Macrocephatriolides A and B: Two Guaianolide Trimers from <i>Ainsliaea macrocephala</i> as PTP1B Inhibitors and Insulin Sensitizers
Yong-Mei Ren, Rui Zhang, Zheling Feng, Chang‐Qiang Ke, Sheng Yao, Chunping Tang, Ligen Lin, Yang Ye
Abstract
Macrocephatriolides A and B (1 and 2), two novel guaiane-type sesquiterpene lactone trimers possessing unique linkage patterns, were identified from the whole plant of Ainsliaea macrocephala. The trimeric architecture of 1 features a cyclohexene linkage and a methylene bridge, which were presumably constructed from three constitutive monomers via a Diels–Alder cycloaddition and a Michael addition, respectively. The three monomers of 2 were tethered by a 1,2-ethanediyl and a methylene linkage at the same time. Their complex structures were established by extensive analysis of spectroscopic data inclusive of band-selective CT-HSQC and CT-HMBC and time-dependent density functional theory (TDDFT) ECD calculations. Compound 2 showed potent inhibition against protein tyrosine phosphatase 1B (PTP1B) with an IC50 value of 26.26 ± 0.88 μM but not compound 1. In the kinetic study, compound 2 was disclosed as a competitive inhibitor of PTP1B with a Ki value of 16.34 ± 4.72 μM. In insulin-stimulated C2C12 myotubes, compound 2 dose-dependently enhanced glucose uptake by activating the insulin signaling pathway. Compound 2 might represent a new scaffold of insulin sensitizers.