Flavonoids with Inhibitory Effects on NLRP3 Inflammasome Activation from Millettia velutina

Abstract

Eight new flavonoids, including two β-hydroxy/methoxychalcones, velutones A and B (1 and 2), two 1,3-diarylpropan-1-ols, velutols C and D (3 and 4), a dihydroxychalcone, velutone E (5), a chalcone, velutone F (6), a furanoflavanone, velutone G (7), and a furanoflavonol, velutone H (8), and 14 known compounds were isolated from Millettia velutina. Their structures were determined by high-resolution electrospray ionisation mass spectrometry (HR-ESIMS) and spectroscopic data analyses and time-dependent density functional theory electronic circular dichroism (TD-DFT–ECD) calculations. Among the isolated constituents, compound 6 exhibited the most potent inhibitory effect (IC50: 1.3 μM) against nigericin-induced IL-1β release in THP-1 cells. The initial mechanism of action study revealed that compound 6 suppressed NLRP3 inflammasome activation via blocking ASC oligomerization without affecting the priming step, which subsequently inhibited caspase-1 activation and IL-1β secretion. Most importantly, compound 6 exerted potent protective effects in the LPS-induced septic shock mice model by improving the survival rate of mice and suppressing serum IL-1β release. These results demonstrated that compound 6 had the potential to be developed as a broad-spectrum NLRP3 inflammasome inhibitor for the treatment of NLRP3-related disease.

Chalcone Derivatives From Abelmoschus manihot Seeds Restrain NLRP3 Inflammasome Assembly by Inhibiting ASC Oligomerization

“…The persistent activation of NLRP3 promotes the overexpression of inflammatory factors, leading to diabetes, atherosclerosis, gout, and tumor occurrence ( Fusco et al, 2020 ). Therefore, NLRP3 inflammasome inhibitors are important in the treatment of NLRP3-related diseases ( Yang et al, 2019 ; Zahid et al, 2019 ; Ma et al, 2020 ).…”

Synthesis and NLRP3-Inflammasome Inhibitory Activity of the Naturally Occurring Velutone F and of Its Non-Natural Regioisomeric Chalconoids

“…The NLRP3 inflammasome is a large protein complex controlling the production of caspase-1 and ultimately of pro-inflammatory cytokines (IL-1 and IL-18). In this context, it was reported that velutone F ( 1 ) ( Figure 1 ), a retrochalcone [ 20 , 21 , 22 ] recently identified in the ethanolic extract of the leguminous plant Millettia velutina [ 23 , 24 ], inhibits the formation of the NLRP3 active complex. Among the eight new flavonoids identified in the lipophilic crude residue derived from 10 kg of dry vine stems of Millettia velutina , compound 1 exhibited the most potent inhibitory effect against nigericin-induced IL-1 release in THP-1 cells.…”

Total Synthesis and Anti-Inflammatory Activity of Velutone F

“…4 The initial mechanism of action study by Chen and her co-workers revealed that velutone F (1) suppressed NLRP3 inflammasome activation via blocking ASC oligomerization without affecting the priming step, which subsequently inhibited caspase-1 activation and IL-1β secretion (Figure 1). 4 Detailed pharmacological study of velutone F (1) so far has been minimal due to limited supply from a natural resource (0.000113% from M velutina). Such insufficient quantities to optimally explore the interesting biological properties of velutone F prompted efforts by Wu and co-workers to develop a semisynthesis route toward the natural product.…”

“…4 The initial mechanism of action study by Chen and her co-workers revealed that velutone F ( 1 ) suppressed NLRP3 inflammasome activation via blocking ASC oligomerization without affecting the priming step, which subsequently inhibited caspase-1 activation and IL-1β secretion (Figure 1). 4…”

“…[1][2][3] Velutone F {2,5-dimethoxyfurano[4 ′′ ,5 ′′ :3,4]chalcone, compound 1}, a natural chalcone isolated from Millettia velutina in 2020, was reported to exhibit significant anti-inflammatory activity against nigericin-induced IL-1β release in THP-1 cells (IC 50 1.3 μM). 4 The initial mechanism of action study by Chen and her co-workers revealed that velutone F (1) suppressed NLRP3 inflammasome activation via blocking ASC oligomerization without affecting the priming step, which subsequently inhibited caspase-1 activation and IL-1β secretion (Figure 1). 4 Detailed pharmacological study of velutone F (1) so far has been minimal due to limited supply from a natural resource (0.000113% from M velutina).…”