In recent years, a large number of pharmacologically active compounds containing a butenolide functional group have been isolated from secondary metabolites of marine microorganisms. Butyrolactone I was found to be produced by Aspergillus terreus isolated from several marine-derived samples. The hypoglycemic activity of butyrolactone I has aroused our great interest. In this study, we synthesized six racemic butenolide derivatives (namely BL-1-BL-6) by modifying the C-4 side chain of butyrolactone I. Among them, BL-3 and BL-5 improved the insulin resistance of HepG2 cells and did not affect the proliferation of RIN-m5f cell line, which indicated the efficacy and safety of BL-3 and BL-5. Furthermore, BL-3, BL-4, BL-5, and BL-6 displayed a significant protein tyrosine phosphatase 1B (PTP1B) inhibitory effect, while the enantiomers of BL-3 displayed different 50% percentage inhibition concentration (IC50) values against PTP1B. The results of molecular docking simulation of the BLs and PTP1B explained the differences of biological consequences observed between the enantiomers of BL-3, which supported BLs as PTP1B inhibitors, and also indicated that the chirality of C-4 might influence the inhibitory effect of the BLs. Our findings provide a novel strategy for the development of butyrolactone derivatives as potential PTP1B inhibitors for the treatment of type 2 diabetes mellitus.
Keywords: butenolide; chirality; insulin resistance; secondary metabolites.