Cladribine Property

Melting point:

181-185 °C(lit.)

alpha 

D25 -18.8° (c = 1 in DMF)

Boiling point:

547.6±60.0 °C(Predicted)

Density 

2.03±0.1 g/cm3(Predicted)

storage temp. 

-20°C

solubility 

Slightly soluble in water, soluble in dimethyl sulfoxide, slightly soluble in methanol, practically insoluble in acetonitrile. It shows polymorphism (5.9).

form 

White solid

pka

13.75±0.60(Predicted)

color 

White to Pale Yellow

λmax

265nm(EtOH aq.)(lit.)

Merck 

14,2337

Stability:

Store in Freezer

InChIKey

PTOAARAWEBMLNO-HSUXUTPPSA-N

CAS DataBase Reference

4291-63-8(CAS DataBase Reference)

Safety

Hazard Codes 

T

Risk Statements 

36/37/38-23/24/25

Safety Statements 

26-37/39-45-36-22

RIDADR 

UN 2811 6.1 / PGIII

WGK Germany 

3

RTECS 

AU7357560

HS Code 

29349990

Hazardous Substances Data

4291-63-8(Hazardous Substances Data)

Toxicity

LD50 intraperitoneal in mouse: 150mg/kg

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Danger

Hazard statements

H301Toxic if swalloed

H341Suspected of causing genetic defects

H372Causes damage to organs through prolonged or repeated exposure

Precautionary statements

P201Obtain special instructions before use.

P202Do not handle until all safety precautions have been read and understood.

P260Do not breathe dust/fume/gas/mist/vapours/spray.

P264Wash hands thoroughly after handling.

P264Wash skin thouroughly after handling.

P270Do not eat, drink or smoke when using this product.

P301+P310IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.

Cladribine Chemical Properties,Usage,Production

Description

Cladribine (2-chloro-2′-deoxyadenosine) is an adenosine deaminase-resistant analogue of deoxyadenosine. The drug has a broad range of in vitro activity against both lymphoid and myeloid neoplasms [mean IC50values (drug concentration required to inhibit cell growth by 50% of control): 20 to 87 nmol/L]. But it possesses little activity against multiple myeloma specimens and many solid tumor cell lines. Monocytes are highly sensitive to cladribine in vitro. Cladribine demonstrates activity against both dividing and nondividing cells and this activity distinguishes it from many other agents. It has activity in murine models of leukaemia. Cladribine is used to treat chronic progressive multiple sclerosis, hairy cell leukemia, systemic mastocytosis, and histiocytosis (including Erdheim–Chester disease and Langerhans cell histiocytosis).
After a 2-hour intravenous infusion of cladribine 0.14 mg/kg/day, the mean maximum plasma drug concentration was 198 nmol/L. Intracellular concentrations of phosphorylated cladribine derivatives exceed plasma concentrations 128- to 375-fold. Cladribine penetrates into the CSF. The terminal elimination half-life (6.7 hours) is long, which suggests that the drug may be administered intermittently without loss of efficacy. The volume of distribution of cladribine is 9.2 L/kg.

References

[1] J.C Sipe,  J. S Romine, R. McMillan, E. Beutler, J. C. Sipe, J. S. Romine, J. Zyroff (1994) Cladribine in treatment of chronic progressive multiple sclerosis, 344, 9-13
[2] Alan Saven, Carol Burian (1999) Cladribine Activity in Adult Langerhans-Cell Histiocytosis, 93, 4125-4130
[3] https://en.wikipedia.org/wiki/Cladribine
[4] Harriet M. Bryson, Eugene M. Sorkin (1993) Cladribine: A Review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in haematological malignancies, 46, 872-894

Description

Cladribine, an adenosine deaminase inhibitor, was introduced in the United States as a single intravenous treatment for hairy cell leukemia. The incorporation of a chlorine atom at the 2-position of deoxyadenosine renders cladribine more resistant to enzymatic attack by adenosine deaminase, resulting in a more prolonged cytotoxic effect. Cladribine efficiently crosses lymphocyte and monocyte cell membranes and is metabolized in cells to the biologically active triphosphate, which inhibits DNA synthesis. While most antineoplastic drugs are active primarily against dividing cells, cladribine destroys both resting and proliferating cells. Its potential uses in the treatment of autoimmune hemolytic anemia, multiple sclerosis, chronic lymphocytic leukemia and various lymphomas have also been evaluated.

Chemical Properties

White Crystalline Solid

Originator

Johnson & Johnson (U.S.A.)

Uses

2-Chloro-2′-deoxyadenosine (2-CdA) is a chlorinated purine nucleoside with activity against lymphoproliferative disorders, such as hairy cell leukemia (HCL) and multiple myeloma (MM). 2-CdA resists ADA degradation and is phosphorylated to CdATP in lymphocytes. CdATP incorporation into DNA induces strand breaks and the activation of apoptosis. 2-CdA may also be used in studies involving the inhibition of DNA polymerase(s).
Cladribiane, like fludarabine, is a prodrug that is must be phosphorylated intracellularly to the monophosphate by the nuclear/cytosol enzyme deoxycytidine kinase (dCK) and possibly by the mitochondrial enzyme deoxyguanosine kinase (dGK).

Uses

It is a substituted purine nucleoside with antileukemic activity

Indications

Cladribine (Leustatin) is a synthetic purine nucleoside that is converted to an active cytotoxic metabolite by the enzyme deoxycytidine kinase. Like the other purine antimetabolites, it is relatively selective for both normal and malignant lymphoid cells and kills resting as well as dividing cells by mechanisms that are not completely understood.
The drug is highly active against hairy cell leukemia, producing complete remissions in more than 60% of patients treated with a single 7-day course. Activity has also been noted in other low-grade lymphoid malignancies. The major side effect is myelosuppression.

Definition

ChEBI: 2'-Deoxyadenosine in which the hydrogen at position 2 on the purine ring has been substituted by chlorine. It inhibits the synthesis and repair of DNA, particularly in lymphocytes and monocytes, and is used as an antimetabolite antineoplastic drug for the treatment of lymphoid malignancies including hairy-cell leukaemia and chronic lymphocytic leukaemia.

Manufacturing Process

Manufacturing process for Cladribine includes these steps as follows: Preparation of 2',3',5'-O-triacetyl guanosine;Preparation of 9-(2',3',5'-O-triacetyl-β-D-ribofuranosyl)-2-amino-6- chloropurine;Preparation of 9-(2',3',5'-O-triacetyl-β-D-ribofuranosyl)-2,6-dichloropurine;Preparation of 2-chloroadenosine;Preparation of 2-chloro-(3',5'-O-tetraisopropyldisiloxyl)adenosine; Preparation of 2-chloro-2'-O-phenoxythiocarbonyl-(3',5'-O-tetraisopropyldisiloxyl)adenosine; Preparation of 2-chloro-2'-deoxy-(3',5'-O-tetraisopropyldisiloxyl)adenosine; Preparation of 2-chloro-2'-deoxy-adenosine.

brand name

Leustatin (Ortho Biotech).

Therapeutic Function

Cytostatic

General Description

The drug is available in a 10-mg or 10-mL single-use vialfor IV use. Cladribine is used for chronic lymphocyticleukemia, hairy cell leukemia, and non-Hodgkin’s lymphoma.The mechanism of action of this purine deoxyadenosineanalog involves incorporation into DNA resultingin inhibition of DNA chain extension and inhibitionof DNA synthesis and function. This incorporation intoDNA occurs via the triphosphate metabolite active species.The 2-chloro group on the adenine ring produces resistanceto breakdown by adenosine deaminase. Resistance to the anticancereffects can occur because of decreased expressionof the activating enzyme or overexpression of the catabolicenzymes. Oral bioavailability is variable and averages about50%. The drug crosses the blood-brain barrier; however,CSF concentrations reach only 25% of those in plasma. Thedrug is selectively activated inside the cell, and intracellularconcentrations of phosphorylated metabolites exceed thosein plasma. Toxicities include myelosuppression, neutropenia,immunosuppression, fever, nausea, and vomiting.

Biochem/physiol Actions

Deoxyadenosine analog resistant to adenosine deaminase; antileukemic with immunosuppressive activity

Clinical Use

Antineoplastic agent:
Hairy cell leukaemia (HCL)

Chronic lymphocytic leukaemia (CLL) in patients who have failed to respond to standard regimens.

Drug interactions

Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine - increased risk of agranulocytosis.
Antivirals: avoid with lamivudine.
Caution when administering with any other immunosuppressive or myelosuppressive therapy

Metabolism

Cladribine is extensively distributed and penetrates into the CNS. Cladribine is phosphorylated within cells by deoxycytidine kinase to form 2-chlorodeoxyadenosine- 5′-monophosphate which is further phosphorylated to the diphosphate by nucleoside monophosphate kinase and to the active metabolite 2-chlorodeoxyadenosine-5′- triphosphate (CdATP) by nucleoside diphosphate kinase. CdATP inhibits DNA synthesis and repair, particularly in lymphocytes and monocytes
There is little information available on the route of excretion of cladribine in man. An average of 18% of the administered dose has been reported to be excreted in urine of patients with solid tumours during a 5-day continuous intravenous infusion.

storage

Store at +4°C