Penicillamine derivatives

Ring Opening of Serine (3-Lactone with Penicillamine Derivatives... 

No structure determinations on simple bis(thiolato)gold(I) complexes have yet been reported, but they are assumed to have linear stereochemistry as in [Au(S203)2]3 and in the complex D-penicillamine derivative Na[Au2Ni2(pen)4], of structure (21)., 269 270... 

Buccastem" prochlorperazine, bucillamine [inn, jan] (de oi9 sa 96) is a mercaptocysteine derivative, a penicillamine derivative. It is a CHELATING AGENT that can be used as an ANTIINFLAMMATORY in antirheumatic therapy. 

Subsequently, two pathways may be entered, one leading to perthiyl (plus thio-late), while the other results in thiyl radicals (plus perthiolate). An example shedding light on the strong influence of structural parameters on the relative yields of these two options has been described by Everett et alJ who report reaction 31a to dominate for penicillamine derivative (> 95%), as opposed to an only =20% yield of this process in the reduction of cysteine trisulfide. A similarly striking difference between these two trisulfides was found with respect to the OH-induced formation of perthiyl radicals (63% for R=Pen and 10% for R=Cys). 

Not long after List published his three-component methodology, the group of Barbas reported a fairly similar procedure [3]. Besides L-proUne (1), a penicillamine derivative appeared to effectively catalyze the reaction. Later on, various ketone donors 7b, 7e-g were successfully subjected to the preformed iV-PMP-protected a-imino ethyl glyoxylate 10a as imine acceptor, thereby yielding y-oxo-a-amino acid derivatives lla-d as the products (Scheme 5.4). Analogous to the results of List, the reactions proceeded smoothly resulting in Mannich products with excellent yn-selectivity in complete enantiomerically pure form [4],... 

Ionizing radiation has been applied successfully to generate thiyl radicals in crystalline cysteine [26, 32-34, 36,42] and penicillamine derivatives [35]. Thiyl radicals in these systems are probably produced through direct ionization of the parent thiols followed by S-deprotonation of the initially formed radical cation ... 

Other catalysts besides proline have also been investigated. A particularly large amount of data has been collected for the aldol reaction of acetone tvith p-nitrobenzaldehyde (Scheme 4.32). Simple primary a-amino acids and acyclic N-methylated a-amino acids are not catalytically active under standard reaction conditions. Of the simple cyclic amino acids studied, azeti-dine, pyrrolidine, and piperidine 2-carboxylate, proline is clearly the best catalyst, a-, a -, and, in particular, N-methylation reduce the efficiency and vhereas substitution of the 3- and 4-positions are tolerated vithout dramatic effects. Proline amide is essentially catalytically inactive under the standard reaction conditions (DMSO, room temperature, 2 h) but after three days, the aldol could be isolated in good yields, albeit vith very low enantiose-lectivity. Clearly, the carboxylic acid plays an important role in the catalysis and in determining enantioselectivity. That the enantioselectivity can be improved vas sho vn vith penicillamine derivative 168, proline derived diamine salt 169, and amide 170 [129-132]. 

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. 

Acquired disease of muscle is more common than is generally appreciated. It may result from the use of drugs—prescription or nonprescription—that have a recognized capacity to compromise the structure or function of skeletal muscle. Drugs particularly well recognized as myotoxic include clofibrate and its derivatives, anabolic steroids, penicillamine, and emetine. Many nonprescription drugs, including alcohol and laxatives, are directly or indirectly myotoxic. Other forms of acquired myopathies include the acute myopathic conditions caused by the bites of many snakes. 

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. 

The 1H NMR spectrum of (DL)-penicillamine in D20 was obtained on a Bruker 500 MHz instrument, and the resulting spectrum is shown in Fig. 3. Confirmation of the spectral assignments was derived from a COSY experiment (see Fig. 4), and these assignments are summarized in Table 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]. 

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. 

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%. 

Reaction between D-Cys and an oxazoline aldehyde, prepared from l-Phe gave the bicyclic compound 83 [92H(34)903], A derivative of the same system was obtained from penicillamine with a functionalized AA (88CC1128). 

The use of Trt-protected 3-iodoalanines for lanthionine synthesis is also a highly promising method for the synthesis of 3-methyl- and 3,3-dimethyllanthionines. 40 This method is based on the use of A-trityl-3-iodoalanine benzyl ester (54) and the symmetrically protected bis(Boc)-cystine-derivative dimethyl esters derived from L-t/treo-3-methylcysteine and d-penicillamine. Yields of the respective lanthionine derivatives are >80% however, enantiomeric excesses have not been determined for the 3-substituted lanthionines (Scheme 18). 

Penicillamine (Figure 57-3) is a white crystalline, water-soluble derivative of penicillin. D-Penicillamine is less toxic than the l isomer and consequently is the preferred therapeutic form. Penicillamine is readily absorbed from the gut and is resistant to metabolic degradation. 

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