Abstract:
Protein tyrosine phosphatase 1B (PTP1B) has led to an intense interest in developing its inhibitors as anti-diabetes, anti-obesity and anti-cancer agents. The fruits of
Rubus chingii (Chinese raspberry) were used as a kind of dietary traditional Chinese medicine. The methanolic extract of
R. chingii fruits exhibited significant PTP1B inhibitory activity. Further bioactivity-guided fractionation resulted in the isolation of three PTP1B inhibitory ursane-type triterpenes:ursolic acid (
1 ), 2-oxopomolic acid (
2 ), and 2α, 19α-dihydroxy-3-oxo-urs-12-en-28-oic acid (
3 ). Kinetics analyses revealed that
1 was a non-competitive PTP1B inhibitor, and
2 and
3 were mixed type PTP1B inhibitors. Compounds
1-3 and structurally related triterpenes (
4-8 ) were further analyzed the structure-activity relationship, and were evaluated the inhibitory selectivity against four homologous protein tyrosine phosphatases (TCPTP, VHR, SHP-1 and SHP-2). Molecular docking simulations were also carried out, and the result indicated that
1 , 3-acetoxy-urs-12-ene-28-oic acid (
5 ), and pomolic acid-3
β-acetate (
6 ) bound at the allosteric site including α3, α6, and α7 helix of PTP1B.