喷司他丁, Pentostatin

Pentostatin is a purine nucleotide analogue antibiotic isolated from the bacterium Streptomyces antibioticus. Also known as 2'-deoxycoformycin, pentostatin binds to and inhibits adenine deaminase (ADA), an enzyme essential to purine metabolism; ADA activity is greatest in cells of the lymphoid system with T-cells having higher activity than B-cells and T-cell malignancies higher ADA activity than B-cell malignancies. Pentostatin inhibition of ADA appears to result in elevated intracellular levels of dATP which may block DNA synthesis through the inhibition of ribonucleotide reductase. This agent may also inhibit RNA synthesis and may selectively deplete CD26+ lymphocytes. (NCI04)

Pentostatin is a purine analogue and antineoplastic agent used in the therapy of hairy cell leukemia and T cell lymphomas. Pentostatin is associated with a low rate of serum enzyme elevations during therapy and has been linked to rare instances of severe acute liver injury with jaundice.

Pentostatin, also known as nipent or deoxycoformycin, belongs to the class of organic compounds known as imidazodiazepines. These are organic compounds containing an imidazole ring fused to a diazepine ring. Imidazole is 5-membered ring consisting of three carbon atoms, and two nitrogen centers at the 1- and 3-positions. Diazepine is a 7-membered ring consisting of five carbon and two nitrogen atoms. Pentostatin is a drug which is used for the treatment of hairy cell leukaemia refractory to alpha interferon. Pentostatin exists as a solid, soluble (in water), and a very weakly acidic compound (based on its pKa). Pentostatin has been detected in multiple biofluids, such as urine and blood. Within the cell, pentostatin is primarily located in the cytoplasm. Pentostatin is a potentially toxic compound.

2'-Deoxycoformycin is a drug that inhibits the synthesis of DNA, RNA, and proteins. It is an analog of coformycin which has been shown to be effective against congestive heart failure. 2'-Deoxycoformycin inhibits the surface glycoprotein on T-cells and also inhibits the proliferation of human T-cell lymphoma cells in culture. This drug has minimal toxicity and can be used to treat infectious diseases. 2'-Deoxycoformycin binds to the mcl-1 protein which regulates apoptosis, hematopoiesis, and inflammation. The drug may inhibit multidrug resistance by binding to a site that is not accessible to pentostatin or other nonsteroidal anti-inflammatory drugs. The drug has been shown to inhibit the growth of bowel disease in animals. 2'-Deoxycoformycin binds reversibly to DNA polymerase alpha or beta at concentrations that are 10 times lower than those needed for inhibition

Title: Pentostatin

CAS Registry Number: 53910-25-1

CAS Name: (8R)-3-(2-Deoxy-b-D-erythro-pentofuranosyl)-3,4,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol

Additional Names: 2'-deoxycoformycin; DCF; 2'-dCF

Manufacturers' Codes: CL-67310465; NSC-218321; CI-825

Trademarks: Nipent (SuperGen)

Molecular Formula: C11H16N4O4

Molecular Weight: 268.27

Percent Composition: C 49.25%, H 6.01%, N 20.88%, O 23.86%

Literature References: Adenosine deaminase inhibitor. Isoln from Streptomyces antibioticus and structure determn: P. W. K. Woo et al., J. Heterocycl. Chem. 11, 641 (1974). Isoln and purification: A. Ryder et al., DE 2517596; eidem, US 3923785 (both 1975 to Parke-Davis). Total synthesis: E. Chan et al., J. Org. Chem. 47, 3457 (1982). Preliminary biosynthetic study: J. C. Hanvey et al., Biochemistry 27, 5790 (1988). Inhibition of deaminases in vitro: T. Rogler-Brown et al., Biochem. Pharmacol. 27, 2289 (1978); C. Frieden et al., Biochem. Biophys. Res. Commun. 91, 278 (1979); in vivo: W. Plunkett et al., Biochem. Pharmacol. 28, 201 (1979). Toxicology study: J. F. Smyth et al., Cancer Chemother. Pharmacol. 1, 49 (1978). Clinical pharmacology: J. F. Smyth et al., ibid. 5, 93 (1980); P. P. Major et al., Blood 58, 91 (1981); F. J. Cummings et al., Clin. Pharmacol. Ther. 44, 501 (1988). Enzymatic determn in biological fluids: M. M. Chassin et al., Biochem. Pharmacol. 28, 1849 (1979); A. E. Staubus et al., ibid. 33, 1633 (1984). Clinical evaluation in hairy cell leukemia: J. B. Johnston et al., J. Natl. Cancer Inst. 80, 765 (1988). Brief review: P. O'Dwyer et al., Ann. Intern. Med. 108, 733 (1988). Review of clinical pharmacology and immunosuppressive effects: M. Higman et al., Expert Opin. Pharmacother. 5, 2605-2613 (2004).

Properties: White crystals from methanol/water, mp 220-225° (Woo), also reported as 204-209.5° with darkening at >150° (Chan). uv max (water, pH 7): 282 nm (e 8000); (pH 11): 283 nm (e 7970); (pH 2): 273 nm (e 7570 initially, 3143 after 6.5 hrs). [a]D25 +76.4° (c = 1 in water); [a]D23 +73.0° (c = 1, pH 7 buffer). pKa 5.2 in water. Freely sol in distilled water.

Melting point: mp 220-225° (Woo), also reported as 204-209.5° with darkening at >150° (Chan)

pKa: pKa 5.2 in water

Optical Rotation: [a]D25 +76.4° (c = 1 in water); [a]D23 +73.0° (c = 1, pH 7 buffer)

Absorption maximum: uv max (water, pH 7): 282 nm (e 8000); (pH 11): 283 nm (e 7970); (pH 2): 273 nm (e 7570 initially, 3143 after 6.5 hrs)

Therap-Cat: Antineoplastic.

Keywords: Antineoplastic.