Penicillaminic acid

Chain and I then began a collaboration with Sir Robert Robinson and Dr. Wilson Baker, who were later joined by John Cornforth and others in the Dyson Perrins Laboratory. One of the first questions asked by Robinson was whether sulfur was present in the molecule, and we told him of the analytical report. However, after Dorothy Hodgkin had determined the molecular weight of crystalline penicillaminic acid, she pointed out that it would not be possible to write a structure for this compound if it contained only C, H, O, and N. The presence of sulfur... 

In order to demonstrate that 5-(a-aminoadipyl)-cysteinylvaline is the penicillin precursor, cell-free biosynthetic systems had to be employed as the tripeptide is not taken up by intact cells. Fawcett et al. 244,250) were the first to prepare such a cell-free system using enzymic digestion of the cell wall of C. acremonium in an isotonic medium to give protoplasts, which were then lysed by dilution. Again, an energy-generating system was added. A variety of labelled peptides were synthesised and added to the cell-free system. After incubation for 2 hours each reaction was divided into two. One half was oxidised so that any penicillin formed would be converted to penicillaminic acid (266) which was detected by two dimensional paper... 

P. E. Smith and B. M. Pettitt. Amino acid side-chain populations in aqueous and saline solution Bis(penicillamine) enkephalin. Biopolymers, 32 1623-1629,... 

The amino acids L-leucine, T-phenylalanine, L-tyrosine, and L-tryptophan all taste bitter, whereas their D-enantiomers taste sweet (5) (see Amino ACIDS). D-Penicillamine [52-67-5] a chelating agent used to remove heavy metals from the body, is a relatively nontoxic dmg effective in the treatment of rheumatoid arthritis, but T.-penicillamine [1113-41 -3] produces optic atrophy and subsequent blindness (6). T.-Penicillamine is roughly eight times more mutagenic than its enantiomer. Such enantioselective mutagenicity is likely due to differences in renal metaboHsm (7). (R)-ThaHdomide (3) is a sedative—hypnotic (3)-thaHdomide (4) is a teratogen (8). 

The following trivial names have been assigned to the penicillin transformation products shown (6), benzylpenicilloate (7), benzylpenaldic acid (8), D-penicillamine (9), a-methyl D-a-benzylpenicilloate (10), benzylpenillic acid (11), benzylpenillamine (12), benzyl-isopenillic acid (13), benzylpenilloic acid (14), benzylpenilloaldehyde (15), benzylpenicil-lenic acid (16) benzylpenillonic acid methyl ester and (17), dethiobenzylpenicillin methyl ester. 

Certain amino acids and their derivatives, although not found in proteins, nonetheless are biochemically important. A few of the more notable examples are shown in Figure 4.5. y-Aminobutyric acid, or GABA, is produced by the decarboxylation of glutamic acid and is a potent neurotransmitter. Histamine, which is synthesized by decarboxylation of histidine, and serotonin, which is derived from tryptophan, similarly function as neurotransmitters and regulators. /3-Alanine is found in nature in the peptides carnosine and anserine and is a component of pantothenic acid (a vitamin), which is a part of coenzyme A. Epinephrine (also known as adrenaline), derived from tyrosine, is an important hormone. Penicillamine is a constituent of the penicillin antibiotics. Ornithine, betaine, homocysteine, and homoserine are important metabolic intermediates. Citrulline is the immediate precursor of arginine. 

Penicilloic acid 5, the substrate for the projected lactamization reaction, could be derived from the suitably protected intermediate 6. Retrosynthetic disassembly of 6, in the manner illustrated, provides D-penicillamine hydrochloride (7) and tert-butyl phthalimido-malonaldehydate (8) as potential building blocks. In the synthetic direction, it is conceivable that the thiol and amino groupings in 7 could be induced to converge upon the electrophilic aldehyde carbonyl in 8 to give thiazolidine 6 after loss of a molecule of water. 

The absorption of oral iron is decreased when tlie agent is administered with antacids, tetracyclines, penicillamine, and the fluoroquinolones. When iron is administered with levothyroxine, there may be a decrease in tlie effectiveness of levothyroxine When administered orally, iron deceases the absoqition of lev-odopa. Ascorbic acid increases tlie absoqition of oral iron. Iron dextran administered concurrently with chloramphenicol increases serum iron levels. 

Systemic muscle damage, often associated with pain and discomfort, is a well known problem associated with specific drugs such as epsilon amino caproic acid (EACA), clofibrate, emetine, vincristine, chloroquine, D-penicillamine, and anabolic steroids. Notes on each of these drugs follow, but for a detailed discussion of drug-induced muscle damage refer to Argov and Mastaglia (1988) and Harris and Blain (1990). 

CHN 74-90-8) see L-Alanine Alfentanil Dimethadione Edetic acid Ibuprofen Indanorex Mecamylamine Molsidomine Nadoxolol D-Penicillamine Phensuximide L-Tryptophan Vetrabutine hydrogen peroxide... 

CiiHuOn 112-05-0) see Azelaic acid D-penicillamine Hg complex (CjH Cl2HgN02S 14062-65-8) see D-Penicillamine D-penicillamine hydrochloride (C5H12CINO2S 2219-30-9) see D-Penicillamine DL-penicillamine hydrochloride (CjH,2C1N02S 22572-05-0) see D-Penicillamine penicillin G... 

A substantial number of bioactive molecules, such as polypeptides, N-acetyl-DL-penicillamine, p-(dipropylsulfamoyl)benzoic acid, and nicotinic acid, contain a carboxylic acid function, and this provides a site for linkage to a polyphosphazene chain. A number of prototype polymers have been synthesized in which pendent amino groups provide coupling sites for the carboxylic acid (34). The amide linkages so formed are potentially bioerodible, but the use of a hydrolytic sensitizing cosubstituent would be expected to accelerate the process. 

Atenolol, hydralazine, procainamide, quinidine, carbamazepine, chlorpromazine, ethosuximide, isoniazid, methyldopa, minocycline, penicillamine, phenylbutazone, phenytoin, thiazides, and valproic acid... 

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 ... 

The titration curve of penicillamine hydrochloride at 25 °C revealed the presence of three ionizable groups with pKa values of 1.8 (carboxyl group), 7.9 (oc-amino group), and 10.5 (/J-thiol group). Recently, the ionization constants for the acidic functions of (D)-penicillamine were verified by pH titration at 37 °C and 0.15 M ionic strength [2], A 1% solution in water has a pH of 4.5-5.5 [3],... 

Penicillamine reacts with pyridoxal-5-phosphate to form a thiazolidine derivative, and is able to displace many amino acids from their Schiff base complexes, forming stable compounds of this type. The reactivity of the thiol group of penicillamine is less than that of cysteine, probably because of steric hindrance by the adjacent methyl groups of penicillamine, which in consequence is less rapidly oxidized in vivo [7]. 

Examine the sample by thin-layer chromatography, using silica gel G R as the coating substance. Dissolve 10 mg of the substance to be examined in 4 mL of water R as a test solution, and dissolve 10 mg of penicillamine reference substance in 4 mL of water R as a reference solution. Apply 2 pL of each solution separately to the plate. Develop over a path of 10 cm using a mixture of 18 volumes of glacial acetic acid R, 18 volumes of water R, and 72 volumes of butanol R. Dry the plate at 100-105 °C for 5-10 min, and expose to iodine vapor for 5-10 min. The principal spot in the chromatogram obtained with the test solution is similar in position, color, and size to the principal spot in the chromatogram obtained with the reference. 

The British Pharmacopoeia [2] describes a potentiometric titration method for the determination of penicillamine as the pure drug substance. The method is performed by dissolving 100 mg of the substance in 30 mL of anhydrous acetic acid. The mixture is titrated with 0.1 M perchloric acid, and the endpoint determined potentiometrically. Each milliliter of 0.1 M perchloric acid is equivalent to 14.92 mg of C6HnN02S. 

Rizk et al. [3] used 2,3-dichloro-5,6-dcyano-/)-benzoquinone as a redox titrant in the aqueous titration of penicillamine. Finely ground tablets were mixed with H20 and the mixture was filtered. The filtrate (or an injectable solution) was diluted with H20 and acidified with H3PO4 before titration with the redox titrant. The titration was conducted in anhydrous acetic acid using thiethylperazine dihydrochloride as the indicator. The endpoint was detected by a color change to green, and recoveries of penicillamine were 98.4-100.5%. 

Fakhr Eldin et al. [22] described a simple sequential spectrophotometric method for the assay of penicillamine. The method is based on the complex formed when the drug is reacted with Fe(III) solution in hydrochloric acid media. The deep blue colored drug Fe(III) complex is monitored at a maximum wavelength of 600 nm. 

Al-Ghannam et al. [25] described a simple fluorimetric procedure for determination of three pharmaceutical compounds containing thiol groups, including penicillamine. In this method, the drugs are treated with 1,2-naphthoquinone-4-sulfonic acid. The later compound is reduced to l,2-dihydroxynaphthalene-4-sulfonic acid, which is measured fluorimetrically (excitation = 318 nm, emission = 480 nm). The method is sensitive to 0.5 1.5 pg/mL, with a detection limit of 0.05 pg/mL (S/N = 2). 

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. 

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. 

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