(±)-Hypandrone A, a pair of polycyclic polyprenylated acylphloroglucinol enantiomers with a caged 7/6/5/6/6 pentacyclic skeleton from Hypericum androsaemum

Abstract

(±)-Hypandrone A (1), a pair of highly modified polycyclic polyprenylated acylphloroglucinol (PPAP) enantiomers, with an unprecedented caged 2,8,17-trioxapentacyclo-[11.4.2.0^1,9.0^4,9.0^10,15]-nonadecane core, were isolated from the fruits of Hypericum androsaemum. The racemate (±)-1 was successfully separated into the two optically pure enantiomers (ee ≥ 99%) using a preparative HPLC system. Their structures including absolute configurations were elucidated via spectroscopic analyses, electronic circular dichroism calculations, and single-crystal X-ray diffraction. Biological studies revealed that (−)-1 is a potent inhibitor of the NLRP3 inflammasome pathway and could inhibit the protein expression of NLRP3, ASC, cleaved caspase-1 and the active form N-GSDMD fragment, thereby blocking NLRP3 inflammasome-induced pyroptosis.

---

Introduction

Natural products are definitely important compounds for innovative drug discovery, and over nearly four decades, more than a third of FDA-approved medications are related to natural products.^1,2 Polycyclic polyprenylated acylphloroglucinols (PPAPs), possessing highly oxygenated and rearranged acylphloroglucinol-derived cores decorated with isoprenyl or geranyl side chains, are an important group of structurally fascinating and synthetically challenging natural products widely discovered in the genera Hypericum and Garcinia,^3–5 and have proven to be a prolific source of fascinating natural products possessing diverse pharmacological activities, such as lipid-lowering nor-PPAPs,⁶ cytotoxic seco-PPAPs and PPAP dimers,⁷ anti-inflammatory PPAP enantiomers,⁸ anti-angiogenesis and antibacterial spiro-bridged PPAPs,⁹ immunosuppressive PPAPs,¹⁰ anti-HIV PPAPs,¹¹ anti-leukemic PPAP adducts,¹² cholinesterase inhibiting PPAPs,¹³ and so on. Hence, the discovery of new drugs from the secondary metabolites of the genera Hypericum and Garcinia seems feasible.

Hypericum androsaemum, a common small evergreen shrub, is widely distributed in Europe, North Africa and West Asia, and it is now planted as an ornamental plant in small amounts in Yunnan, Guizhou, and Sichuan regions of China where it is traditionally used as a diuretic and hepatoprotective herbal drug.¹⁴ As part of our study on biologically active and structurally unique PPAPs from Hypericum plants, (±)-hypandrone A ((±)-1) (Fig. 1), a pair of highly oxygenated and rearranged PPAP enantiomers with a unique caged 2,8,17-trioxapentacyclo-[11.4.2.0^1,9.0^4,9.0^10,15]-nonadecane core, were isolated from the fruits of H. androsaemum. Notably, (±)-1 possess a unique aromatic ring assembled by two isopentenyl groups through cationic cyclization and aldol condensation, which has never been reported in the field of PPAPs.^5,15 In this paper, the structural elucidation, plausible biosynthetic pathway, and biological evaluation of the isolated compounds are reported.

Fig. 1 Chemical structures of compounds (±)-1.

Results and discussion

Hypandrone A (1), isolated as a colorless crystal (m.p. 236–238 °C), possesses the molecular formula C₂₉H₃₀O₈ as deduced from the HRESIMS ion at m/z 529.1840 [M + Na]⁺ (calcd for C₂₉H₃₀O₈Na⁺, 529.1838), indicating 15 degrees of unsaturation. The IR spectrum implied the existence of hydroxyl (3461 cm⁻¹), carbonyl (1743, 1713, and 1684 cm⁻¹), and phenyl (1637 and 1452 cm⁻¹) groups. A mono-substituted benzene ring in 1 corresponds to five aromatic protons at δ_H 8.13 (2H, dd, J = 8.4, 1.2 Hz), 7.67 (1H, dd, J = 8.4, 7.8 Hz), and 7.54 (2H, dd, J = 7.8, 1.2 Hz) (Table 1). In addition, the ¹H NMR data of 1 (Table 1) displayed signals ascribed to six singlet methyls at δ_H 2.25, 1.64, 1.46, 1.44, 1.09, and 0.84, two olefinic protons at δ_H 7.39 (s) and 6.59 (s), and an oxygenated methine at δ_H 5.62 (H-2, s). Combined with its DEPT, HSQC, and HMBC spectra, the ¹³C NMR data of 1 (Table 1) revealed 29 carbon signals, including a nonconjugated carbonyl (δ_C 199.6), a benzoyl [δ_C 167.1, 130.8, 131.0 (×2), 134.7 (×2), and 129.6], one carboxyl (δ_C 173.6) and six olefinic carbons at δ_C 123.7 (C-7), 132.0 (C-8), 126.7 (C-9), 157.9 (C-11), 110.3 (C-12), and 141.3 (C-13), which accounted for ten degrees of unsaturation. Apart from the aforementioned 15 carbons, the remaining 14 carbon signals were assigned to three oxygenated tertiary carbons (δ_C 84.6, 81.8, and 76.3), one oxygenated secondary carbon (δ_C 107.1), one quaternary carbon (δ_C 54.6), two methine carbons (δ_C 82.2 and 49.6), one methylene carbon (δ_C 35.8), and six methyl carbons (δ_C 33.7, 31.1, 30.8, 27.7, 18.7, and 16.0). The remaining five degrees of unsaturation implied that 1 had a pentacyclic system.^9,16

Table 1 ¹H and ¹³C NMR data of (±)-hypandrone A (1) in methanol-d₄ (δ in ppm, J in Hz)

No.	1
	δ H	δ C
a Recorded at 600 MHz. b Recorded at 150 MHz.
1		199.6, C
2	5.62, s	82.2, CH
3		107.1, C
4		84.6, C
5		173.6, C
6		54.6, C
7		123.7, C
8	7.39, s	132.0, CH
9		126.7, C
10	2.25, s	16.0, CH3
11		157.9, C
12	6.59, s	110.3, CH
13		141.3, C
14		76.3, C
15	1.44, s	33.7, CH3
16	1.64, s	30.8, CH3
17	1.46, s	18.7, CH3
18	2.40, dd (15.0, 10.2); 2.33, d (15.0)	35.8, CH2
19	3.14, d (10.2)	49.6, CH
20		81.8, C
21	1.09, s	27.7, CH3
22	0.84, s	31.1, CH3
23		167.1, C
24		130.8, C
25/29	8.13, dd (8.4, 1.2)	131.0, CH
27	7.67, dd (8.4, 7.8)	134.7, CH
26/28	7.54, dd (7.8, 1.2)	129.6, CH

---

Compound 1 was deduced to feature an unprecedented trioxapentacyclo-[11.4.2.0^1,9.0^4,9.0^10,15]-nonadecane core by detailed analysis of its 2D NMR correlations (Fig. 2). The HMBC correlations from H₃-17 to C-1, C-5, and C-6 and from H-2 to C-1, C-3, C-4, C-6, and C-23 could be assigned to the seven-membered lactone moiety (A-ring) linked to a benzoyl group at C-2. Moreover, the HMBC correlations from H₃-17 to C-5, C-6, and C-18 and from H₂-18 to C-4, C-5, and C-6, along with the ¹H–¹H COSY correlation of H₂-18/H-19, established a six-membered lactone moiety (B-ring). The HMBC correlations from protons of the gem-dimethyl (Me-21 and Me-22) to C-20 and C-19 and from H-19 to C-3, C-4, and C-20 form a tetrahydrofuran moiety (C-ring), which fused to rings A and B via the “C-3–C-4–C-19” bond. Subsequently, a phenyl moiety (E-ring) was deduced from the HMBC correlations from H₃-10 to C-8, C-9, and C-11, from H-8 to C-11 and C-13, and from H-12 to C-7 and C-9. Taking the above evidence together, fourteen degrees of unsaturation were occupied and the remaining one degree of unsaturation indicated an additional ring in the structure of 1. The HMBC correlations (Fig. 2) from H₃-15 to C-13, C-14, and C-16, from H-8 to C-4, C-7, and C-13, and from H-2 to C-3 and C-4, as well as the downfield chemical shifts of C-3 (δ_C 107.1) and C-14 (δ_C 76.3), revealed the presence of a 2,2-dimethylpyran ring (ring D). Accordingly, the planar structure of 1 was determined.

Fig. 2 (A) Key ¹H–¹H COSY and HMBC correlations of 1. (B) Key NOESY correlations of 1. (C) The nomenclature of the unusual bridged system (numbering in red) of 1.

The relative configuration of 1 was assigned by the NOESY experiment (Fig. 2), in which the cross-peaks of H-2/H₃-15, H₃-16/H₃-22, and H₃-22/H-19 indicated that these groups were cofacial and randomly assigned as β-oriented. In contract, the evident NOESY correlations of H₃-21/H-18α and H-18α/H₃-17 implied the α-orientations of these groups. Because of the rigid caged tetraoxatricyclo-[4.3.2.0^4,9]-undecane core, the C-20–C-19 and C-3–O-3–C-20 bonds occupied the α-orientations, and H-19 was fixed as β-oriented. Unfortunately, the relative configurations between rings A and B in 1 were still ill-defined because of the structural segment independence and lack of sufficient NOESY correlations, so we were unable to assign such a complex scaffold with multiple quaternary carbon atoms. However, after repeated attempts with different solvent systems, a high-quality crystal was finally obtained in MeOH–H₂O (10 : 1). The crystal was immediately subjected to the single-crystal X-ray diffraction analysis (CCDC 2310824†) (Fig. 3), which not only confirmed the complete structure and relative configurations of all asymmetric carbon centers (Fig. 3), but also revealed 1 to be racemic with the space group Pbca. It was further supported by the line of the CD spectrum as well as the small optical value ([α]²⁵_D −0.21). Luckily, with the help of a CHIRALPAK IG column, (+)-hypandrone A ((+)-1, [α]²⁵_D +33.8) and (−)-hypandrone A ((−)-1, [α]²⁵_D −33.8) with opposite cotton effects in the CD spectra and opposite optical rotations were successfully obtained. The absolute configurations of (+)-1 and (−)-1 were assigned by comparing the calculated electronic circular dichroism (ECD) results with the experimental data (Fig. 4). Ultimately, from the systematic analysis above, we could unquestionably identify the structure of 1 possessing an unprecedented caged trioxapentacyclo-[11.4.2.0^1,9.0^4,9.0^10,15]-nonadecane core.

Fig. 3 X-ray ORTEP drawing of compound 1.

Fig. 4 Calculated and experimental ECD spectra of (+)-1 and (−)-1.

(±)-Hypandrone A ((±)-1) represent a new type of PPAPs with an unprecedented 7/6/5/6/6 pentacyclic skeleton, and are distinguished from the reported PPAP-class natural products. In nature, chiral natural products are usually produced in the optically pure form, where on occasion nature is known to produce opposite enantiomeric metabolites, such as (±)-garmultin A,¹⁷ (±)-garcimulin A,⁹ (±)-walskiiglucinol A,¹⁸etc. Presumably, different precursors before the biosynthetic cyclization reactions may be the main reason for the phenomenon. Herein, a putative biosynthetic pathway for (±)-1 was proposed to explain this special phenomenon. Inspired by Pepper's biomimetic syntheses of type III PPAPs,¹⁹ we envisioned that divergent cationic cyclization steps and aldol condensation would play key roles in the biosynthesis of (±)-1. As shown in Scheme 1, multiple oxidation reactions of the MPAP precursor, followed by electron transfer, could generate the cationic intermediate (i). Afterward, the intermediate i underwent a selective carbocyclization to form racemic mixtures (ii and vi) due to the stereo-center at C-6, which converted to the corresponding iii and vii after aldol condensation.²⁰ The attack from C-4 to C-19 and the aldol condensation between C-3 and C-20 built the caged dioxatricyclo-[4.3.2.0^4,9]-undecane core in (±)-1. The precursors iii and vii underwent an epoxidation reaction on the allyl group of the molecule to produce iv or viii, respectively.²¹ The 1,3-allylic shift of the C-9 carbocation to C-8, followed by the intramolecular cyclization with C-7 and the O-selective cyclization between C-3 and C-14 generated intermediates v and ix, and the subsequent elimination reaction and oxidation reactions could finally decorate (±)-1.²²

Scheme 1 Calculated and experimental ECD spectra of (+)-1 and (−)-1.

In the next phase of this study, the anti-inflammatory effect of the isolates was investigated. First, the cytotoxicity of these compounds was determined by a CCK-8 assay to confirm the safe maximum dosages. Compounds (±)-1 did not display obvious cytotoxicity on RAW264.7 macrophages at a concentration of 12.5 μM or below (Fig. 5A), and (−)-1 dose-dependently inhibited NO production with an IC₅₀ value of 7.51 ± 0.85 μM (Fig. 5B and C). Since IL-1β is a critical pro-inflammatory mediator and its release is mainly regulated by the NOD-like receptor (NLR)-family pyrin domain-containing (NLRP3) inflammasome, inhibition of NLRP3-caspase 1-mediated IL-1β production in macrophages is an important strategy to ameliorate inflammation. Lipopolysaccharide (LPS) plus nigericin-stimulated THP-1 macrophages were recruited to evaluate whether (−)-1 suppressed IL-1β secretion. As a result, (−)-1 significantly reduced IL-1β production and secretion in LPS plus nigericin-stimulated THP-1 macrophages at a concentration of 10.13 μM, as assessed by ELISA, which is better than that of the positive control curcumin (IC₅₀ = 24.2 μM)²³ (Fig. 5D and E). Furthermore, we evaluated the expression of NLRP3 inflammasome-related proteins by western blot. As a result (Fig. 5F–H), (−)-1 effectively inhibited the expression of NLRP3, ASC, and cleaved caspase 1 in LPS plus nigericin-induced THP-1 cells (Fig. 5F and G). Furthermore, at the molecular level, less cleavage of the N-terminal domain of gasdermin D further verified that the pyroptosis induced by NLRP3 inflammasome activation was inhibited by (−)-1.

Fig. 5 Anti-inflammatory activity of compound 1. (A) The viability of RAW264.7 cells treated with different concentrations of 1 (n = 6). (B and C) The inhibitory rate against NO production of (±)-1 in LPS-stimulated RAW264.7 macrophages (n = 6). (D and E) The level of IL-1β in the culture medium from THP-1 cells detected using an ELISA kit. THP-1 cells were cultured in the presence or absence of (±)-1 for 12 h, and stimulated with LPS (1 μg mL⁻¹) for 4 h and then nigericin (5 μM) for 1 h (n = 6). (F–H) The expression of NLRP3, cleaved caspase 1, pro-caspase 1, ASC, and GSDMD in the lysates of THP-1 cells, detected by western blotting. β-Actin was chosen as an internal loading control (n = 3). ***P < 0.001, LPS or LPS + Nig vs. vehicle control. ^#P < 0.05, ^##P < 0.01, ^###P < 0.001, compound 1 or Dex vs. LPS or LPS + Nig.

Conclusions

In conclusion, (±)-hypandrone A ((±)-1), a pair of novel PPAP enantiomers, were identified and isolated from the fruits of H. androsaemum. Structurally, compounds (±)-1 represent the first examples of PPAPs with an unprecedented caged 2,8,17-trioxapentacyclo-[11.4.2.0^1,9.0^4,9.0^10,15]-nonadecane core, which might be decorated via complicated biosynthetic pathways involving multiple oxidation reactions and divergent cationic cyclization steps, as well as the dehydration reaction. Biological studies revealed that (−)-1 was a potent inhibitor of the NLRP3 inflammasome pathway, and it prevented caspase-1 activation and inhibited the protein expression of NLRP3, ASC as well as the active form N-GSDMD fragment, thereby blocking NLRP3 inflammasome-induced pyroptosis. This finding may expand the search for alternative natural small molecules for further research programs on NLRP3 inflammasomes and provide new bioactive scaffolds.

Author contributions

Y. Zhang, Z. Hu, Z. Wu, and J. Wei: funded and designed the study. J. Wei: chemistry study and design and drafting of the manuscript. J. Wei, P. Fan, and Y. Huang: designed and performed the experiments, obtained compounds, and analysed the data. R. Jiang and H. Zeng: performed the statistical analysis, purification of the compounds, UV and IR tests, and ECD calculations.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82273811, 81574038, and U22A20380), the National Program for Support of Top-notch Young Professionals (No. 0106514050), the National Key R&D Program of China (No. 2021YFA0910500), the Major New Drug Innovation Project of the Ministry of Science and Technology of China (No. 2017ZX09301001), the Special Key Project of Science, Shenzhen Basic Discipline Layout Project (No. JCYJ20220818101806014), the China Postdoctoral Science Foundation (No. 2023M742415), and the Guangdong Basic and Applied Basic Research Foundation (No. 2023A1515110763).

Notes and references

1. L. Wang, Y. Yan, L. Wu and J. Peng, Natural products in non-alcoholic fatty liver disease (NAFLD): novel lead discovery for drug development, Pharmacol. Res., 2023, 196, 106925.
2. J. L. Wolfender, M. Litaudon, D. Touboul and E. F. Queiroz, Innovative omics-based approaches for prioritisation and targeted isolation of natural products–new strategies for drug discovery, Nat. Prod. Rep., 2019, 36, 855–868.
3. J. Cao, J. Chen, R. Du, Q. Zhang, L. Gan, P. Zhang and L. Lin, Garcimultiflins A-C, unusual polycyclic polyprenylated acylphloroglucinols from the pericarps of Garcinia multiflora as interleukin-1 beta and pyroptosis inhibitors, Org. Chem. Front., 2023, 10, 4311–4319.
4. L. Tao, S. Xu, Z. Zhang, Y. Li, J. Yang, W. Gu, P. Yi, X. Hao and C. Yuan, Bioassay-guided isolation of α-glucosidase inhibitory constituents from Hypericum sampsonii, Chin. J. Nat. Med., 2023, 21, 443–453.
5. X. W. Yang, R. B. Grossman and G. Xu, Research progress of polycyclic polyprenylated acylphloroglucinols, Chem. Rev., 2018, 118, 3508–3558.
6. L. Huang, Z. Z. Zhang, Y. N. Li, P. Yi, W. Gu, J. Yang, Y. M. Li, X. J. Hao and C. M. Yuan, Hypersampones A–C, three nor-polycyclic polyprenylated acylphloroglucinols with lipid-lowering activity from Hypericum sampsonii, Org. Lett., 2022, 24, 5967–5971.
7. (a) W. Lu, Y. Zhang, Y. Li, S. Ye, J. Luo, L. Kong and W. Xu, Hyperbenzones A and B, two 1,2-seco and rearranged polycyclic polyprenylated acylphloroglucinols from Hypericum beanii, Chin. Chem. Lett., 2022, 33, 4121–4125; (b) Y. L. Wang, Y. S. Ye, W. W. Fu, R. Wu, Q. Xiang, Y. Z. Lao, J. L. Yang, H. S. Tan, X. W. Yang, B. C. Yang, H. X. Xu and G. Xu, Garsubelone A, the first dimeric polycyclic polyprenylated acylphloroglucinols with complicated heptacyclic architecture from Garcinia subelliptica, Org. Lett., 2019, 21, 1534–1537.
8. Y. M. Fan, P. Yi, Y. Li, C. Yan, T. Huang, W. Gu, Y. Ma, L. J. Huang, J. X. Zhang and C. L. Yang, Two unusual polycyclic polyprenylated acylphloroglucinols, including a pair of enantiomers from Garcinia multiflora, Org. Lett., 2015, 17, 2066–2069.
9. (a) B. Yang, J. C. Su, L. Huang, S. Lin, X. Jin, X. Lei, Z. Hu and Y. Zhang, Hyperispirones A and B, spiro-bridged polycyclic polyprenylated acylphloroglucinols with anti-angiogenesis activity from Hypericum beanii, Org. Chem. Front., 2022, 9, 3460–3466; (b) N. Zhang, Z. Shi, Y. Guo, S. Xie, Y. Qiao, X. N. Li, Y. Xue, Z. Luo, H. Zhu and C. Chen, The absolute configurations of hyperilongenols A-C: rare 12,13-seco-spirocyclic polycyclic polyprenylated acylphloroglucinols with enolizable beta,beta′-tricarbonyl systems from Hypericum longistylum Oliv., Org. Chem. Front., 2019, 6, 1491–1502.
10. S. Xie, Y. Zhou, X. Tan, W. Sun, Y. Duan, H. Feng, L. Sun, Y. Guo, Z. Shi, X. Hao, G. Chen, C. Qi and Y. Zhang, Norwilsonnol A, an immunosuppressive polycyclic polyprenylated acylphloroglucinol with a spiro[5-oxatricyclo[6.4.0.0^3,7]dodecane-6′,1-1′,2′-dioxane] system from Hypericum wilsonii, Org. Chem. Front., 2021, 8, 2280–2286.
11. H. Zhu, C. Chen, J. Yang, X. N. Li, J. Liu, B. Sun, S. X. Huang, D. Li, G. Yao, Z. Luo, Y. Li, J. Zhang, Y. Xue and Y. Zhang, Bioactive acylphloroglucinols with adamantyl skeleton from Hypericum sampsonii, Org. Lett., 2014, 16, 6322–6325.
12. Z. Shi, J. Yin, Y. Xiao, Z. Hou, F. Song, J. Wang, Q. Tong, C. Qi and Y. Zhang, Unprecedented sesquiterpene–polycyclic polyprenylated acylphloroglucinol adduct against acute myeloid leukemia via inhibiting mitochondrial complex V, Chin. Chem. Lett., 2023 DOI:10.1016/j.cclet.2023.109458.
13. Y. Guo, N. Zhang, C. Chen, J. Huang, X. N. Li, J. Li, H. Zhu, Q. Tong, J. Zhang and Z. Luo, Tricyclic polyprenylated acylphloroglucinols from St John’s Wort, Hypericum perforatum, J. Nat. Prod., 2017, 80, 1493–1504.
14. V. López, F. Les, R. Iannarelli, G. Caprioli and F. Maggi, Methanolic extract from red berry-like fruits of Hypericum androsaemum: chemical characterization and inhibitory potential of central nervous system enzymes, Ind. Crops Prod., 2016, 94, 363–367.
15. Y. Ye, N. Jiang, X. Yang and G. Xu, Polycyclic polyprenylated acylphloroglucinol with an unprecedented spirocyclic core from Hypericum patulum, Chin. Chem. Lett., 2020, 31, 2433–2436.
16. Y. Liu, Z. Ao, G. Xue, X. Wang, J. Luo and L. Kong, Hypatulone A, a homoadamantane-type acylphloroglucinol with an intricately caged core from Hypericum patulum, Org. Lett., 2020, 20, 7953–7956.
17. D. Tian, P. Yi, L. Xia, X. Xiao, Y. Fan, W. Gu, L. Huang, Y. Ben-David, Y. Di, C. Yuan and X. Hao, Garmultins A–G, biogenetically related polycyclic acylphloroglucinols from Garcinia multiflora, Org. Lett., 2016, 18, 5904–5907.
18. Y. Duan, P. Bu, Y. Guo, Z. Shi, Y. Cao, Y. Zhang, H. Hu, H. Hu, C. Qi and Y. Zhang, (±)-Walskiiglucinol A, a pair of rearranged acylphloroglucinol derivative enantiomers from Hypericum przewalskii, Org. Biomol. Chem., 2022, 20, 4970–4975.
19. H. P. Pepper, S. J. Tulip, Y. Nakano and J. H. George, Biomimetic total synthesis of (±)-doitunggarcinone A and (+)-garcibracteatone, J. Org. Chem., 2014, 79, 2564–2573.
20. J. C. Huang, L. Sheng, J. F. Zong, Y. B. Zhou, J. Li and A. J. Hou, Enantiomeric pairs of meroterpenoids with 11/5/6 spiro-heterocyclic systems from Hypericum kouytchense, Org. Chem. Front., 2022, 9, 6475–6483.
21. A. B. zur Bonsen, R. A. Peralta, T. Fallon, D. M. Huang and J. H. George, Intramolecular tricarbonyl-ene reactions and α-hydroxy-β-diketone rearrangements inspired by the biosynthesis of polycyclic polyprenylated acylphloroglucinols, Angew. Chem., Int. Ed., 2022, 61, e202203311.
22. C. Chen, Y. M. Ren, J. Z. Zhu, J. L. Chen, Z. L. Feng, T. Zhang, Y. Ye and L. G. Lin, Ainsliadimer C, a disesquiterpenoid isolated from Ainsliaea macrocephala, ameliorates inflammatory responses in adipose tissue via Sirtuin 1-NLRP3 inflammasome axis, Acta Pharmacol. Sin., 2022, 43, 1780–1792.
23. X. Ma, M. Zhao, M. Tang, L. Xue, R. Zhang, L. Liu, H. Ni, X. Cai, S. Kuang, F. Hong, L. Wang, K. Chen, H. Tang, Y. Li, A. H. Peng, J. Yang, H. Pei, H. Ye and L. Chen, Flavonoids with inhibitory effects on NLRP3 inflammasome activation from Millettia velutina, J. Nat. Prod., 2020, 83, 2950–2959.

---

Footnotes

† Electronic supplementary information (ESI) available: NMR, HRESIMS, UV, and IR spectra of compound 1. CCDC 2310824 (1). For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo00444b

‡ These authors contributed equally to this work.

---