Auranofin Chemical Properties

Melting point:

112-115°

storage temp. 

room temp

solubility 

DMSO: ≥5mg/mL

form 

solid

color 

Crystals

Stability:

Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20° for up to 2 months.

Safety Information

Hazard Codes 

Xn

Risk Statements 

63-22

Safety Statements 

36/37

RIDADR 

UN 2811 6.1 / PGIII

WGK Germany 

3

RTECS 

MD6500000

Hazardous Substances Data

34031-32-8(Hazardous Substances Data)

Toxicity

LD50 in rats, mice (mg/kg): 265, 310 orally (Payne, Walz)

MSDS

• Language:English Provider:Auranofin

Auranofin Usage And Synthesis

Description

Auranofin is the first orally effective gold compound to be marketed for the treatment of severe rheumatoid arthritis. It is better tolerated and more convenient than gold sodium thiomalate, which is administered intramuscularly.

Chemical Properties

White to Off-White Solid

Originator

Smith Kleiu & French (USA)

Uses

Auranofin is a new oral gold-based antiarthritis drug. Auranofin inhibits various leukocyte activation pathways at multiple sites. Auranofin inhibits the release of inflammatory mediators from human m acrophages, basophils, and pulmonary mast cells. Auranofin is an efficient inducer of mitochondrial membrane permeability transition pore in the presence of calcium ions related to its inhibition of m itochondrial thioredoxin reductase.

Uses

Auranofin inhibits both leukocyte activation pathways at multiple sites and the release of inflammatory mediators from human macrophages, basophils, and pulmonary mast cells. Auranofin also inhibits 5-lipoxygenase in human neutrophils, IKB kinase (IKK) by modifying Cys-179 of the IKKβ subunit 5 and selenoenzyme thioredoxin reductase (TrxR) which is involved in the defense against oxidative stress. Auranofin is a disease-modifying antirheumatic drug (DMARD) and has been used to study the anti-proliferative effects against OVCAR-3 human ovarian carcinoma cells.

Definition

ChEBI: An S-glycosyl compound consisting of 2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranose with the sufur atom coordinated to (triethylphosphoranylidene)gold. It is administered orally fo the treatment of active progressive rheumatoid arthritis.

Manufacturing Process

(A) Triethylphosphine gold chloride: A solution of 10.0 g (0.08 mol) of thiodiglycol in 25 ml of ethanol is mixed with a solution of 15.76 g (0.04 mol) of gold acid chloride trihydrate in 75 ml of distilled water. When the bright orange-yellow solution is almost colorless, it is cooled to -5°C and an equally cold solution of 5.0 g (0.0425 mol) of triethylphosphine in 25 ml of ethanol is added dropwise to the stirred solution. After the addition is complete, the cooled mixture is stirred for ? hour. Solid that separates is removed and the filtrate is concentrated to about 30 ml to yield a second crop. The combined solid is washed with aqueous-ethanol (2:1) and recrystallized from ethanol by adding water to the cloud point. The product is obtained as white needles, MP 85° to 86°C.
(B) Auranofin: A cold solution of 1.66 g (0.012 mol) of potassium carbonate in 20 ml of distilled water is added to a solution of 5.3 g (0.011 mol) of S- (2,3,4,6-tetra-O-acetylglucopyranosyl)-thiopseudourea hydrobromide [Methods in Carbohydrate Chemistry, vol 2, page 435 (1963)] in 30 ml of water at -10°C. A cold solution of 3.86 g (0.011 mol) of triethylphosphine gold chloride in 30 ml of ethanol containing a few drops of methylene chloride is added to the above mixture before hydrolysis of the thiouronium salt is complete. After the addition is complete, the mixture is stirred in the cold for ? hour. The solid that separates is removed, washed first with aqueous ethanol then water and dried in vacuum. There is obtained colorless crystals, MP 110° to 111°C, of S-triethylphosphine gold 2,3,4,6-tetra-O-acetyl-1-thio-β- D-glucopyranoside.

brand name

Ridaura (Promethus, Smith Kline Beecham, USA), Aktil (Lek, Yugoslavia), Ridauran (Robapharm, France).

Therapeutic Function

Antiarthritic

Pharmaceutical Applications

Auranofin ([tetra-O-acetyl-β-D- (glucopyranosyl)thio]-triethylphosphine)gold(I) is a second-generation gold-based drug, licensed as an orally available gold drug for the treatment of RA. It features a linear S Au P geometry, as shown by X-ray analysis. It is more lipophilic than the first-generation drugs, which makes oral administration possible. Treatment with Auranofin requires less visits to the clinic, but it is believed to be less successful in the treatment of RA compared to gold drugs being administered intramuscularly.

Biochem/physiol Actions

Auranofin inhibits various leukocyte activation pathways at multiple sites. Auranofin inhibits the release of inflammatory mediators from human macrophages, basophils, and pulmonary mast cells. The compound also inhibits 5-lipoxygenase in human neutrophils. Auranofin is a disease-modifying antirheumatic drug (DMARD). The compound is a potent inhibitor of selenoenzyme thioredoxin reductase (TrxR), which is involved in defense against oxidative stress. Auranofin is an efficient inducer of mitochondrial membrane permeability transition pore in the presence of calcium ions related to its inhibition of mitochondrial thioredoxin reductase. Auranofin inhibits IKB kinase (IKK) by modifying Cys-179 of the IKKβ subunit 5.

Clinical Use

Auranofin is indicated in adults with active rheumatoid arthritis who have not responded sufficiently to one or more NSAIDs.

Safety Profile

Poison by ingestion,intraperitoneal, and intravenous routes. Human systemiceffects by ingestion: ulceration or bleeding from stomach.An experimental teratogen. Other experimentalreproductive effects. Human mutation data reported.When heated to decomp

Synthesis

Synthesis: ethanolic thiodiglycol is treated first with aqueous gold(I) acid chloride trihydrate, then with ethanolic triethylphosphine to give triethylphosphine gold(I) chloride, which is added to an aqueous solution of S-(2,3,4,6-tetra-O-acetylglucopyranosyl)pseudothiourea hydrobromide and potassium carbonate to give the desired auranofin.

Veterinary Drugs and Treatments

Auranofin has been used to treat idiopathic polyarthritis and pemphigus foliaceous in dogs and cats. Several clinicians report that while auranofin may be less toxic, it also less efficacious than injectable gold (aurothioglucose).

Metabolism

On a mg gold/kg basis, it is reported to be as effective in the rat adjuvant arthritis assay as the parenterally effective drugs. Daily oral doses produce a rapid increase in kidney and blood gold levels for the first 3 days of treatment, with a more gradual increase on subsequent administration. Plasma gold levels are lower than those attained with parenteral gold compounds. The major route of excretion is via the urine. Auranofin may produce fewer adverse reactions than parenteral gold compounds, but its therapeutic efficacy also may be less.

References

1) Columbo et al. (1990), Modulation of mediator release from human basophils and pulmonary mast cells and macrophages by auranofin; Biochem. Pharmacol., 39 285 2) Rigobello et al. (2002), Induction of mitochondrial permeability transition by auranofin, a gold(I)-phosphine derivative; Br. J. Pharmacol., 136 1162 3) Merck 14 878

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