Synthesis and biological evaluation of (20S,24R)-epoxy-dammarane-3ß,12ß,25-triol derivatives as α-glucosidase and PTP1B inhibitors.

The dammarane triterpenoid (20S,24R)-epoxy-dammarane-3ß,12ß,25-triol obtained from Cyclocarya paliurus in our previous study showed inhibitory activity on α-glucosidase in vitro with an inhibitory ratio of 32.2% at the concentration of 200 µM. In order to reveal the structure-activity relationships (SARs) and get more active compounds, 42 derivatives of (20S,24R)-epoxy-dammarane-3ß,12ß,25-triol were synthesized by chemical modification on the hydroxyls (C-3 and C-12), rings A and E, and assayed for their α-glucosidase and PTP1B inhibitory activities. Two compounds (8, 26) increased activity against α-glucosidase, and four compounds (8, 15, 26, 42) significantly inhibited PTP1B. It was noted that compounds 8 and 26 could inhibit both α-glucosidase and PTP1B as dual-target inhibitors with IC50 values of 489.8, 467.7 µM (α-glucosidase) and 319.7, 269.1 µM (PTP1B). Compound 26 was revealed to be a mix-type inhibitor on α-glucosidase and a noncompetitive-type inhibitor on PTP1B based on enzyme kinetic study. Furthermore, compound 42 could selectively inhibited PTP1B as a mix-type inhibitor with IC50 value of 134.9 µM, which was 2.5-fold higher than the positive control, suramin sodium (IC50 339.0 µM), but not inhibit α-glucosidase.