Cysteine anhydrides

Poly-L-cysteine (XXXIV) was prepared by polymerization of S-carbobenzoxy-N-carboxy-L-cysteine anhydride (XXXIII), followed by reduction with sodium in liquid ammonia 47). The reactivity of the thiol groups in this polymer toward iodoacetic add indicated that quantitative liberation of mercapto groups had beat effected but selective reactivity was observed with methyl mercuric nitrate in the presence of sodium nitroprusside, an internal indicator. These reactivity differences result from sterk exclusion of the nitroprusside dye from about one third of the available mercaptan moities. Thus the concept of sluggish-SH groups in a protein has been demonstrated with a synthetic homopolymer. 

Acetic anhydride Acetaminophen Acetazolamide Acetrizoate sodium Acetyl cysteine Acetyl sulfisoxazole Afloqualone... 

Protein functional groups able to react with anhydrides include the oc-amines at the N-terminals, the s-amine of lysine side chains, cysteine sulfhydryl groups, the phenolate ion of tyrosine residues, and the imidazolyl ring of histidines. However, acylation of cysteine, tyrosine, and histidine side chains forms unstable complexes that are easily reversible to regenerate the original group. Only amine functionalities of proteins are stable to acylation with anhydride reagents (Fraenkel-Conrat, 1959 Smyth, 1967). 

Maleic acid imides (maleimides) are derivatives of the reaction of maleic anhydride and ammonia or primary amine compounds. The double bond of a maleimide may undergo an alkylation reaction with a sulfhydryl group to form a stable thioether bond (Chapter 2, Section 2.2). Maleic anhydride may presumably undergo the same reaction with cysteine residues and other sulfhydryl compounds. 

Dimethyl-3,5-dimethyl-l//,3//-pyrrolo[l,2-r ][l,3]thiazole-6,7-dicarboxylate 399 (R = H) was prepared from cysteine 396 using the method developed of Padwa et al. <1989JOC644>. The thiazolidine carboxylic acid 397 (R = H), obtained by reaction of the cysteine with formaldehyde, was heated in the presence of acetic anhydride and DMAD to give the sulfide 399 by dipolar cycloaddition of the acetylene to the intermediate dipole 398 (Scheme 59) <2002J(P1)1795>. 

Acyl residues are usually activated by transfer to coenzyme A (2). In coenzyme A (see p. 12), pantetheine is linked to 3 -phos-pho-ADP by a phosphoric acid anhydride bond. Pantetheine consists of three components connected by amide bonds—pantoic acid, alanine, and cysteamine. The latter two components are biogenic amines formed by the decarboxylation of aspartate and cysteine, respectively. The compound formed from pantoic acid and p-alanine (pantothenic acid) has vitamin-like characteristics for humans (see p. 368). Reactions between the thiol group of the cysteamine residue and carboxylic acids give rise to thioesters, such as acetyl CoA. This reaction is strongly endergonic, and it is therefore coupled to exergonic processes. Thioesters represent the activated form of carboxylic adds, because acyl residues of this type have a high chemical potential and are easily transferred to other molecules. This property is often exploited in metabolism. 

Acetylcysteine Acetylcysteine, A-acetyl-L-cysteine (23.2.4), is synthesized by reacting L-cysteine hydrochloride with acetic anhydride in the presence of sodium acetate [11-13],... 

Perhaps more significantly they were also able to isolate a polar, water-soluble compound that they believed was 55 in which the cysteine residue had been incorporated into the artemisinin backbone. The broadness of the signals in the proton NMR spectrum made characterization problematic, but treatment of 55 with acetic anhydride afforded 56, which was fully characterized (Scheme 16A). More recently, the same group has isolated and characterized another product from artemether. Adduct 57 was derived from the C4 secondary radical and cysteine (Scheme 16B). 

Ascorbate, cysteine, hydroquinone, and NADH are capable of acting as re-ductants for NOMb formation in model systems containing sodium nitrite and Mb (Fox and Ackerman, 1968). Ascorbate, cysteine, and hydroquinone all form nitroso-reductant intermediates which released NO, forming a NO-MMb complex which was then reduced to NOMb. Release of NO from the reductant-NO complex was rate limiting in production of NOMb. For NADH as reductant, reduction of NOMMb to NOMb was the rate limiting step. In summary, two reduction steps were required, the reduction of nitrite (as nitrous acid or its anhydride, N2O3) to NO, and reduction of NOMMb to NOMb. 

Mixed anhydride 6b is a sulfonylating rather than a phos-phorylating agent. Thus, hydrolysis with 0 gives acid 6c and propylsulfonic acid in which the - -°0 isotope is incorporated only in the sulfonic acid (Eq. 2). Compound 6b reacts with either alcohols (methanol, ethanol, sec-butanol) or L-cysteine to yield acid 6c and with triethylamine to give the anion of 6c. probably via propylsulfene (4) (Eq. 2). 

As a synthetic application to biologically active compounds, eq. 8.19a shows the preparation of nucleoside antibiotics (44a) and (44b). Tyromycin (45) inhibits the leucine and cysteine aminopeptidases, and it can be prepared in good yield from the photolytic treatment of the Af-acyloxy diester with citraconic anhydride, followed by silica gel treatment, as shown in eq. 8.19b [55-60]. Other synthetic applications using intra- and intermolecular tandem reactions were also studied [61, 62]. 

Heating N- acetyl-5- (a-ketoalkyl)cysteine (308) for a brief period with acetic anhydride gives dihydro-2-methylthieno[3,4-d]oxazole-3a(4//)-carboxylic acids (310) (79JOC825). While the mechanism has not been investigated in detail, the isolation of several compounds suggests the existence of the intermediate spiro compound (309). Rearrangement to (310) is feasible since the anhydride character of (309) is changed to the ester character of (310). 

Succinic anhydride reacts with free amino groups, the phenolic and thiol groups of tyrosine and cysteine. The latter esters spontaneously hydrolyze in aqueous solution (39). The e-amino group of lysine reacts most readily. Succinylation has three major effects on the physical character of proteins it increases net negative charge, changes conformation and increases the propensity of proteins to dissociate into subunits (39,40,41,42). 

L-Ethyl cysteinate and Na2C03 were dissolved in a minimum amount of water and acetic anhydride (1.05 eq) and formic acid (1.2 eq) added. The pH of the solution was kept basic by the addition of solid Na2C03 and the mixture stirred 60 minutes. The solids were removed and the mixture extracted 3 times with chloroform. The organic phase was neutralized with 6M HCl, concentrated, the residue suspended in benzene containing a catalytic amount of paratoluenesulfonic acid and refluxed over night with a Dean-Stark trap. Thereafter the organic phase was evaporated, dissolved in chloroform, washed with NaHC03, and the product isolated. 

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