Aliphatic acids, conjugation

The potential of benzoylformate decarboxylase (BFD, E.C. 4.1.1.7) to catalyze C-C bond formation was first reported by Wilcocks at al. using crude extracts of Pseudomonas putidsL [50]. They observed the formation of (S)-2-hydroxy-l-phenylpro-panone (S)-2-HPP when benzoyl formate was decarboxylated in the presence of acetaldehyde. Advantageously, aldehydes - without a previous decarboxylation step - can be used instead of the corresponding more expensive a-keto acids [51]. We could show that BFD is able to bind a broad range of different aromatic, heteroaromatic, and even cyclic aliphatic and conjugated olefinic aldehydes to ThDP before ligation to acetaldehyde or other aldehydes (Table 2.2.7.3) [52]. 

In sheep orally dosed with 40 mg/kg bw radiolabeled thiophanate, only the parent drug and its major metabolite lobendazole could be detected in plasma for 65 h after dosing. In sheep liver, thiophanate was metabolized to lobendazole at a rate of approximately 34%. Other metabolites included 2-aminobenzimidaz-ole, low molecular-weight aliphatic acids, and limited amounts of the glucuronide and sulfate conjugates. 

Other aromatic and aliphatic acid chlorides give good to excellent yields of the desired ketones using this procedure. Hindered or a. -unsaturated acid chlorides also function effectively, the latter forms a, -unsaturated ketones without competing conjugate addition (equations 75 and 76). 

This presentation is realized through the study of glucuronic acid conjugation of aliphatic alcohols (12), previously studied by Hansch et al. (13). In this population, the environment contains no heteroatoms, thus clearly showing the influence of topology when... 

Table 5.1. Glucuronic acid conjugation capacity ot aliphatic alcohols in the rabbit...

Aliphatic Chain oxidation glucuronic acid conjugation sulphate conjugation (to a lesser extent)... 

Many xenobiotic carboxylic acids undergo conjugation with one of a variety of amino acids. In which the carboxyl group of the xenobiotic Is linked In an amide (peptide) bound with the alpha-amino group of the amino acid (78). The chemical classes of acid Involved In amino acid conjugation are relatively few In number, and the reactions are restricted to certain aliphatic, aromatic, heteroaromatic, cinnamic and arylacetlc acids (28). The occurrence of the reaction Is markedly dependent on the steric hindrance around the carboxyl group by substituents on the aryl moiety or the side chain bearing the acid function (79). 

Novel Biotransformation Pathways - The recent literature contains examples of some of the newly discovered pathways in addition to those covered in the excellent review by Jenner and Testa.Formation of an aliphatic 0-methyl metabolite (26) of the antiinflammatory agent cicloprofen (27) in the rat, has been demonstrated,and it was proposed that it formed via 0-raethylation of a dihydroxy intermediate (28). Thiomethyl metabolites of phenacetin and acetaminophen have been found in dogs and man. An S-methyl metabolite (29) of bromazepam (50), a minor tranquilizer, in the rat was shown to be formed vitro by biotransformation of a mecapturic acid conjugate (31). 

Use more flexible aliphatic acids with aromatic bases. Move to more highly substituted acids that destroy crystal symmetry. DECREASE Increase solubility Form oil Melting Point-e- INCREASE Process problems Reduce solubility Use small counter-ions, e.g., Cl", Br". Use aromatic conjugate anions if aromatic base. Use small hydroxy acids if drug has good hydrogen bonding potential. 

The methods just outlined permit the characterization of organic acids in blood and urine, with the exception of volatile acids (which are totally or partly lost during the concentration of the eluate obtained from the ion exchange column) and of unstable acids, like most a-keto acids, which are also totally or partly lost. They are especially useful for the study of non-a-keto aliphatic acids and of aromatic acids conjugated with glycine or glutamine. 

Acid chlorides show a very strong band for the C=0 group that appears in the range of 1810-1775 cm for aliphatic acid chlorides. Acid chloride and anhydrides are the most common functional groups that have a C=0 appearing at such a high frequency. Conjugation lowers the frequency. 

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