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.

Alliaxylines A-E: five new mexicanolides from the stem barks of Dysoxylum alliaceum (Blume) Blume ex A.Juss.

A total of five new mexicanolides (1-5), namely alliaxylines A-E, together with two known limonoids 6 and 7, were isolated and identified from Dysoxylum alliaceum (Blume) Blume ex. A.Juss. (Meliaceae). The structures of these compounds were elucidated based on extensive spectroscopic analyses, including HR-ESI-MS, UV, IR, 1D, and 2D NMR, as well as theoretical stimulation of NMR shifts with the DP4 + algorithm. Consequently, this study aimed to examine cytotoxic activities of these compounds against MCF-7 and A549 cell lines. The results implied that compound 2 was the most potent against the two tested cells, with IC50 values of 34.95 ± 0.21 and 44.39 ± 1.03 µM.

A Green Extraction Method to Achieve the Highest Yield of Limonin and Hesperidin from Lime Peel Powder (Citrus aurantifolia).

Green extraction is aimed at reducing energy consumption by using renewable plant sources and environmentally friendly bio-solvents. Lime (Citrus aurantifolia) is a rich source of flavonoids (e.g., hesperidin) and limonoids (e.g., limonin). Manufacturing of lime products (e.g., lime juice) yields a considerable amount of lime peel as food waste that should be comprehensively exploited. The aim of this study was to develop a green and simple extraction method to acquire the highest yield of both limonin and hesperidin from the lime peel. The study method included ethanolic-aqueous extraction and variable factors, i.e., ethanol concentrations, pH values of solvent, and extraction temperature. The response surface methodology was used to optimize extraction conditions. The concentrations of limonin and hesperidin were determined by using UHPLC-MS/MS. Results showed that the yields of limonin and hesperidin significantly depended on ethanol concentrations and extraction temperature, while pH value had the least effect. The optimal extraction condition with the highest amounts of limonin and hesperidin was 80% ethanol at pH 7, 50 °C, which yields 2.072 and 3.353 mg/g of limonin and hesperidin, respectively. This study illustrates a green extraction process using food waste, e.g., lime peel, as an energy-saving source and ethanol as a bio-solvent to achieve the highest amount of double bioactive compounds.

Identification of limonoids from Walsura yunnanensis and evaluation of their cytotoxicity against cancer cell lines.

Three new limonoids, walsurauias A-C (1-3), along with four known ones, were isolated from the leaves and twigs of Walsura yunnanensis C. Y. Wu. Their structures were determined on the basis of comprehensive spectroscopic data analysis. The new limonoids were screened for their cytotoxic activity (IC50 0.81-5.73 µM) against four human cancer cell lines, including A549, HepG2, HCT116 p21KO and CNE-2. And α,ß-unsaturated ketone moieties in rings A and B are essential for their cytotoxic activity. Selected compounds were further investigated. Compounds 1-3 effectively induced G2/M cell cycle arrest and apoptosis in a dose-dependent manner in cancer cells. In addition, compounds 1-3 inhibited the colony formation and compounds 2 and 3 suppressed the migration of cancer cells.

Anticancer potential of limonoids from Swietenia macrophylla: Genotoxic, antiproliferative and proapoptotic effects towards human colorectal cancer.

AIMS: Swietenia macrophylla have been considered for the treatment of various diseases, including anticancer activity. This study aimed to investigate the anticancer activity of S. macrophylla leaves extract and its isolated compound towards human colorectal cancer cell line. MAIN METHODS: Hexanic extract of S. macrophylla leaves demonstrated relevant cytotoxicity only against colon cancer cell line HCT116. KEY FINDINGS: Our results showed significant DNA damage and apoptosis after treatment with the hexanic extract of S. macrophylla. Moreover, no toxicity was noticed for the animal model. The isolated compound limonoid L1 showed potent cytotoxicity against cancer cell lines with IC50 at 55.87 µg mL-1. Limonoid L1 did not trigger any cell membrane rupture in the mice erythrocytes suggesting no toxicity. The antiproliferative effect of L1 was confirmed in colorectal cancer cells by clonogenic assay, inducing G2/M arrest, apoptosis, and DNA damage in cancer-type cells. SIGNIFICANCE: L1 reduced BCL2 and increased ATM, CHK2, TP53, ARF, CDK1, CDKN1A, and CASP3 in the colorectal cancer cell line. These findings suggest that limonoid L1 isolated from S. macrophylla can be a promising anticancer agent in managing colorectal cancer.

Khayalactone- and phragmalin-type limonoids with PTP1B inhibitory activity from Trichilia sinensis Bentv.

An investigation on the extract from the plant Trichilia sinensis Bentv. led to the isolation of 13 new limonoids (1-13), in which two were of khayalactone skeleton and 11 were phragmalin-type limonoids, and eight known phragmalin-type limonoids (14-21). Their structures were elucidated by using spectroscopic techniques and HRESIMS experiment. Compounds 6 and 17 displayed potent protein tyrosine phosphatase 1B inhibitory activity with IC50 values of 1.2 ± 0.1 and 8.1 ± 0.5 µM, respectively.

Natural molecule Munronoid I attenuates LPS-induced acute lung injury by promoting the K48-linked ubiquitination and degradation of TAK1.

Acute lung injury (ALI) is a severe lung disease with limited therapeutic strategies. Munronoid I, a limonoid, which is extracted and purified from Munronia sinica, exhibits effective anti-neoplastic activities. In this study, we attempted to determine the anti-inflammatory effects of Munronoid I using both the lipopolysaccharide (LPS)-induced in vivo murine ALI models and in vitro assays. Our results demonstrated that Munronoid I treatment ameliorated LPS-induced ALI and inflammation in mice. Moreover, it also significantly inhibited LPS-induced pathological injuries, infiltration of inflammatory cells, and production of IL-1ß and IL-6. Furthermore, the in vitro assay showed that Munronoid I could inhibit the LPS-induced expression of inflammatory mediators such as iNOS, COX2, and production of pro-inflammatory cytokines by suppressing the activation of NF-κB signaling pathway in mouse peritoneal macrophages. Munronoid I reduced the LPS-, tumor necrosis factor alpha (TNF-α)- or interleukin 1 beta (IL-1ß)-induced transforming growth factor beta-activated kinase 1 (TAK1) phosphorylation and protein expression. Furthermore, the Munronoid I also promoted K48-linked ubiquitination and proteasomal degradation of TAK1. Taken together, these results demonstrated that Munronoid I exhibited anti-inflammatory activities both in vitro and in vivo, which might be a potential therapeutic candidate for the treatment of ALI and pulmonary inflammation.

Structurally diverse limonoids and bio-active evaluation from Trichilia connaroides.

Four new limonoids, named as trichiconlide G (1), 2-hydroxyltrijugin F (2), 23-oxo-21-hydroxyltrijugin F (3), 21-oxo-23-hydroxyltrijugin F (4), along with sixteen known analogues (5-20) were isolated from the leaves and twigs of Trichilia connaroides. Their structures and absolute configurations were determined by spectroscopic analyses, X-ray diffraction analysis, and TD-DFT-ECD calculations. Trichiconlide G (1) is one rare naturally occurring 1,2-seco phragmalin-type limonoid bearing a C-7/28 δ-lactone ring. Additionally, 2-hydroxyltrijugin F (2), 23-oxo-21-hydroxyltrijugin F (3), and 21-oxo-23-hydroxyltrijugin F (4) are three naturally occurring limonoids with a rare C-16/8 δ-lactone ring. All isolates were evaluated for their cytotoxic and anti-inflammatory activities. None of compounds exhibited cytotoxicity against five human cancer cell lines A-549, HepG2, 5-8F, Siha, and SCC-4 at the concentration of 40 µM. Compounds 16 and 17 showed moderate anti-inflammatory activity with IC50 values of 28.45 ± 2.51 and 22.66 ± 2.01 µM, respectively.

Trichilones A-E: New Limonoids from Trichilia adolfi.

In addition to the trichilianones A-D recently reported from Trichilia adolfi, a continuing investigation of the chemical constituents of the ethanol extract of the bark of this medicinal plant yielded the five new limonoids 1-5. They are characterized by having four fused rings and are new examples of prieurianin-type limonoids, having a ε-lactone which in 4 and 5 is α, ß- unsaturated. The structures of the isolated metabolites were determined by high field NMR spectroscopy and HR mass spectrometry. The new metabolites were shown to have the ε-lactone fused with a tetrahydrofuran ring which is connected to an oxidized hexane ring joined with a cyclo-pentanone having a 3-furanyl substituent. As the crude extract possesses antileishmanial activity, the compounds were assayed for cytotoxic and antiparasitic activities in vitro in murine macrophage cells (raw 264.7 cells) and in Leishmania amazoniensis as well as L. braziliensis promastigotes. Metabolites 1-3 and 5 showed moderate cytotoxicity (between 30-94 µg/mL) but are not responsible for the antileishmanial effect of the extract.

Granatripodins A-B, limonoids featuring a Tricyclo[3.3.1.02,8]nonane motif: Absolute configuration and agonistic effects on human pregnane-X-receptor.

Two unprecedented limonoids incorporating a sterically encumbered cyclopropane ring, named granatripodins A (1) and B (2), featuring the presence of a tricyclo[3.3.1.02,8]nonane motif, were obtained from seeds of the Thai Xylocarpus granatum. The planar structures and absolute configurations of these limonoids were unambiguously established by NMR investigations, TDDFT-ECD and DFT-NMR calculations, and single-crystal X-ray diffraction analysis (Cu Kα). Most notably, granatripodin A (1) exhibited agonistic effects on human pregnane-X-receptor at the concentration of 100.0 nM. The biosynthetic origins of these limonoids via a radical cascade reaction are proposed. This study exemplifies a universal approach for the stereochemical assignment of polycyclic compounds with a cyclopropane-embedded cage scaffold.

New limonoids and quinolone alkaloids with cytotoxic and anti-platelet aggregation activities from Evodia rutaecarpa (Juss.) Benth.

One new limonoid, named 19-hydroxy methyl isoobacunoate diosphenol (1); one new degraded limonoid, named 9α-methoxyl dictamdiol (9); two new quinolone alkaloids, 1-methyl-3-[(7E,9E,12Z)-7,9,12-pentadecadienyl]-4(1H)-quinolone (11) and 1-methyl-3-[(7E,9E,11E)-7,9,11-pentadecadienyl]-4(1H)-quinolone (12), along with eight known compounds, evodol (2), 7ß-acetoxy-5-epilimonin (3), rutaevine (4), 6ß-acetoxy-5-epilimonin (5), limonin (6), obacunone (7), clauemargine L (8), hiiranlactone E (10) were isolated from the fruits of Evodia rutaecarpa (Juss.) Benth.. Structures of the four new compounds were elucidated on the basis of extensive spectroscopic techniques, including 1D and 2D NMR techniques. Compounds 3, 5, 9, 11 and 12 showed obviously cytotoxic activity against six human tumor lines, while compounds 11, 12 displayed anti-platelet aggregation induced by ADP at 50 µM and 100 µM.

Chisosiamens A-E, five new ring-intact limonoids with isomerized furan ring from the fruit of Chisocheton siamensis.

Five new ring-intact limonoids with isomerized furan ring, chisosiamens A-E (1-5), along with four known compounds (6-9) were isolated from the fruit of Chisocheton siamensis Craib. Their structures were elucidated based on 1D and 2D NMR spectroscopic data, HRESIMS, circular dichroism, and exciton chirality method. The biological activities screening showed that new limonoid 5 exhibited significant NO inhibitory activity in LPS-activated RAW 264.7 macrophages (IC50: 10.13 ± 1.40 µM) and 1, 2, 5, and 9 effectively reversed the resistance in MCF-7/DOX cells with the range IC50 values of 10.20-15.06 µM (RI: 4.05-5.98).

Limonoids from Guarea guidonia and Cedrela odorata: Heat Shock Protein 90 (Hsp90) Modulator Properties of Chisomicine D.

Nine new limonoids (1-9) were isolated from the stem bark of Guarea guidonia (1-4) and Cedrela odorata (5-9). Their structures were elucidated using 1D and 2D NMR and MS data and chemical methods as three A2,B,D-seco-type limonoids (1-3), a mexicanolide (4), three nomilin-type (5-7) limonoids, and two limonol derivatives (8 and 9). A DFT/NMR procedure was used to define the relative configurations of 1 and 3. A surface plasmon resonance approach was used to screen the Hsp90 binding capability of the limonoids, and the A2,B,D-seco-type limonoid 8-hydro-(8S*,9S*)-dihydroxy-14,15-en-chisomicine A, named chisomicine D (1), demonstrated the highest affinity. By means of mass spectrometry data, biochemical and cellular assays, and molecular docking, 1 was found as a type of client-selective Hsp90 inhibitor binding to the C-terminus domain of the chaperone.

Cytotoxic guaianolides and seco-guaianolides from Artemisia atrovirens.

A phytochemical investigation of a medicinal plant Artemisia atrovirens was carried out, resulting in the characterization of a novel bis-nor seco-guaianolide, seco-atrovirenolide A (1), a new 1,10-seco-guaianolide derivative, seco-atrovirenoic acid A (2), and a new artifact 10-methanoyloxy-seco-atrovirenoic acid A (3), together with eight known guaianolide and seco-guaianolide derivatives (4-11). The structures of new compounds were fully established by extensive analysis of MS, 1D and 2D NMR spectroscopic data. The absolute configurations of the isolated compounds were confirmed by TDDFT ECD calculation, Mosher's method, and X-ray crystal diffraction experiment. All the compounds were tested in vitro for their cytotoxicity against HL-60 and A549 cell lines. Some of them showed moderate inhibitory activity against HL-60 cell lines with IC50 values ranging from 5.99 to 11.74 µM.

Limonoids and other triterpenoids from Entandrophragma angolense.

Four new compounds (1-4) were isolated from the stem bark of Entandrophragma angolense along with eleven known structures (5-15). The chemical structures were elucidated on the basis of spectroscopic and HRMS data, and the absolute configuration was established with the aid of electronic circular dichroism. Compound 5 displayed moderate cytotoxicity against MDA-MB-231, OVCAR3, MDA-MB-435, and HT29 cell lines, with IC50 values ranging from 2.0-5.9 µM.

Krishnolides E-K: New limonoids from the Krishna mangrove Xylocarpus moluccensis.

Seven new limonoids, named krishnolides E-K (1-7), including three khayanolides, two mexicanolides, a derivative of trangmolin A, and an andirobin, were isolated from seeds of the Indian Krishna mangrove, Xylocarpus moluccensis. The structures of these limonoids were established by HRESIMS, extensive NMR investigations, and X-ray crystallography. Most notably, the absolute configurations of 1, 5, 6, and 7 were unequivocally determined by single-crystal X-ray diffraction analyses (Cu Kα). Krishnolide F (2) exhibited significant agonistic effects on human pregnane-X-receptor (hPXR) at the concentration of 10.0 µM. Molecular docking revealed that 2 could bind a helix near the region of the Helix 12 of hPXR. Polar contribution could be electrostatic effects from the formation of two stable protein-ligand hydrogen bonds between Gln285/1-OH and His407/1-OH, respectively. This is the first report of agonistic effects of a khayanolide-type limonoid on hPXR.

Selective and reliable determination of obacunone in rat plasma using solid-phase extraction by liquid chromatography tandem mass spectrometry: Application to a pharmacokinetic study.

This study aimed to develop a highly selective, sensitive and fast liquid chromatography tandem mass spectrometric (LC-MS/MS) method for the determination of obacunone in rat plasma. Sample preparation was accomplished by a simple solid-phase extraction procedure. Chromatographic separation was carried out on an ACQUITY BEH C18 column using acetonitrile/methanol (1:1, v/v) and 0.1% formic acid in water as mobile phase at a flow rate of 0.4 mL/min. Quantification was performed with multiple reactions monitoring in positive ion mode with the precursor-to-product ion transitions at m/z 455.2 > 161.1 for obacunone and m/z 515.2 > 161.1 for nomilin (internal standard). The assay was demonstrated to be linear over the concentration range of 0.1-1,000 ng/mL with correlation coefficient >0.999 (r > 0.999). The intra- and inter-day accuracy ranged from -8.33 to 10.40%, while the precision was <10.41%. The mean extraction recovery was >75.32%, and the assay was free of matrix effect. The validated LC-MS/MS method was successfully applied to the pharmacokinetic study of obacunone in rats after oral and intravenous administrations. The oral bioavailability of obacunone was 13.59%.

Bioactive Limonoids and Triterpenoids from the Fruits of Melia azedarach.

Nine new limonoids, meliazedarines A-I (1-9), seven known analogues (10-16), and five known triterpenoids (17-21) were isolated from the fruits of Melia azedarach. Their structures were determined by analysis of 1D and 2D NMR, HRESIMS, X-ray diffraction, and electronic circular dichroism (ECD) data. Compound 7 showed significant cytotoxicity against the HCT116 cell line with IC50 values of 0.3 ± 0.1 µM.

Limonoids with diverse structures of rings-A,B from the Thai mangrove, Xylocarpus moluccensis.

Nine new limonoids, named thaixylomolins S-Z (1-8) and 2-O-acetylthaixylomolin Z (9), were isolated from seeds of the mangrove, Xylocarpus moluccensis, collected in the mangrove swamp of Trang Province, Thailand. Thaixylomolin S (1) is the fourth member of the khayalactone class of limonoids containing a hexahydro-2H-2,5- propanocyclopenta[b]furan motif. Thaixylomolins T-Y (2-7) are structurally diverse mexicanolides; whereas thaixylomolin Z (8) and 2-O-acetylthaixylomolin Z (9) are phragmalin 8,9,30-orthoesters. The structures of these compounds were established by HRESIMS and extensive 1D and 2D NMR investigations. The absolute configurations of thaixylomolins S (1), U (3), and Z (8) were unambiguously established by single-crystal X-ray diffraction analyses, conducted with Cu Kα radiation; whereas that of 2-O-acetylthaixylomolin Z (9) was determined to be the same as that of thaixylomolin Z (8) by the accurate fit of their experimental electronic circular dichroism spectra. Thaixylomolin S (1), featuring the presence of a 30-(2'-methyl)butyryloxy group, is the first limonoid of the khayalactone class, whose constitution and absolute configuration are unequivocally determined by X-ray crystallography. The inhibitory activities of all the compounds, except for the epimers 4, were assayed against human carboxylesterase 2. All the tested compounds exhibited inhibition rates in the range of 16-65% at the concentration of 100.0 µM.

Toonaolides A-X, limonoids from Toona ciliata: Isolation, structural elucidation, and bioactivity against NLRP3 inflammasome.

Twenty-four new limonoids, toonaolides A-X (1-24), characterized with an α,ß-unsaturated-γ-lactone A-ring were isolated from the twigs of Toona ciliata. Their structures and absolute configurations were elucidated by spectroscopic data, X-ray diffraction crystallography, and quantum chemistry calculations. Most of the isolated compounds (except 9, 18, and 24 which possessed the maleimide ring) featured the rare 21-hydroxybutenolide or 23-hydroxybutenolide moieties. In particular, compound 1 has an unprecedented limonoid architecture with 6/6 cis-fused A/B ring system and 2 has an unusual tetrahydrofuran ring B skeleton, featuring a 7/5/6/5 ring system. The biological evaluation showed that compounds 9, 11, 12, 14, and 18 exhibited significantly anti-NLRP3 inflammasome activity with IC50 values ranging from 3.2 to 9.7 µM. Analysis of IL-1ß and caspase-1 expression revealed that compounds 11 and 12 are selective inhibitors of NLRP3 inflammasome, which could ameliorate cell pyroptosis by blocking NLRP3 inflammasome activation.