In the present study, seven previously undescribed resin glycosides, designated cusponins I-VII (
1–
7), together with one known analog (
8), were isolated from the seeds of
Cuscuta japonica, a traditional medicine used in China. Structural elucidation revealed
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In the present study, seven previously undescribed resin glycosides, designated cusponins I-VII (
1–
7), together with one known analog (
8), were isolated from the seeds of
Cuscuta japonica, 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 NH
2-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
1 and
3–
7 contained the uncommon aglycone, 11
S-hydroxypentadecanoic acid. Bioactivity assessments demonstrated that compounds
1–
4,
6 and
8 suppressed
α-glucosidase activity, with IC
50 values between 8.02 and 71.39 μM. In addition, compounds
3 and
5 exhibited inhibitory effects on protein tyrosine phosphatase 1B (PTP1B), with IC
50 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
2 acted as an uncompetitive
α-glucosidase inhibitor (
Kis = 3.02 μM), whereas compound
3 inhibited PTP1B via a mixed-type mechanism (
Kᵢ = 24.82 μM;
Kis = 64.24 μM). Molecular docking combined with molecular dynamics simulations suggested that compounds
2 and
3 interacted with
α-glucosidase-pNPG and PTP1B, respectively, forming stable complexes with favorable binding free energies. Collectively, this study reported eight resin glycosides from
C. japonica, seven of them newly identified, with compounds
2 and
3 highlighted as promising scaffolds for antidiabetic drug discovery.
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