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An ethanolic extract of Russian tarragon, Artemisia dracunculus L., with antihyperglycemic activity in animal models was reported to decrease phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression in STZ-induced diabetic rats. A quantitative polymerase chain reaction (qPCR) assay was developed for the bioactivity-guided purification of the compounds within the extract that decrease PEPCK expression. The assay was based on the inhibition of dexamethasone-stimulated PEPCK upregulation in an H4IIE hepatoma cell line. Two polyphenolic compounds that inhibited PEPCK mRNA levels were isolated and identified as 6-demethoxycapillarisin and 2′,4′-dihydroxy-4-methoxydihydrochalcone with IC₅₀ values of 43 and 61 μM, respectively. The phosphoinositide-3 kinase (PI3K) inhibitor LY-294002 showed that 6-demethoxycapillarisin exerts its effect through the activation of the PI3K pathway …