Thiols, nucleophiles

The only available evidence to support this is the fate of intermediates generated from the reaction of A-acyloxy-A-alkoxyamides with cysteine derivatives in methanol described in Section IV.C.3.b. The nucleophilic thiol reacts preferentially at the sulfur atom rather than at nitrogen, generating the hydroxamic ester and the disulfide (Scheme 24). 

The cleavage mechanism of the caspases is shown schematically in Fig. 15.5. They use a typical protease mechanism with a catalytic diad for cleavage of the peptide bond. The nucleophilic thiol of an essential Cys residue forms a covalent thioacyl bond to the substrate during the catalysis. The imidazole ring of an essential histidine is also involved in catalysis and this facilitates hydrolysis of the amide bond in the sense of an acid/base catalysis. 

Probably the most important protective mechanisms involve the tripeptide GSH (chap. 4, Fig. 59). This compound is found in most cells, and in liver cells, it occurs at a relatively high concentration, about 5 mM or more. There are three pools of GSH cytosolic, mitochondrial, and nuclear. GSH structure is unusual for a peptide in the glutamyl, and cysteine residues are not coupled via a peptide bond, hence the molecule is resistance to peptidase attack. It has a nucleophilic thiol group, and it can detoxify substances in one of three ways ... 

Chemiluminescent probes based on the dioxetane moiety are now being developed for the detection of cholinesterase activity <2002JA4874>. In this particular case, the nucleophilic thiol generated from hydrolysis of acetylthiocholine iodide triggers the formation of the thiolate 61 and by-product 62 through nucleophilic attack on the disulfide bond of 60 (Scheme 14). 

Catalyst 3 is proposed to function in a manner similar to the cinchona alkaloid catalysts (1 and 2), with the tertiary amine providing activation for the nucleophilic thiol, which is held in close proximity to the thiourea-bound carbonyl substrate. 

Likewise, perfluorinated radicals react more rapidly with electron-rich aUcenes (X=H) than with electrophilic alkenes (X=F) in some intramolecular processes [124] (Figure 4.52). Similarly, rates of hydrogen abstraction by perfluoroalkyl radicals from a series of aromatic thiols were greatest from the most nucleophilic thiol [125] clearly, taken together, these data show that perfluoroalkyl radicals are highly electrophilic in character, in comparison with alkyl radicals, which are of course more nucleophilic. 

Additional tests such as the addition of nucleophilic scavengers (e.g., thiols such as dithiothreitol or j8-mercaptoethanol) can provide further evidence for the presence of a free, reactive electrophilic species. The scavengers should quench all of the free reactive species, thereby protecting the enzyme from inhibition. Unfortunately, this method cannot exclude the possibility that a nucleophilic thiol may even attack the bound reactive species at the active site of the enzyme (which would also give rise to protection from inactivation). However, the use of a bulky thiol, such as reduced glutathione, should limit that possibility. An alternative scenario occurs wherein the released reactive species returns and reacts faster with an active-site nucleophile than with the added thiol. Clearly this is a complex problem and, consequently,it is advisable to use several different tests to avoid misleading conclusions. 

The formation of 2-ethylthioethanol (23) involves selective nucleophilic attack by the mercapto (SH) moiety while the hydroxy group remains intact, showing that the former is a more powerful nucleophile. Thiols, as their sodio derivatives, will react with alkyl and even with aryl halides in polar aprotic solvents like DMSO and DMF to give good yields of dialkyl and diaryl sulfides (24) and (25) (Scheme 8). 

This stereoselectivity as observed previously in levoglucosenone conjugate addition proceeds by the attack of an incoming nucleophile (thiol) at the alkene face opposite the 1,6-anhydro ring. The sterically hindered 1,6-anhydro bridge in isolevoglucosenone is, therefore assumed to effectively prevent formation of the opposite stereoisomer. 

Similarly, 3-substituted 1,2,4-triazole-5-thiols 349 react with A -chloromethyl carbamoyl chlorides 346 to afford 5,6-dihydro-7-thia-l,3,3a,5-tetraaza-inden-4-ones 351. The N-1 and N-2 positions of r-triazoles are more nucleophilic than the N-4 position. The nucleophilic thiol group of 349 attacks the chloromethyl group of A -chloromethyl carbamoyl chloride 346 in preference to the carbamoyl chloride moiety. After the initial attack, the carbamoyl group reacts with N-1 of the triazole to afford the corresponding 5,6-dihydro-7-thia-l,3,3a,5-tetraaza-inden-4-one 351 (Scheme 71) <2000M953>. 

Amino acid residues, except hydrocarbon chains, may provide nucleophilic sites (electron-rich centers) or electrophilic sites (electron-deficient centers) for chemical modifications. Electron-rich centers include sulfur nucleophiles (thiol of Cys and thioether of Thr), nitrogen nucleophiles (e-amino of Lys, imidazole of His and Guanidyl of Arg), oxygen nucleophiles (phenolic of Tyr, carboxyl of Asp and Glu and hydroxyl of Ser and Thr), and carbon nucleophile (a-position of indole ring of Trp), with an increasing nucleophilicity in that order. They provide nucleophilic sites for alkylation (nncleophilic substitution), acylation, addition and oxidation at pH near or above their pK values. Electron-deficient centers include ammonium cation of Lys, guanidiiun cation of Arg and imidazolium cation of His. They provide electrophilic sites for metalation and reduction at pH near or below their pK values. 

In an analogous fashion, a flavin-type redox cofactor was attached to the nucleophilic thiol group in the active site of papain. By this means, a hydrolase was transformed into the artificial redox enzyme flavopapain [499-504]. 

X- and y-rays Cell cycle effects, modulation of proliferation kinetics Increased activity of repair enzymes Enhanced expression of anti-apoptotic proteins Selection of apoptosis-resistant cells Elevated intracellular levels of glutathione and associated nucleophilic thiols Hall and Giaccia (2006)... 

Like tetrafluoroallene, the tetrakis(trifluoromethyI)allene is attacked by thiols and by chlorine in the dark under autogenous pressure, although chlorination of the branched allene is much more slu sh than that of tetra-fluoroallene and requires a temperature of 140—180 °C. The nucleophilic thiol additions follow the pattern established previously for this allene, so that the sulphur atom bonds to the central carbon atom, e.g. 

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