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Trans-Resveratrol(tRes) has been shown to havepowerful antioxidant, anti-inflammatory, anticarcinogenic, and antiagingproperties; however, its use as a therapeutic agent is limited byits rapid metabolism into its conjugated forms by UDP-glucuronosyltransferases(UGTs). The aim of the current study was to test the hypothesis thatthe limited bioavailability of tRes can be improved by modifying itsstructure to create analogs which would be glucuronidated at a lowerrate than tRes itself. In this work, three synthetic stilbenoids,(E)-3-(3-hydroxy-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)acrylicacid (NI-12a), (E)-2,4-dimethoxy-6-(4-methoxystyryl)benzaldehydeoxime (NI-ST-05), and (E)-4-(3,5-dimethoxystyryl)-2,6-dinitrophenol(DNR-1), have been designed based on the structure of tRes and synthesizedin our laboratory. UGTs recognize and glucuronidate tRes at each ofthe 3 hydroxyl groups attached to its aromatic rings. Therefore, eachof the above compounds was designed with the majority of the hydroxylgroups blocked by methylation and the addition of other novel functionalgroups as part of a drug optimization program. The activities of recombinanthuman UGTs from the 1A and 2B families were examined for their capacityto metabolize these compounds. Glucuronide formation was identifiedusing HPLC and verified by β-glucuronidase hydrolysis and LC–MS/MSanalysis. NI-12a was glucuronidated at both the −COOH and −OHfunctions, NI-ST-05 formed a novel N–O-glucuronide, and noproduct was observed for DNR-1. NI-12a is primarily metabolized bythe hepatic and renal enzyme UGT1A9, whereas NI-ST-05 is primarilymetabolized by an extrahepatic enzyme, UGT1A10, with apparent Kmvalues of 240 and 6.2 μM, respectively.The involvement of hepatic and intestinal UGTs in the metabolism ofboth compounds was further confirmed using a panel of human liverand intestinal microsomes, and high individual variation in activitywas demonstrated between donors. In summary, these studies clearlyestablish that modified, tRes-based stilbenoids may be preferablealternatives to tRes itself due to increased bioavailability via alteredconjugation. [ABSTRACT FROM AUTHOR]