克罗拉宾, 氯法拉宾, Clofarabine

6-Amino-2-chloro-9-(2'-deoxy-2'-fluoro-b-D-arabinofuranosyl)purine

Antimetabolite agent. Purine analogue. Deoxycytidine kinase substrate. Competes with dATP for DNA polymerase-α and -ε. Potent ribonucleotide reductase inhibitor (IC50 = 65 nM). Induces apoptosis by directly altering mitochondrial transmembrane potential. Shows antitumor effects in vivo.

Clofarabine is a nucleoside analog that inhibits ribonucleotide reductase and DNA polymerase-α (IC50s = 65 and 3.9 nM, respectively) and is cytotoxic to K562 myelogenous leukemia cells (IC50 = 5 nM). It induces apoptosis in primary chronic lymphocytic leukemia cells by directly altering mitochondrial transmembrane potential. Clofarabine demonstrates growth inhibition and cytotoxic activity in a variety of leukemias and solid tumors.

Clofarabine is a second generation purine nucleoside analog with antineoplastic activity. Clofarabine is phosphorylated intracellularly to the cytotoxic active 5'-triphosphate metabolite, which inhibits the enzymatic activities of ribonucleotide reductase and DNA polymerase, resulting in inhibition of DNA repair and synthesis of DNA and RNA. This nucleoside analog also disrupts mitochondrial function and membrane integrity, resulting in the release of pre-apoptotic factors, including cytochrome C and apoptotic-inducing factors, which activate apoptosis.

Clofarabine is a purine analogue and antineoplastic agent used in the therapy of acute lymphoblastic leukemia (ALL) in children. Clofarabine is associated with frequent transient serum enzyme elevations during therapy, but they are usually asymptomatic and transient and it has only rarely been implicated in causing clinically apparent acute liver injury with jaundice.

Clofarabine, also known as clolar or CL-F-ara-a, belongs to the class of organic compounds known as purine 2'-deoxyribonucleosides. Purine 2'-deoxyribonucleosides are compounds consisting of a purine linked to a ribose which lacks a hydroxyl group at position 2. Clofarabine is a drug which is used for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphocytic (lymphoblastic) leukemia after at least two prior regimens. it is designated as an orphan drug by the fda for this use. Clofarabine is slightly soluble (in water) and a very weakly acidic compound (based on its pKa). Clofarabine has been detected in multiple biofluids, such as urine and blood. Within the cell, clofarabine is primarily located in the cytoplasm.

Clofarabine is a nucleoside that is used as an antileukemia drug. It is a metal chelate, and its mechanism of action involves incorporation into the DNA chain, which prevents DNA elongation by inhibiting DNA methyltransferase. Clofarabine has minimal toxicity and side-effect profiles. This agent inhibits the proliferation of leukemia cells in vitro by interfering with the synthesis of RNA and DNA. Clofarabine has been shown to be effective against acute toxicities caused by nonsteroidal anti-inflammatory drugs in pediatric patients.

Title: Clofarabine

CAS Registry Number: 123318-82-1

CAS Name: 2-Chloro-9-(2-deoxy-2-fluoro-b-D-arabinofuranosyl)-9H-purin-6-amine

Additional Names: 2-chloro-9-(2-deoxy-2-fluoro-b-D-arabinofuranosyl)adenine; 2-chloro-2¢-arabinofluoro-2¢-deoxyadenosine; Cl-F-ara-A

Trademarks: Clolar (Genzyme)

Molecular Formula: C10H11ClFN5O3

Molecular Weight: 303.68

Percent Composition: C 39.55%, H 3.65%, Cl 11.67%, F 6.26%, N 23.06%, O 15.81%

Literature References: Second generation purine nucleoside analog; antimetabolite that inhibits DNA synthesis and resists deamination by adenosine deaminase. Prepn: K. A. Watanabe et al., EP 219829; eidem, US 4918179 (1987, 1990 both to Sloan-Kettering Inst. Cancer Res.); J. A. Montgomery et al., J. Med. Chem. 35, 397 (1992). Improved synthesis: W. E. Bauta et al., Org. Process Res. Dev. 8, 889 (2004). Antineoplastic activity: W. R. Waud et al., Nucleosides Nucleotides Nucleic Acids 19, 447 (2000). Clinical pharmacology: H. M. Kantarjian et al,. J. Clin. Oncol. 21, 1167 (2003). Clinical pharmacokinetics: V. Gandhi et al., Clin. Cancer Res. 9, 6335 (2003). Clinical evaluation in acute leukemia: H. Kantarjian et al., Blood 102, 2379 (2003); in pediatric patients: S. Jeha et al., ibid. 103, 784 (2004). Review of development: A. Sternberg, Curr. Opin. Invest. Drugs 4, 1479-1487 (2003); of mechanism of action and clinical experience: S. Faderl et al., Cancer 103, 1985-1995 (2005).

Properties: Crystals from water, mp 225-227° (Montgomery). Also reported as crystals from methanol, mp 237° (Bauta). uv max (water): 212, 263 nm (e 22500, 15989).

Melting point: mp 225-227° (Montgomery); crystals from methanol, mp 237° (Bauta)

Absorption maximum: uv max (water): 212, 263 nm (e 22500, 15989)

Therap-Cat: Antineoplastic.

Keywords: Antineoplastic; Antimetabolites; Purine Analogs.