Xenobiotic conjugates synthesis

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. 

Except in the case of N-acetyl-cysteine, the chemical problems encountered In synthesis of the conjugates summarized under this heading are similar due to the amphoteric character of the nucleophiles. In general Che reactions with thiol compounds must be carried out In an inert atmosphere in order to minimize oxidation. The starting material, for synthesis of some of Che xenobiotic conjugates below, require multistep syntheses, but the procedures for their preparations will not be discussed here. 

Some metabolic conjugative processes result in the production of lipophilic derivatives that are not readily eliminated. While their physical properties are different from the classical hydrophilic conjugates, the mechanism of formation clearly defines them as conjugates (i.e., they are formed as the result of a union of xenobiotic metabolites with endogenous molecules). The reactions involve the coupling of xenobiotic acids and alcohols with endogenous intermediates of lipid synthesis (i. e., the acids with glycerol and cholesterol and the alcohols with the fatty acids). 

Modulation of liver and kidney function. Nutrients and xenobiotics (such as secondary metabolites) are transported to the liver after resorption in the intestine. In the liver, the metabolism of carbohydrates, amino acids, and lipids takes place with the subsequent synthesis of proteins and glycogen. The liver is also the main site for detoxification of xenobiotics. Lipophilic compounds, which are easily resorbed from the diet, are often hydroxylated and then conjugated with a polar, hydrophilic molecule, such as glucuronic acid, sulfate, or amino acids (312). These conjugates, which are more water soluble, are exported via the blood to the kidney, where they are transported into the urine for elimination. 

Botran was one of the first xenobiotics reported to be metabolized to an N-malonyl conjugate by this mechanism In plant tissues (120) (Equation 28). The N-malonyl conjugate of botran was the major metabolite In both soybean and soybean callus culture. It was Isolated by chromatographic methods and Identified by synthesis and by chemical and mass spectral methods. 

Chemical synthesis of glucuronic acid conjugates of poly-functlonal xenobiotics may yield undesirable side products enzymatic methods may be preferable for glucuronic acid... 

Even though the number of glycoside conjugates of xenobiotics that have been synthesized so far Is limited, the methods described here are convenient both for large and small scale operations. No specific restrictions In synthesis of Isotopically labeled conjugates should be encountered due to the synthetic methods. 

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