Resin Glycosides with α-Glucosidase and Protein Tyrosine Phosphatase 1B Inhibitory Activities from the Seeds of Cuscuta japonica

In the present study, seven previously undescribed resin glycosides, designated cusponins I-VII (<b>1</b>-<b>7</b>), together with one known analog (<b>8</b>), were isolated from the seeds of <i>Cuscuta japonica</i>, a traditional medicine used in China. Structural elucidation revealed them to be glycosidic acid methyl esters, generated through on-column methyl esterification of naturally occurring resin glycosides catalyzed by NH₂-functionalized silica gel. All isolates were characterized as either pentasaccharides or tetrasaccharides, incorporating D-glucose, L-rhamnose, or D-fucose units as the sugar residues. Notably, compounds <b>1</b> and <b>3</b>-<b>7</b> contained the uncommon aglycone, 11<i>S</i>-hydroxypentadecanoic acid. Bioactivity assessments demonstrated that compounds <b>1</b>-<b>4</b>, <b>6</b> and <b>8</b> suppressed <i>α</i>-glucosidase activity, with IC₅₀ values between 8.02 and 71.39 μM. In addition, compounds <b>3</b> and <b>5</b> exhibited inhibitory effects on protein tyrosine phosphatase 1B (PTP1B), with IC₅₀ values of 14.19 ± 1.29 μM and 62.31 ± 8.61 μM, respectively, marking the first report of PTP1B inhibitory activity among resin glycosides. Enzyme kinetic analyses indicated that compound <b>2</b> acted as an uncompetitive <i>α</i>-glucosidase inhibitor (<i>K</i>_is = 3.02 μM), whereas compound <b>3</b> inhibited PTP1B via a mixed-type mechanism (<i>K</i>ᵢ = 24.82 μM; <i>K</i>_is = 64.24 μM). Molecular docking combined with molecular dynamics simulations suggested that compounds <b>2</b> and <b>3</b> interacted with <i>α</i>-glucosidase-pNPG and PTP1B, respectively, forming stable complexes with favorable binding free energies. Collectively, this study reported eight resin glycosides from <i>C. japonica</i>, seven of them newly identified, with compounds <b>2</b> and <b>3</b> highlighted as promising scaffolds for antidiabetic drug discovery.