L-Penicillamine

A successful synthesis (Scheme 19) of the phosphonic acid analogues of D-and L-penicillamine commences with the cyclic phosphorochloridite (132). Other attempts using (132 ... 

Using this procedure, the S-labeled rhena-/8-ketoimine derivatives of benzyl mercaptan, ethanethiol, Me3COC(O)NH0H2CH2SH, iV-acetyl-L-cysteine, and iV-acetyl-D,L-penicillamine have been prepared. 

Kovacs-Hadady and Kiss [27] studied the chromatographic characteristics of thia-zolidinecarboxylic acid derivatives, formed by reaction of (i>) and (L)-penicillamine with various substituted benzaldehydes and heterocyclic aldehydes in order to evaluate the aldehydes as derivatizing agents for separation of the penicillamine enantiomers. The TLC method of Martens et al. [28] was used. Transformation to thiazolidine carboxylic acids with benzaldehyde and substituted benzaldehydes was not complete, so formaldehyde is still the preferred reagent for separation of the enantiomers. 

Penicillamine (50 mg) was mixed with 50 mg of formaldehyde, 50 pL of concentrated HC1, and 2.5 mL of propan-2-ol, and the solution heated at 60 °C for 2 h. An aliquot of the reaction mixture was subjected to TLC on a Chiralplate (Macherey-Nagel) with a mobile phase of methanol-H20-aeetonitrile (1 1 4). Detection was made using 0.1% ninhydrin reagent, and the limit of detection was approximately 0.5%. Good separation of (d)- and (L)-penicillamine was achieved. 

According to a Macherey-Nagel application note [35], a mixture of 20 ng each of (i)-cysteine, (L)-glutathione, and (L)-penicillamine was resolved in less than 12 min by HPLC. The method used a Nucleosil 100-5SA column (15 cm x 4.6 mm i.d.) with aqueous 4.5 g/L ammonium citrate-6 g/L phosphoric acid at pH 2.2 as the mobile phase (eluted at 1 mL/min) and electrochemical detection at a gold electrode polarized at +800 mV. 

Gotti et al. [42] reported an analytical study of penicillamine in pharmaceuticals by capillary zone electrophoresis. Dispersions of the drug (0.4 mg/mL for the determination of (/q-penicillaminc in water containing 0.03% of the internal standard, S -met hy I - r-cystei ne, were injected at 5 kPa for 10 seconds into the capillary (48.5 cm x 50 pm i.d., 40 cm to detector). Electrophoresis was carried out at 15 °C and 30 kV, with a pH 2.5 buffer of 50 mM potassium phosphate and detection at 200 rnn. Calibration graphs were linear for 0.2-0.6 pg/mL (detection limit = 90 pM). For a more sensitive determination of penicillamine, or for the separation of its enantiomers, a derivative was prepared. Solutions (0.5 mL, final concentration 20 pg/mL) in 10 mM phosphate buffer (pH 8) were mixed with 1 mL of methanolic 0.015% 1,1 -[ethylidenebis-(sulfonyl)]bis-benzene and, after 2 min, with 0.5 mL of pH 2.5 phosphate buffer. An internal standard (0.03% tryptophan, 0.15 mL) was added and aliquots were injected. With the same pH 2.5 buffer and detection at 220 nm, calibration graphs were linear for 9.3-37.2 pg/mL, with a detection limit of 2.5 pM. For the determination of small amounts of (L)-penicillamine impurity, the final analyte concentration was 75 pg/mL, the pH 2.5 buffer contained 5 mM beta-cyclodextrin and 30 mM (+)-camphor-10-sulfonic acid, with a voltage of 20 kV, and detection at 220 nm. Calibration graphs were linear for 0.5-2% of the toxic (L)-enantiomer, with a detection limit of 0.3%. 

For this method S-nitroso-N-acetyl-D, L-penicillamine (SNAP, FW = 220.3) is decomposed to NO in solution in the presence of a Cu (I) catalyst [77], The resultant NO generated can then be used to calibrate the sensor. The reaction proceeds in accordance to the following reaction ... 

Hoppe, I., Schollkopf, U., Nieger, M., and Egert, E., Asymmetric addition of a chiral cyclic phosphite to a cyclic imine — synthesis of phosphonic acid analogues of d- and L-penicillamine, Angew. Chem., Int. Ed. Engl., 24, 1067, 1985. 

Abbreviations BSO, D.L-buthionine-. i -sulfoxime L , lipid alkyl radicals LH, lipid LO, Upid alkoxyl radicals LOO, Upid peroxyl radicals L-NAME, yV -nitro-L-arginine-methyl ester MBl, methylene bridge index (mean number of h -aUytic methylene positions per fatty add) NO, nitric oxide NOS, nitric oxide synthase NO, nitrite N02, nitrogen dioxide NO2CI, nitryl chloride O2 , superoxide OH, hydroxyl radical OL, epoxyaUyhc radical OLOO, epoxyperoxyl radical 0=NOO , peroxynitrite SNAP, S-nitroso-iV-acetyl-D.L-penicillamine SOD, superoxide dismutase contd. onp. 98, Subcellular Biochemistry, Volume 36 Phospholipid Metabolism in Apoptosis. 

A particularly well-studied ligand is L-3,4-dihydroxyphenylalanine (l-DOPA) this may coordinate like alaninate or a pyrocatechol 700 Zn11 appears to favour binding to l-DOPA as to pyrocatechols.701 Formation constants have been measured for the ternary complexes Zn11 dopamine alanine/pyrocatechol702 and Zn11 l-DOPA L (L = penicillamine, L-alanine, glycine, 2,2 -bipyridine, citric add, tartaric acid or sulfosalicylic add). 3... 

Readily accessible, using L-penicillamine as starting material... 

Cellulose was the first sorbent for which the resolution of racemic amino acids was demonstrated [23]. From this beginning, derivatives such as microcrystalline triacetylcellulose and /3-cyclodextrin bonded to silica were developed. The most popular sorbent for the control of optical purity is a reversed-phase silica gel impregnated with a chiral selector (a proline derivative) and copper (II) ions. Separations are possible if the analytes of interest form chelate complexes with the copper ions such as D,L-Dopa and D.L-penicillamine [24], Silica gel has also been impregnated with (-) brucine for resolving enantiomeric mixtures of amino acids [25] and a number of amino alcohol adrenergic blockers were resolved with another chiral selector [26]. A worthwhile review on enantiomer separations by TLC has been published [27],... 

Bekannter als die Toxizitat des L-Penicillamin ist jedoch wegen der nun schon fast fiinfzig Jahre zuriickliegenden und wohl groGten Arz-... 

C,H 02 112-05-0) see Azelaic acid l>-penicillamine Hf1 complex (C,H, CI2HgN02S 14062-65-8) sec D-Penicillamine l>-penicillamine hydrochloride (C5H,2CIN02S 2219-30-9) see D-Penicillamine DL-penicillamine hydrochloride (C,HI2C1N02S 22572-05-0) see D-Penicillaminc penicillin G... 

Chan, C.-Y., Baker, A.L. Penicillamine hypersensitivity successful desensitization of a patient with severe hepatic Wilson s disease. Amer. J. Gastroenterol. 1994 89 442-443... 

Penicillamine, both L-penicillamine and the racemic mixture, strongly inhibit pyridoxal-dependent enzymes, cause pyridoxine deficiency in animal experiments, and are neurotoxic. Although this effect is much weaker with D-penicillamine, a few case reports have shown that D-penicillamine can also occasionally cause a polyneuropathy, as either a toxic or an allergic reaction (69-72). Rarely, an optic neuropathy (73) or a polyradiculoneuropathy (Guillain-Barre syndrome) (74,75) can occur. 

L-penicillamine strongly inhibits pyridoxal-dependent enzymes and causes pyridoxine deficiency in animals. Although D-penicillamine is much less active in this respect, there is some reduction in pyridoxine, and in a report of penicillamine-associated polyneuropathy, pyridoxine supplements for patients receiving D-penicillamine were advised (69). 

Almirall J, Alcorta I, Botey A, Revert L. Penicillamine-induced rapidly progressive glomerulonephritis in a patient with rheumatoid arthritis. Am J Nephrol 1993 13(4) 286-8. 

There is no known useful treatment for methylmercury poisoning. A variety of chelating agents, such as D-penicillamine, l-acetyl-D,L-penicillamine, thiol resins, activated charcoal, BAL (British Antilewisite 2,3-dimercaptopropanol), and meso-2,3-dime-rcaptosuccinic acid, have been used to treat methyl-mercury exposure but with limited to no success. 

DMSA] or - acetyl-D,L-penicillamine [NAP]) and lowering of urinary mercury levels did not result in improvement in depression, anxiety, phobias, psychotic-like behavior, interpersonal sensitivity, and hostility observed in another group of workers exposed to high concentrations of mercury vapor for up to 16 hours (Bluhm et al. 1992a). 

---