Dihydroxanthyletin-type coumarins from Angelica decursiva that inhibits the formation of advanced glycation end products and human recombinant aldose reductase.

Abstract

The formation of advanced glycation end-products (AGE) and aldose reductase activity have been implicated in the development of diabetic complications. The present study was aimed to evaluate human recombinant aldose reductase (HRAR) and AGE inhibitory activity of seven natural dihydroxanthyletin-type coumarins, 4-hydroxy Pd-C-III (1), 4'-methoxy Pd-C-I (2), Pd-C-I (3), Pd-C-II (4), Pd-C-III (5), decursidin (6), and (+)-trans-decursidinol (7) from Angelica decursiva. Coumarins 1-7 showed potent HRAR and AGE inhibitory activities with ranges of IC50 values of 1.03-21.31 and 0.41-5.56µM, respectively. In the kinetic study for HRAR enzyme inhibition, coumarins 1, 3, 4, and 7 were competitive-type inhibitors, 6 was a mixed-type inhibitor, whereas 2 and 5 were noncompetitive-type inhibitors. Furthermore, we also predicted the docking interactions of HRAR with coumarins 1-7 using AutoDock Vina, and as a result, the simulated enzyme-inhibitor complexes exhibited negative binding energies (Autodock Vina=-9.6 to -8.1kcal/mol for HRAR), indicating a high affinity and tight binding capacity for the HRAR active site. Our results clearly indicate the potential HRAR and AGE formation inhibitory activities of dihydroxanthyletin-type coumarins, which could be further explored to develop therapeutic modalities for the treatment of diabetes and related complications.