Chemical Properties
White to Off-White Solid
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.
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.
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.
Originator
Smith Kleiu & French (USA)
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).
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
