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.
Highlights
Natural products (NPs) are a diverse family of organic molecules, most of which exhibit significant bioactivities to treat human diseases [1,2,3,4,5,6,7,8]
NPs [10,11], (2) expansion of NP space catalysed by uncommon P450 reactions [12], (3) construction of new lead compounds inspired by bioactive NPs [13], (4) recombined NP moieties generated via coupling reactions [14], (5) diversity-enhanced extraction directly from plants [15]
Due to the electron donation of O-19a in the coumarin building blocks, the major products can be rationalized by the reaction mechanism shown in Scheme 3
Summary
Natural products (NPs) are a diverse family of organic molecules, most of which exhibit significant bioactivities to treat human diseases [1,2,3,4,5,6,7,8]. Interest in generating novel synthetic scaffolds has recently declined in pharmaceutical research due to the elaborate isolation procedures required or lengthy total synthesis pathways [9]. There has been increased interest in NP-inspired or NP-like products to improve the chemical diversity of NPs through different routes: (1) diversity-oriented synthesis (DOS) starting from isolated. Natural meroterpenes derived from phloroglucinols and β-caryophyllene have shown high inhibitory activity against α-glucosidase or cancer cells, 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. Compound 7 exhibited the most potent inhibition of α-glucosidase (IC50 3.56 μM)
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