Synthesis of Glucuronic Acid - Sponsored Whitepaper

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Analysis of drugs and metabolites is accomplished via the use of labeled internal standards. However, stable isotope labeling of parent drugs can be synthetically challenging. Since glucuronides are primary metabolites of many drugs, one alternative would be the incorporation of the stable isotope into the glucuronic acid moiety.To this end, a 13C -glucuronic acid sugar donor was synthesized and 6 used in the synthesis of ethynylestradiol and AZT 13C -glucuronides. 6

• Monitoring and quantitation of drugs and their metabolites in serum, plasma and urine represents an important facet of clinical and pharmacological laboratory work. Therapeutic monitoring of drugs can play an important role in clinical treatment decisions. For drug development and PKDM, identification and quantitation of drug metabolites are key to understanding the distribution, half life and toxicity of new drugs. • Since many drugs are metabolized in vivo, detection of the metabolites is often the primary means of drug quantitation. A common metabolic product is the conjugation of glucuronic acid to the parent drug. • In the analysis and quantitation of drugs and their metabolites, the use of stable isotopically labeled versions of these compounds as internal standards for GC/MS and LC/MS applications is desirable. • Traditionally, labeled glucuronides are made by first synthesizing the labeled parent drug followed by glycosylation. • Labeling of the parent drug can be synthetically challenging. Suitable labeled reagents may not be available or costly. The structure of the drug may not be suitable for introduction of a stable label. A viable alternative would be to incorporate the label into the glucuronic acid moiety. • A 13C -glucuronic acid sugar donor was synthesized and used to 6 make two metabolites, ethynylestradiol-3-glucuronide-13C and AZT- 6 glucuronide-13C . 6

OH O O O O O Labeled versions of the O aglycones are readily HO OH O available, e.g.ethyl-d5 HO OH OH N glucuronide and OH morphine-3-glucuronide HO Ethyl glucuronide Morphine-3-glucuronide

H NH Labeled versions of OH the aglycones are OH H H N O not available; good O O O O O O candidates for O labeling of the HO OH HO glucuronic acid OH OH N3 OH Ethynylestradiol glucuronide AZT glucuronide

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