Description
Amifostine, an organic thiophosphate, was introduced for the reduction
of cisplatin-induced renal toxicity in patients with advanced ovarian cancer. It is also a
radio-protective agent. Amifostine is a prodrug which is rapidly dephosphorylated,
preferentially in non-tumor tissues to the active thiol. This agent binds to
chemotherapeutic drugs and free radicals released by radiotherapy. The protective
effect of amifostine was observed in a wide range of normal organs including bone
marrow and gastrointestinal mucosa without interfering with the anti-tumor effect of
chemohadiotherapy, indicating an increased therapeutic index for existing cancer
treatment. Amifostine is also being evaluated as a cytoprotective in other types of
tumors including lung, breast, head and neck cancers. It was reported to be a potent
mucolytic with potential in cystic fibrosis.
Chemical Properties
White Solid
Originator
US Bloscience (U.S.A.)
Uses
It is a thiophosphate derivative of cysteamine; provides normal cells with selective protection against the toxic effects of cancer chemotherapy and radiation treatment
Definition
ChEBI: An organic thiophosphate that is the S-phospho derivative of 2-[(3-aminopropyl)amino]ethanethiol. A prodrug for the free thiol, WR-1065, which is used as a cytoprotectant in cancer chemotherapy and radiotherapy.
Manufacturing Process
A solution of 2-(3-aminopropylamino)ethanol (25.0 g, 0.212 mole) in 48 %
hydrobromic acid (200 ml) was distilled until 35 ml of distillate had been
collected. The solution was refluxed and, periodically, more distillate was
collected. The total volume of distillate removed in 7 distillation periods was
160 ml, or 80 % of the original volume of 48% hydrobromic acid, and the
time of continuous boiling was approximately 48 hours. The residual solution
was then evaporated to dryness under reduced pressure with the aid of
several added portions of methanol. The crystalline residue was thoroughly
triturated with acetone, collected, and washed on the funnel with acetone.
After the product had been pressed as dry as possible on the funnel, it was
dissolved in a slight excess of boiling methanol and the solution was filtered.
Addition of acetone to the filtrate precipitated pure N-(2-bromoethyl)-1,3-
propanediamine dihydrobromide as colorless crystals, which were dried in
vacuum over phosphorus pentoxide: yield 58.0 g (80%), melting point 205-
206°C. Trisodium phosphorothioate (6.93 g, 38.5 mmoles) was gradually
added in small portions with vigorous stirring to water (38 ml) cooled
externally by means of a water bath (15°-20°C). To the resulting suspension
was added N-(2-bromoethyl)-1,3-propanediamine dihydrobromide (13.3 g,
38.8 mmoles). After a few minutes, complete solution occurred, and N,Ndimethylformamide
(19 ml) was added with continued external cooling at 15°-
20°C. After the solution had been stirred at about 20°C for 90 min, it was
poured into methanol (250 ml), and the mixture was refrigerated at 4°C
overnight. The white precipitate that formed was collected and pressed as dry
as possible on the funnel. The solid was dissolved in water (40 ml), and the
solution was filtered. Addition of methanol (250 ml) reprecipitated the
product. After the mixture had been refrigerated about 1 hour, the product
was collected and washed on the funnel, first with methanol and finally with
ether. The white solid was dried in vacuo at room temperature, then exposed
to ambient conditions of the laboratory for 5 hours, and bottled under
nitrogen and stored in a freezer. The yield of S-2-(3-aminopropylamino)ethyl
dihydrogen phosphorothioate monohydrate, melting point (from methanol)
160-161°C, dec., was 8.15 g (91%).
Brand name
Ethyol (MedImmune) [USAN previously used: Ethiofos.].
Therapeutic Function
Radioprotective, Chemoprotectant, Mucolytic
Safety Profile
Poison by intravenous,intramuscular, and intraperitoneal routes. Moderately toxicby ingestion. An experimental teratogen. Otherexperimental reproductive effects. Mutation data reported. When heated todecomposition it emits very toxic fumes of SOx, PO
References
1) Capizzi et al. (2000), Chemoprotective and radioprotective effects of amifostine: an update of clinical trials; Int. J. Hematol., 72 425
2) Provinciali et al. (1999), In vivo amifostine (WR-2721) prevents chemotherapy-induced apoptosis of peripheral blood lymphocytes from cancer patients; Life Sci., 64 1525
3) Koukourakis et al. (2004), Amifostine before chemotherapy: improved tolerance profile of the subcutaneous over the intravenous route; Cancer Chemother. Pharmacol., 53 8
4) Maurici et al. (2001), Amifostine (WR2721) restores transcriptional activity of specific p53 mutant proteins in a yeast functional assay; Oncogene, 20 3533
