α-Glucosidase and PTP-1B Inhibitors from Malbranchea dendritica.

Abstract

An extract from a PDB static culture of Malbranchea dendritica exhibited α-glucosidase and PTP-1B inhibitory activities. Fractionation of the active extract led to the isolation of gymnoascolide A (1), a γ-butenolide, and xanthones sydowinin A (2), sydowinin B (3), and AGI-B4 (4), as well as orcinol (5). Compound 1 exhibited important inhibitory activity against yeast α-glucosidase (IC50 = 0.556 ± 0.009 mM) in comparison to acarbose (IC50 = 0.403 ± 0.010 mM). Kinetic analysis revealed that 1 is a mixed-type inhibitor. Furthermore, compound 1 significantly reduced the postprandial peak in mice during a sucrose tolerance test at the doses of 5.16 and 10 mg/kg. Compound 1 was reduced with Pd/C to yield a mixture of enantiomers 1a and 1b; the mixture showed similar activity against α-glucosidase (IC50 = 0.396 ± 0.003 mM) and kinetic behavior as the parent compound but might possess better drug-likeness properties according to SwissADME and Osiris Property Explorer tools. Docking analysis with yeast α-glucosidase (pdb: 3A4A) and the C-terminal subunit of human maltase-glucoamylase (pdb: 3TOP) predicted that 1, 1a, and 1b bind to an allosteric site of the enzymes. Compounds 1–5 were evaluated against PTP-1B, but only xanthone 3 moderately inhibited in a noncompetitive fashion the enzyme with an IC50 of 0.081 ± 0.004 mM. This result was consistent with that of docking analysis, which revealed that 3 might bind to an allosteric site of the enzyme. From the inactive barley-based semisolid culture of M. dendritica, the natural pigment erythroglaucin (6) and the nucleosides deoxyadenosine (7), adenosine (8), thymidine (9), and uridine (10) were also isolated and identified.