Physical: Solid

2.8 pKa: 12.56±0.70(Predicted)

2.9 Water Solubility: DMSO: >10mg/mL

2.10 StorageTemp: 2-8°C

3. Use and Manufacturing

3.1 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 metabolie, 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.

3.2 GHS Classification: Signal: Danger
GHS Hazard Statements
Aggregated GHS information provided by 31 companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

H300 (77.42%): Fatal if swallowed [Danger Acute toxicity, oral]
H341 (19.35%): Suspected of causing genetic defects [Warning Germ cell mutagenicity]
H360 (19.35%): May damage fertility or the unborn child [Danger Reproductive toxicity]
H372 (19.35%): Causes damage to organs through prolonged or repeated exposure [Danger Specific target organ toxicity, repeated exposure]

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

Precautionary Statement Codes
P201, P202, P260, P264, P270, P281, P301+P310, P308+P313, P314, P321, P330, P405, and P501

3.3 Usage: ISecond generation purine nucleoside analog; antimetabolite that inhibits DNA synthesis and resists deamination by adenosine deaminase. Antineoplastic

4. Safety and Handling

4.1 Symbol: GHS06;

4.1 Hazard Codes: Xi; C

4.1 Signal Word: DANGER

4.1 Risk Statements: 25

4.1 Safety Statements: 45

4.1 Packing Group: III

4.1 Hazard Class: 8

4.1 Hazard Declaration: H300

4.1 RIDADR: UN 2811 6.1 / PGIII

4.1 Caution Statement: P264-P301 + P310

4.1 WGK Germany: 3

4.1 RTECS: DP5550000

4.1 Safety: Mutation data reported. When heated to decomposition it emits toxic vapors of NOx, F?, and Cl?.

4.2 Specification: Side effects
1.Side effects on tumor lysis syndrome (TLS): TLS is very serious and can lead to death if it is not treated right away.?
Clofarabine can?quickly kills leukaemia cells in the blood. Then the body may react to this. Symptoms include fast breathing, fast heartbeat, low blood pressure, and fluid in the lungs.
2.Side effects on Bone marrow problems (suppression). Clofarabine can stop the bone marrow from making enough red blood cells, white blood cells, and platelets. Serious side effects that can happen because of bone marrow suppression include severe infection (sepsis), bleeding, and anemia.
3.Effects on pregnancy and breastfeeding. Girls and women should not become pregnant or breastfeed during treatment which harm the baby.
4.Effects on Dehydration and low blood pressure.?Clofarabine (CAS NO.123318-82-1) can cause vomiting and diarrhea which may lead to low body fluid (dehydration). Signs and symptoms of dehydration include dizziness, lightheadedness, fainting spells, or decreased urination.
5.Other side effects. The most common side effects are stomach problems (including vomiting, diarrhea, and nausea), and effects on blood cells (including low red blood cells count, low white blood cell count, low platelet count, fever, and infection. Clofarabine can also cause tachycardia and can affect the liver and kidneys.

4.3 Toxicity

CHEMICAL IDENTIFICATION

RTECS NUMBER :: UD7473000

CHEMICAL NAME :: 9H-Purin-6-amine, 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) -

CAS REGISTRY NUMBER :: 123318-82-1

LAST UPDATED :: 199706

DATA ITEMS CITED :: 1

MOLECULAR FORMULA :: C10-H11-Cl-F-N5-O3

MOLECULAR WEIGHT :: 303.71

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

MUTATION DATA

TYPE OF TEST :: DNA inhibition

TEST SYSTEM :: Human Leukocyte

DOSE/DURATION :: 50 nmol/L

REFERENCE :: CNREA8 Cancer Research. (Public Ledger Building, Suit 816, 6th & Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- Volume(issue)/page/year: 51,2386,1991

5. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

Acute toxicity - Oral, Category 2

2.2 GHS label elements, including precautionary statements

Pictogram(s)
Signal word	Danger
Hazard statement(s)	H300 Fatal if swallowed
Precautionary statement(s)
Prevention	P264 Wash ... thoroughly after handling. P270 Do not eat, drink or smoke when using this product.
Response	P301+P310 IF SWALLOWED: Immediately call a POISON CENTER/doctor/\u2026 P321 Specific treatment (see ... on this label). P330 Rinse mouth.
Storage	P405 Store locked up.
Disposal	P501 Dispose of contents/container to ...

2.3 Other hazards which do not result in classification

none

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6. NMR Spectrum

13C NMR : Predict

1H NMR : Predict

Predict 1H proton NMR

7. Synthesis Route

123318-82-1Total: 12 Synthesis Route

5451-40-1 335 Suppliers

123318-82-1 308 Suppliers

Literatures:
Nucleosides, Nucleotides and Nucleic Acids, , vol. 19, # 10-12 p. 1861 - 1884
Yield: null

1839-18-5 173 Suppliers

123318-82-1 308 Suppliers

Literatures:
US2012/10397 A1, ;
Yield: null

6974-32-9 228 Suppliers

123318-82-1 308 Suppliers

Literatures:
US2012/10397 A1, ;
Yield: null

View all

8. Precursor and Product

precursor:

5451-40-1

355138-50-0

1055168-98-3

1839-18-5

329187-80-6

97614-44-3

1353040-42-2

103884-99-7

75788-35-1

97614-43-2

6974-32-9

1234346-14-5

product :

1839-18-5

850883-62-4

9. Other Information

9.0 Merck: 14,2372

9.1 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.

9.2 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.

9.3 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.

9.4 Category: toxic substances.

9.5 Flammability and hazard characteristics: It is combustible with fire decomposition releasing toxic nitrogen oxides; fluorides and chlorides fume.

9.6 Storage characteristics: warehouse: low-temperature, dry and ventilated.

9.7 Extinguishing media: Water, carbon dioxide, dry, sandy soil.

9.8 Chemical Properties: White Solid

9.9 Uses: ISecond generation purine nucleoside analog; antimetabolite that inhibits DNA synthesis and resists deamination by adenosine deaminase. Antineoplastic

9.10 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.

9.11 Target: Value

9.12 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.

9.13 Originator: Southern Research Institute (US)

9.14 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.

9.15 Usage: A purine nucleoside anti-metabolite. Toxic to nondividing lymphocytes and monocytes

10. Computational chemical data

Molecular Weight: 303.678g/mol
Molecular Formula: C₁₀H₁₁ClFN₅O₃
Compound Is Canonicalized: True
XLogP3-AA: null
Exact Mass: 303.0534451
Monoisotopic Mass: 303.0534451
Complexity: 370
Rotatable Bond Count: 2
Hydrogen Bond Donor Count: 3
Hydrogen Bond Acceptor Count: 8
Topological Polar Surface Area: 119
Heavy Atom Count: 20
Defined Atom Stereocenter Count: 4
Undefined Atom Stereocenter Count: 0
Defined Bond Stereocenter Count: 0
Undefined Bond Stereocenter Count: 0
Isotope Atom Count: 0
Covalently-Bonded Unit Count: 1
CACTVS Substructure Key Fingerprint: AAADccBzsQAEAAAAAAAAAAAAAAAAAWJAAAAsAAAAAAAAAFgB+AAAHwIQCAAACBzhlwYF8L9MFgCgAQZhZACAgC0REKABUCAoVBCBWAJAyEAeRAgPAALDACCwMAIAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA==

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ClofarabineCAS NO.: 123318-82-1

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Clofarabine