Molecular networking guided discovery of non-limonoids type ingredients from Citrus medica var. Sarcodactylis fruits

Ten non-limonoids type ingredients with four structural skeletons, including two cyclic peptide (1/3), a 5-hydroxymethylfurfural derivative (2), two monoterpenoid glycosides (4/5), and five coumarins (6-10), were discovered from Citrus medica var. Sarcodactylis fruits guided by single-node based CMN and feature-based molecular networking (FBMN) strategy. Among of them, the new cyclic heptapeptide 1 is with rare asparagine unit, and the new skeleton of 2 is formed between 5-hydroxymethylfurfural and malonic acid through aldol condensation, which were elucidated undoubtedly through NMR and single crystal diffraction. The cyclic dipeptide and monoterpenoid glycosides were also isolated from this plant for the first time. Bioactivities evaluation indicated that the cyclic heptapeptide 1 can significantly inhibit the production of IL-1β (IC_50: 7.65 ± 0.04 μM) in THP-1 Cells and possess potential anti-inflammatory activity. This research provided further basis for clarification of its chemical constituents and development as natural medicine and food.