Total Syntheses and Anti-Inflammatory Studies of Three Natural Coumarins: Glycycoumarin, Glycyrin, and 3-O-Methylglycyrol

Licorice (<i>Glycyrrhiza uralensis</i> Fisch), a significant traditional Chinese herbal medicine, has been extensively utilized in China to treat various ailments. Natural bioactive coumarins, glycycoumarin, glycyrin, and 3-<i>O</i>-methylglycyrol, were isolated from licorice, and they exhibited various pharmacological properties. In this report, we have accomplished the total synthesis of glycycoumarin, glycyrin, and 3-<i>O</i>-methylglycyrol in 5-7 linear steps from commercially available 2,4,6-trihydroxybenzaldehyde with yields of 12.3-21.2%. Additionally, their anti-inflammatory activities were studied and compared. Glycycoumarin, glycyrin, and 3-<i>O</i>-methylglycyrol exhibited different levels of anti-inflammatory activities, with glycyrin being the most potent. Mechanistic studies indicated that glycyrin exerted its anti-inflammatory properties by inhibiting the activation of TNF-α, IL-6, and IL-1β, making it a potential anti-inflammatory lead compound for further optimization and discovery of new agents.