Conjugation reactions with amino acids

Many nonsteroidal anti-inflammatory drugs (NSAIDs) are substituted 2-arylpropionic acids. Most NSAIDs also have a chiral carbon next to the carboxylate and are administered as a racemic mixture of the two enantiomers. In general, the (S)-enantiomcr is responsible for most of the antiinflammatory activity of these agents. It was found that the (/ -enantiomer is converted to the (S)-enantiomer but the reverse does not occur (23). As with amino acid conjugation, the pathway involves reaction with ATP to form an AMP ester, which is, in turn, converted to a Co-A ester, and it is the Co-A ester that undergoes chiral inversion (Fig. 7.14). Substrates include ibuprofen, naproxen, and fenoprofen. 

The H-site is formed of clusters ofnon-polar amino acid side chains which provide a highly hydrophobic surface, which, in the absence of a drug substrate is open to bulk solvent Binding of substrates to this site has been shown to relate to increased lipophilicity for substrates (4-hydroxyalkenes). The actual conjugation reaction, with the thiolate anion acting as a nucleophile proceeds via an SN2-type mechanism yielding the deactivated product... 

Generally amino acid conjugation is a detoxication reaction. However, amino acid conjugation with hydroxylamino groups (N-hydroxy) can lead to the formation of reactive nitrenium ions, as already discussed with sulfate conjugation and acetylation. For example, the conjugation of serine with N-hydroxy-4-aminoquinoline-l-oxide (Fig. 4.40 for structure) leads to such a reactive nitrenium ion. This requires the enzyme serine-tRNA synthetase. 

Carboxylic acids (8.54) are frequently conjugated with amino acids, especially glycine (Scheme 8.18). The carboxylic acid is first activated as a mixed anhydride (8.55). Reaction of the anhydride with the thiol of coenzyme A forms an intermediate (8.56) that reacts with the amine of an amino acid. The new conjugate (8.57) has increased water solubility to improve elimination. 

The reactions commonly involved in Phase II conjugation are acylation, sulphate formation and conjugation with amino acids, glucuronic acid, glutathione and mercapturic acid (Table 9.3). Methylation is also regarded as a Phase II reaction although it is normally a minor metabolic route. However, it can be a major route for phenolic hydroxy groups. In all cases, the reaction is usually catalysed by a specific transferase. 

Phase II This phase consists of conjugation reactions. If the metabolite from Phase I metabolism is sufficiently polar, it can be excreted by the kidneys. However, many metabolites are too lipophilic to be retained in the kidney tubules. A subsequent conjugation reaction with an endogenous substrate, such as glucuronic acid, sulfuric acid, acetic acid or an amino acid results in polar, usually more water-soluble compounds that are most often therapeutically inactive. Glucuronidation is the most common and the most important conjugation reaction. Neonates are deficient in... 

The conjugation of carboxylic acid xenobiotics with amino acids occurs in both liver and kidney and is catalyzed by an enzyme system located in the mitochondria. Conjugation requires initial activation of the xenobiotic to a Co A derivative in a reaction catalyzed by acyl CoA ligase. The acyl CoA subsequently reacts with an amino acid, giving rise to acylated amino acid conjugate and CoA. 

In combinatorial chemistry, the development of multicomponent reactions leading to product formation is an attractive strategy because relatively complex molecules can be assembled with fewer steps and in shorter periods. For example, the Ugi multicomponent reaction involving the combination of an isocyanide, an aldehyde, an amine, and a carboxylic acid results in the synthesis of a-acyl amino amide derivatives [32]. The scope of this reaction has been explored in solid-phase synthesis and it allows the generation of a large number of compounds with relative ease. This reaction has been employed in the synthesis of a library of C-glycoside conjugated amino amides [33]. Scheme 14.14 shows that, on reaction with carboxylic acids 38, isocyanides 39, and Rink amide resin derivatized with different amino acids 40, the C-fucose aldehyde 37 results in the library synthesis of C-linked fucosyl amino acids 41 as potential mimics of sialyl Lewis. ... 

Figure 32 Generalized amino acid conjugation reaction using benzoic acid as substrate. The amino acid conjugation of 2,4-dichlorphenoazcetic acid (2,4-D) and lovastatin with glycine and taurine, respectively.

The synthesis of model compounds to verify the structures of xenobiotic amino acid adducts (products of nonenzymatic reactions of electrophilic xenobiotics with amino acids In proteins) are Included. Methods for synthesis of some rarely observed conjugate types will be briefly Introduced. The major organic methods for synthesis are exemplified and xenobiotic conjugates prepared via these reactions are tabulated with references to the original publications. 

As noted, extensive studies of the effect of site-directed mutagenesis on proton-transfer have been carried out with Rb. sphaeroides reaction centers The most likely candidates for proton relay, the conjugate bases of the amino acids, Asp-213. Ser-223 and Glu-212. have been investigated by replacing them one at a time with amino acids which either can or cannot be protonated under physiological condition. The results of their studies on the effects of mutation as monitored by cytochrome turnover are summarized in Fig. 7. 

Very recently, TcO(N2SCl)-core complexes were obtained by reaction of [TcOCUj with derivatized amino acids in CH2Cl2/EtOH. The tridentate I S ligands (H2L) were synthesized by conjugating N-protected amino acids with S-mcthyl-2-methyldithiocar-bazate. The purple compounds [Tc 0(L)Cl]° arc stable and possess a square pyrami-... 

Upon the discovery of the allenic Alder-ene reaction, Brummond and coworkers have expanded this synthetic protocol to biologically relevant substrates. Allenynes 86 with amino acids as part of the tether were subjected to the Alder-ene reaction and afforded cross-conjugated trienes 87 in high yields. The Alder-ene reaction of these AT-alkynyl allenic amino acids was substantially faster (<10 min) than the previous substrate series. The authors attributed this rate... 

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