Glucuronidation is a major phase II biotransformation of (poly)-phenols leading to potentially bioactive metabolites. Due to the limited availability of authentic standards, in this work, we have focused on the glucuronidation of a series of mono- and dihydroxyphenolic acids. Their reactivity with two glucuronidation reagents, 2,3,4-triaceto-1-bromo-α-d-glucuronic acid methyl ester and Schmidt imidate, was investigated. The use of Schmidt imidate led to the successful synthesis of six target glucuronides in moderate to excellent yields. Subsequent deprotection of these compounds afforded the final glucuronides of 2-hydroxyphenylacetic, 3-hydroxyphenylacetic, 4-hydroxyphenylacetic, 3,4-dihydroxyphenylacetic, 3-(4-hydroxyphenyl)-propionic, and 3-(3,4-dihydroxyphenyl)-propionic acid. These compounds, which are plausible polyphenolic metabolites, were fully characterized and used in a pilot metabolic study in rats after administration of a hawthorn berry extract (475 mg/kg). UHPLC-HRMS analysis identified two of the glucuronides, namely 4-hydroxyphenylacetic acid glucuronide and 3-hydroxyphenylacetic acid glucuronide in rat plasma, confirming their in vivo formation.

Faculty of Pharmacy Charles University Akademika Heyrovského 1203 Hradec Králové CZ 50005 Czech Republic

Institute of Microbiology of the Czech Academy of Sciences Vídeňská 1083 Prague CZ 142 00 Czech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo náměstí 542 2 Prague CZ 160 00 Czech Republic

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