Anti-inflammatory limonoids from Swietenia macrophylla seeds attenuate IL-1β release via NLRP3 inflammasome inhibition.

Seeds of Swietenia macrophylla are recognized as a beneficial dietary supplement due to their pronounced hypoglycemic and hypotensive properties. To explore the pharmaceutical potential of this plant, eight previously undescribed mexicanolide- and phragmalin-type limonoids (1-8), together with twenty known analogues (9-28), were isolated from the seeds. Their planar structures and absolute configurations were elucidated through extensive spectroscopic investigations, electronic circular dichroism (ECD) calculations, and X-ray diffraction analyses. Among them, swimacrolin A (1) was identified as a rare trinor-limonoid possessing a 16,20-dicarboxylic acid mexicanolide skeleton. In an in vitro anti-inflammatory assay, compounds 1-8 did not inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)- stimulated RAW 264.7 macrophages. However, compounds 1-8, 11, 12, 14-18, 20, 21, 23, and 25-28 significantly suppressed interleukin-1β (IL-1β) release in LPS/nigericin (NIG)-induced THP-1 cells, with IC50 values ranging from 0.64 to 23.05 μM. Notably, compound 2 demonstrated marked anti-inflammatory activity (IC50 = 0.64 ± 0.19 μM). Further mechanistic investigation revealed that compound 2 directly binds to the NOD-like receptor family pyrin domain containing 3 (NLRP3) protein, thereby interfering with apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization and inhibiting NLRP3 inflammasome activation.