Undescribed Limonoids Research Articles

Haperforatones A-M, thirteen undescribed limonoids from Harrisonia perforata with anti-inflammatory activity

UPLC-Q-TOF-MS combined with mass defect filtering strategies were applied for the phytochemical investigation of Harrisonia perforata, leading to the isolation of thirteen undescribed limonoids named haperforatones A-M (1–13) and seventeen known compounds (14–30). Particularly, haperforatones D-E (4–5) have an unprecedented A, B, C, D-seco-6, 7-nor-C-24-limonoid skeleton, structurally stripped of the five-membered lactone ring B and formed a double bond at the C-5 and C-10 positions. Their 2D structures and relative configurations were identified using spectroscopic data. The absolute configurations of 1, 4, and 6 were established via X-ray diffraction crystallography. All 30 compounds were evaluated for anti-inflammatory potential in LPS-induced Raw 264.7 cell lines. Among those tested compounds, the most potent activity against LPS-induced NO generation was demonstrated by haperforatone F (6), with the IC50 value of inhibition NO production of 7.2 µM. Additionally, 6 could significantly inhibit IL-1β and IL-6 release and markedly downregulate the protein expression level of iNOS in the LPS-stimulated RAW264.7 cells at 10 µM. The possible mechanism of NO inhibition of 6 was also investigated using molecular docking, which revealed the interaction of compound 6 with the iNOS protein.

Limonoids from the fruits of Chisocheton erythrocarpus and their mosquito larvicidal activities

Phytochemical study of the fruits of Chisocheton erythrocarpus (Hiern) allowed the identification of eight undescribed limonoids, namely erythrocarpines O – V (1–6, 7a and 7b), along with seven known compounds. The structures of these compounds were elucidated based on spectroscopic and HRMS data, along with electronic circular dichroism to configure the absolute configuration. Erythrocarpines O and P are γ-hydroxybutenolide analogs of mexicanolide-type limonoids while erythrocarpine Q – V are phragmalin-type limonoids possessing a 1,29-oxymethylene bridge with either benzoyl or cinnamoyl moiety in their structures. Mosquito larvicidal activity revealed that crude DCM extract of C. erythrocarpus possessed a good larvicidal effect against Aedes aegypti larvae in 48 h (LC50 = 153.0 ppm). Subsequent larvicidal activity of isolated compounds indicated that erythrocarpine G (10) and 14-deoxyxyloccensin K (11) were responsible for the enhanced larvicidal effect of the extract, reporting LC50 values of 18.55 ppm and 41.16 ppm, respectively. Moreover, residual activity testing of the crude DCM extract revealed that the duration of its larvicidal effects is up to 14 days, where it maintained a 98 % larval mortality throughout the test period, under laboratory conditions.

Anti-plasmodial limonoids from Khaya anthotheca (Welw.) C.DC.

The seeds of Khaya anthotheca, (Welv.) yielded two undescribed limonoids, 1α,7α-diacetoxyhavanensin-16-one (1) and 3α,7α-diacetoxyhavanensin-16-one (2), as well as three known limonoids, khayanthone (3), 3,7-di-O-acetyl-14,15-deoxyhavanensin (4) and 1,7-di-O-acetyl-14,15-deoxyhavanensin (5). The antiplasmodial activities of the CH2Cl2 extract and the pure compounds were evaluated in vitro against Plasmodium falciparum (Dd2-B2 strain). Khayanthone (3) showed the highest activity of all the compounds isolated in this study, with an IC50 of 1.32 µg/mL.

Limonoids from the Branches and Leaves of Aglaia lawii and Their Cytotoxic Activities.

Three undescribed limonoids (1-3), named aglaians G-I, and one new natural product azedaralide (4), together with nine known analogues (5-13) were isolated from the branches and leaves of Aglaia lawii by RP C18 column, silica gel column, Sephadex LH-20 column chromatography and preparative HPLC. The structures of the new compounds were elucidated by IR, HRESIMS, 1D, 2D NMR, electronic circular dichroism (ECD) calculations and X-ray crystallography diffraction analysis. The results of bioassay showed that the compound 12 exhibited potential inhibitory activity against six human tumor cell lines (MDA-MB-231, MCF-7, Ln-cap, A549, HeLa and HepG-2) with IC50 values as 8.0-18.6 μM.

Limonoids from the roots of Melia azedarach and their anti-inflammatory activity

Twelve undescribed limonoids, meliazedarines J–U (1–12), along with a known one, were isolated from the roots of Melia azedarach. Their structures were elucidated by extensive spectroscopic investigations, X-ray diffraction analyses, and ECD calculations. Compounds 1–8 were identified as ring intact limonoids, while compounds 9–12 were established as ring C-seco ones. The anti-inflammatory potential of compounds 1–4, 6, 8, 9, and 11–13 was evaluated on macrophages. Compounds 1, 3, 4, 6, and 9 significantly suppressed nitric oxide production in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages, among them compound 3 showed the best inhibitory effect with an IC50 value of 7.07 ± 0.48 μΜ. Furthermore, compound 3 effectively reduced interleukin-1β secretion in LPS plus nigericin-induced THP-1 macrophages by inhibiting NLRP3 inflammasome activation. The results strongly suggested that limonoids from the roots of M. azedarach might be candidates for treating inflammation-related diseases.

Cipacinerasins A–K, structurally diverse limonoids from Cipadessa baccifera

Eleven undescribed limonoids, cipacinerasins A–K, involving of four diverse carbon skeletal types, along with fifteen known analogues, were isolated from the branches and leaves of Cipadessa baccifera. Within them, cipacinerasins A and B feature a rearranged tetrahydropyranyl ring B formed between C-8 and C-30, are unusual miscellaneous-type limonoids. Cipacinerasins E and F are rare trijugin-type limonoids, of which the D-ring δ-lactone is cleaved. Their structures were elucidated on the basis of extensive spectroscopic data (HRESIMS, NMR, UV and IR), electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction analysis. All compounds were evaluated in vitro cytotoxicity against five human tumor cell lines (K562, HeLa, PC3, LN-Cap and Hell), and cipacinerasin E showed moderate antitumor activity with IC50 values ranging from 8.0 to 24.8 μM.

A/D-rings-seco limonoids from the fruits of Aglaia edulis and their bioactivities

Agledulines A-K, eleven previously undescribed limonoids, including eight biogenic A/D-rings-seco limonoid analogs (agledulines A-H), one D-ring-seco limonoid (agleduline I) and two A-ring-seco limonoids with a rare Δ4,28 moiety (agledulines J-K), together with twelve reported limonoids, were isolated from the fruits of Aglaia edulis. Their structures were determined by NMR data, HRESIMS, X-ray diffraction, ECD spectra and the CD exciton chirality method. Observably, the absolute configurations of agleduline A, agleduline C and nymania 2 were unambiguously elucidated by single-crystal X-ray diffraction analyses. The biological evaluation showed that agleduline C exhibited significant cytotoxic activities with IC50 values of 10.05 μM, and 11α-acetoxygedunin showed notable anti-inflammatory activity (IC50: 4.70 μM). In addition, agleduline I and 11α-acetoxygedunin reversed the multidrug resistance with IC50 values of 5.05 and 1.49 μM (RI: 4.64 and 15.77) in the MCF-7/Dox cells.

The bioactive limonoids from Toona ciliate as NLRP3 inflammasome inhibitors

Due to NLRP3 inflammasome has been widely considered as the potential target for the treatment of various immune and inflammation-related diseases, it is significant to discover the natural active ingredients against abnormal NLRP3 inflammasome activation. Toona ciliata M. Roem. as one of the most important industrial wood species has been widely cultivated in southern parts of China, which was usually used in cabinetry for its color, texture, and softness. The twigs of T. cilicata also has been used as a health food and ethnic medicine for the treatment of parasites and rashes. This research mainly investigated the active substances of T. ciliate, and twelve undescribed limonoids, ciliatones A–L (1−12), were isolated from the ethyl acetate extract of the twigs of T. ciliate. The structures of the new compounds were confirmed by comprehensive spectroscopic analyses, semi-synthetic transformations, quantum chemical computations, and X-ray crystal diffractions. Biologically, compound 4 gave a potential inhibiting effect on NLRP3 inflammasome with IC50 values 9.7 ± 3.7 μM and 7.8 ± 4.9 μM against lactate dehydrogenase (LDH) and interleukin 1β (IF-1β), respectively. Western Blot analyses of caspase-1, IL-1β, and gasdermin D (GSDMD) exhibited that 4 could act on nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome and blocked cell pyroptosis. This research could provide support for the medical application of T. ciliate as natural inhibitors of NLRP3 inflammasome.

Limonoids from fruiting bodies of the wood-rot basidiomycete Fulvifomes xylocarpicola associated with the mangrove tree Xylocarpus granatum

Three previously undescribed limonoids, fulvifomins A–C, together with two known compounds, 6-deoxydetigloyl-swietenine acetate and methyl angolensate, were isolated from fruiting bodies of the wood-rot fungus Fulvifomes xylocarpicola (Hymenochaetaceae), growing on the mangrove tree Xylocarpus granatum (Meliaceae). The structures were elucidated on the basis of NMR spectroscopic and mass spectrometry data, and X-ray crystallographic analysis (for fulvifomin A). A number of similar limonoids have been isolated from higher plants of the family Meliaceae, including X. granatum. The present study represents a unique evidence that the associated basidiomycete also contains these limonoids. Fulvifomin B exhibited moderate antimalarial and antitubercular activites.

Highly oxygenated and rearranged limonoids from the stem barks of Entandrophragma utile

Seventeen highly oxygenated and rearranged limonoids, including nine previously undescribed phragmalin-type limonoids with 1,8,9- and 8,9,30-orthesters (entanutilins C–K, 1–9), three undescribed limonoids with rare rearranged-6/6/7/5 skeleton (entanutilins L-N, 10–12), and 5 known limonoids, were isolated from the stem barks of Entandrophragma utile from Ghana (Africa). Their structures including absolute configurations were elucidated based on comprehensive spectroscopic analyses, such as HRESIMS, 1D/2D-NMR, CD exciton chirality method, time-dependent density functional theory (TDDFT)/ECD calculations, and single-crystal X-ray diffraction. Bioactivity screenings suggested that some of these compounds effectively reversed resistance in MCF-7/DOX cells at a nontoxic concentration of 30 μM with 6- to 19-fold enhancing effects.

Isolation of bioactive limonoids from the fruits of Melia azedarach

Two previously undescribed limonoids, 1-O-benzoyl-3-O-deactylnimbolinin C (1) and a pair of epimers named toosendalactonins A and B (12a and 12b), together with ten known compounds (2−11) were isolated from the fruits of Melia azedarach L. Their structures were determined by extensive spectroscopic methods, including 1D-, 2D-nuclear magnetic resonance, and mass spectrometry. All the isolated compounds were evaluated for their nitric oxide (NO) inhibition in lipopolysaccharide-activated microglia and nerve growth factor (NGF) production in astrocytes. Compounds 1−2 and 5−8 significantly inhibited NO production, which is comparable to the positive control, L-NMMA. Previously undescribed limonoid, compound 12, and two known limonoids, munronin K (3) and 12-O-methyl-1-O-deacetyl-nimbolinin B (4), showed the highest potency to increase the NGF production in C6 astrocytes.

Chemical constituents from the twigs and leaves of Trichilia sinensis and their biological activities

Phytochemical investigation on the twigs and leaves of Trichilia sinensis led to the isolation of two previously undescribed limonoids (i.e., trichiliasinenoids D and E, 1 and 2), two previously undescribed phenolic acids (3 and 4), and one previously undescribed natural phenolic acid dimer (5), together with 11 known compounds (6-16). Their structures were elucidated by extensive spectroscopic analysis (IR, UV, HRESIMS, 1D and 2D NMR) and chemical techniques. The potential anti-inflammatory activities of all the compounds were evaluated in lipopolysaccharide-stimulated RAW 264.7 cells. Among these isolates, compounds 1, 2, 6, and 11-13 expressed weak NO inhibition. The antibacterial activities of all the compounds against bacteria were also tested in vitro. Compound 16 exhibited moderate antibacterial activities against Escherichia Coli.

Trijugin- and mexicanolide-type limonoids from the fruits of Heynea trijuga that reverse multidrug resistance in MCF-7/DOX cells

Eleven previously undescribed limonoids, trichisins A-K, including eight structural analogues A-H of trijugin and three H-J mexicanolide derivatives, together with two known mexicanolide derivatives were isolated from the fruits of Heynea trijuga Roxb. ex Sims. The structure determination was based on extensive physical data analyses (NMR, MS), and their basic skeletons and the absolute configurations of trichisins A, B, E, K and trichiconnarone A were assigned via X-ray crystallographic analysis (Cu Kα radiation). The hemiketal motifs in trijugins A, B, and E-G are rare in limonoids. Bioactivity screenings suggested that the trijugin H and mexicanolide-type trichiconnarones A and B limonoids were effective in reversing resistance in MCF-7/DOX cells at a nontoxic concentration of 50 μM with IC50 values of 12.45, 10.86, and 14.96 μM, respectively.