Thielavins A, J and K: α-Glucosidase inhibitors from MEXU 27095, an endophytic fungus from Hintonia latiflora

Bioassay-guided fractionation of the bio-active organic extract obtained from solid-media culture of MEXU 27095, an endophytic fungus isolated from the Mexican medicinal plant Hintonia latiflora (Rubiaceae), led to separation of three tridepsides which were identified as thielavins A, J and K. All three compounds inhibited Saccharomyces cerevisieae alpha-glucosidase (alpha GHY) in a concentration-dependent manner with IC50 values of 23.8, 15.8, and 22.1 mu M, respectively. Their inhibitory action was higher than that of acarbose (IC50 = 545 mu M), used as a positive control. Kinetic analysis established that the three compounds acted as non-competitive inhibitors with k(i) values of 27.8, 66.2 and 55.4 mu M, respectively (alpha =1.0, 1.2, 0.7, respectively); acarbose behaved as competitive inhibitor with a k(i) value of 156.1 mu M. Thielavin J inhibited the activity of alpha-glucosidase from Bacillus stearothermophilus (alpha GHBs) with an IC50 of 30.5 mu M, being less active than acarbose (IC50 = 0.015 mu M); in this case, compound (2) (k(i) = 20.0 mu M and alpha = 2.9) and acarbose (k(i) = 0.008 mu M and alpha = 1.9) behaved as non-competitive inhibitors. Docking analysis predicted that all three thielavins and acarbose bind to homologated alpha GHBs and to alpha GHY (PDB: 3A4A) in a pocket close to the catalytic site for maltose and isomaltose, respectively. The alpha-glucosidase inhibitory properties of thielavin K (3) were corroborated in vivo since it induced a noted antihyperglycemic action during an oral sucrose tolerance test (3.1, 10.0 and 31.6 mg/kg) sin normal and nicotinamide-streptozotocin diabetic mice. In addition, at a dose of 10 mg/kg, it provoked a moderate hypoglycemic activity in diabetic mice. (C) 2013 Elsevier Ltd. All rights reserved.