Meroterpene-Like α-Glucosidase Inhibitors Based on Biomimetic Reactions Starting from β-Caryophyllene

Abstract

Background: Natural meroterpenes derived from phloroglucinols and β-caryophyllene have shown high inhibitory activity against α-glucosidase or cancer cells, however, the chemical diversity of this type of skeletons in Nature is limited. Methods: To expand the chemical space and explore their inhibitory activities against α-glucosidase (EC 3.2.1.20), we employed β-caryophyllene and some natural moieties (4-hydroxycoumarins, lawsone or syncarpic acid) to synthesize new types of meroterpene-like skeletons. All the products (including side products) were isolated and characterized by NMR, HR-MS, and ECD. Results: In total, 17 products (representing seven scaffolds) were generated through a one-pot procedure. Most products (12 compounds) showed more potential activity (IC50 < 25 μM) than the positive controls (acarbose and genistein, IC50 58.19, and 54.74 μM, respectively). Compound 7 exhibited the most potent inhibition of α-glucosidase (IC50 3.56 μM) in a mixed-type manner. The CD analysis indicated that compound 7 could bind to α-glucosidase and influence the enzyme’s secondary structure. Conclusions: Compound 7 could serve as a new type of template compound to develop α-glucosidase inhibitors. Full investigation of a biomimic reaction can be used as a concise strategy to explore diverse natural-like skeletons and search for novel lead compounds.

Keywords

• meroterpene
• 4-hydroxycoumarin
• β-caryophyllene
• lawsone
• hetero[4+2] cycloaddition
• α-glucosidase
• hyperglycemia