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

The dammarane triterpenoid (20 S ,24 R )-epoxy-dammarane-3 β ,12 β ,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 (20 S ,24 R )-epoxy-dammarane-3 β ,12 β ,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 IC ₅₀ 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 IC ₅₀ value of 134.9 μM, which was 2.5-fold higher than the positive control, suramin sodium (IC ₅₀ 339.0 μM), but not inhibit α -glucosidase.
Competing Interests: Conflict of interestThe authors declare no competing interests.
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