Discovery, α-Glucosidase Inhibitory Activity, and Structural Optimization of the Alkaloids from Vanderbylia robiniophila SY636

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Abstract
α-Glucosidase inhibitory activity-guided isolation led to the discovery of ten alkaloids from the medicinal mushroom Vanderbylia robiniophila SY636, including six new compounds ((+)-1a, (-)-1b, (+)-2a, (-)-2b, 3, and (+)-4a) and four newly reported natural products ((-)-4b and 5-7). Compounds (+)-1a, (-)-1b, (+)-2a, and (-)-2b possess a unique lactam-furan ring system, whereas 3 features a rare tetrahydrobenzo[c]oxepine-furan ring system. (+)-1a, (-)-1b, (+)-4a, and (-)-4b exhibited notable α-glucosidase inhibitory activities, with IC50 values of 160-330 μM (acarbose as the positive control, IC50 = 660 μM). Guided by docking results of bioactive compounds with α-glucosidase, derivatives D1-D28 were designed and synthesized, among which D15 and D19 exhibited stronger activities (IC50 = 28 and 130 μM). Molecular docking and kinetic studies suggested that D15 and D19 interact with α-glucosidase at a single binding site, exhibiting an uncompetitive or mixed type of inhibition mechanism. D19 also exhibited notable antioxidant activity (IC50 = 35 μM), comparable to l-ascorbic acid, suggesting its dual role in combating the development of diabetes. This study provides a foundation for the development of natural medicines from V. robiniophila and offers valuable guidance for future structural optimization toward the discovery of more potent and safer antidiabetic agents.
Funding Information
  • Qingdao Agricultural University (665/1120034)
  • National Natural Science Foundation of China (22478217)
  • Natural Science Foundation of Shandong Province (ZR2024QC100)
  • Key Technology Research and Development Program of Shandong Province (2021ZDSYS28)
  • Jiangsu Key Laboratory of Marine Bioresources and Environment, Jiangsu Ocean University (SH20231203)

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