The comparison of neuroprotective effects of isoliquiritigenin and its Phase I metabolites against glutamate-induced HT22 cell death

• Published in: Bioorganic & medicinal chemistry letters 2016-12, Vol.26 (23), p.5639-5643
• Main Authors: Yang, Eun-Ju, Kim, Minjun, Woo, Ji Eun, Lee, Taeho, Jung, Jong-Wha, Song, Kyung-Sik
• Format: Article
• Language: English
• Subjects: Animals; Benzofurans - metabolism; Benzofurans - pharmacology; Butein; Cell Death - drug effects; Cell Line; Chalcone - analogs & derivatives; Chalcone - metabolism; Chalcone - pharmacology; Chalcones - metabolism; Chalcones - pharmacology; Flavonoids - metabolism; Flavonoids - pharmacology; Glutamate; Glutamic Acid - metabolism; Hippocampus - cytology; Hippocampus - drug effects; HT22; Isoliquiritigenin; Mice; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Neuroprotection; Neuroprotective Agents - metabolism; Neuroprotective Agents - pharmacology; Phase I metabolites
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.10.072

[Display omitted] •Isoliquiritigenin (ISOLIQ) and its six Phase I metabolites were prepared.•The neuroprotective effects of seven compounds were compared on glutamate toxicity.•Butein (4) showed better effects than the parent compound, ISOLIQ.•4 is a chalcone containing a catechol group in the B ring.•The neuroprotective effect of ISOLIQ could be elevated by its metabolite 4. It is becoming increasingly important to investigate drug metabolites to evaluate their toxic or preventive effects after administration of the parent compound. In our previous study, isoliquiritigenin isolated from Glycyrrhizae Radix effectively protected mouse-derived hippocampal neuronal cells (HT22) against 5mM glutamate-induced oxidative stress. However, there is little information on the protective effects of the metabolites of isoliquiritigenin on HT22 cells. In this study, isoliquiritigenin and its Phase I metabolites were prepared and their neuroprotective activities on glutamate-treated HT22 cells were compared. The prepared metabolites were liquiritigenin (1), 2′,4,4′,5′-tetrahydroxychalcone (2), sulfuretin (3), butein (4), davidigenin (5), and cis-6,4′-dihydroxyaurone (6). Among the six metabolites, 4 showed better neuroprotective effects than the parent compound, isoliquiritigenin. Our study suggests that the neuroprotective effect of isoliquiritigenin could be elevated by its active metabolite 4, which is a chalcone containing a catechol group in the B ring.