Two new limonoid glycosides from the seeds of Citrus Limon and their PDE4D inhibitory activities.

Two new limonoid glycosides, named limonosides A (1) and B (2), along with four known limonoids (3-6) were obtained from the seeds of Citrus limon. Their structures were deduced based on extensive spectroscopic analysis. Limonoside A (1) and nomilin (4) were found to possess moderate phosphodiesterase type 4D (PDE4D) inhibitory effect with values of 89.8 ± 2.4% and 98.9 ± 3.0% at 10 µM, respectively.

New anti-inflammatory limonoids from the fruits of Melia azedarach.

The phytochemical study of the fruits of Melia azedarach (Meliaceae) led to the isolation and characterisation of two novel natural limonoids1-deoxy- 3, 20-dicinnamoyl-11-methoxy-meliacarpinin (1) and 12ß- O- methyl nimbolinin A (2), along with twelve known limonoids. Its structure was identified by 1D- and 2D-NMR, HR-ESI-MS and comparison with published data. The anti-inflammatory effect of the compounds was measured in vitro in RAW 264.7 cells by evaluating the production of NO stimulated by LPS. Compounds 1, 8 and 14 indicated significant anti-inflammatory effect with inhibition rate of 11.76, 8.45 and 6.59 µM, respectively. Limonoid 1 significantly inhibited the production of NO, TNF-α and IL-1ß in RAW 264.7 cells. Therefore, limonoid derivative may be a promising source of bioactive metabolite for inflammatory diseases.

Computational Binding Study Hints at Ecdysone 20-Mono-Oxygenase as the Hitherto Unknown Target for Ring C-Seco Limonoid-Type Insecticides.

The insecticidal property of ring C-seco limonoids has been discovered empirically and the target protein identified, but, to date, the molecular mechanism of action has not been described at the atomic scale. We elucidate on computational grounds whether nine C-seco limonoids present sufficiently high affinity to bind specifically with the putative target enzyme of the insects (ecdysone 20-monooxygenase). To this end, 3D models of ligands and the receptor target were generated and their interaction energies estimated by docking simulations. As a proof of concept, the tetrahydro-isoquinolinyl propenamide derivative QHC is the reference ligand bound to aldosterone synthase in the complex with PDB entry 4ZGX. It served as the 3D template for target modeling via homology. QHC was successfully docked back to its crystal pose in a one-digit nanomolar range. The reported experimental binding affinities span over the nanomolar to lower micromolar range. All nine limonoids were found with strong affinities in the range of -9 < ΔG < -13 kcal/mol. The molt hormone ecdysone showed a comparable ΔG energy of -12 kcal/mol, whereas -11 kcal/mol was the back docking result for the liganded crystal 4ZGX. In conclusion, the nine C-seco limonoids were strong binders on theoretical grounds in an activity range between a ten-fold lower to a ten-fold higher concentration level than insecticide ecdysone with its known target receptor. The comparable or even stronger binding hints at ecdysone 20-monooxygenase as their target biomolecule. Our assumption, however, is in need of future experimental confirmation before conclusions with certainty can be drawn about the true molecular mechanism of action for the C-seco limonoids under scrutiny.

Obacunone, a Promising Phytochemical Triterpenoid: Research Progress on Its Pharmacological Activity and Mechanism.

Obacunone, a natural triterpenoid, is an active component of the herbs Dictamnus dasycarpus Turcz. and Phellodendron amurense Rupr, and an indicator of the herbs' quality. Owing to its multiple health benefits, several studies have investigated the multi-targeting potential action mechanisms of obacunone. To summarize recent developments on the pharmacological actions of obacunone and focus on the underlying molecular mechanisms and signaling networks, we searched PubMed, Europe PMC, Wiley Online Library, Web of Science, Google Scholar, Wanfang Medical Network, and China National Knowledge Infrastructure for articles published prior to March 2024. Existing research indicates obacunone has great potential to become a promising therapeutic option against tumors, fibrotic diseases, bone and cholesterol metabolism diseases, and infections of pathogenic microorganisms, among others. The paper contributes to providing up-to-date references for further research and clinical applications of obacunone.

Paraxylines A-G: Highly oxygenated preurianin-type limonoids with immunomodulatory TLR4 and cytotoxic activities from the stem bark of Dysoxylum parasiticum.

Seven previously undescribed preurianin-type limonoids, namely paraxylines A-G, and three known analogs were isolated from stem bark of Dysoxylum parasiticum. The structures, including absolute configurations, were established through spectroscopic analyses, quantum chemical calculations using the density functional theory method, as well as the DP4+ algorithm. Paraxylines A-G were identified as the first preurianin-type with full substitution at C, D-rings, leading to the highly oxygenated seco-limonoids skeleton. The secreted alkaline phosphate assay against an engineered human and murine TLR4 of HEK-Blue cells was performed to evaluate the immune regulating effects. Among them, paraxyline B was found to be a remarkable TLR4 agonist whereas two analogs (toonapubesins A and B) were found to antagonise lipopolysaccharide stimulation of the TLR4 pathway. Paraxylines A and C-E acted either as agonists or antagonists depending on the origin of the TLR4 receptor (human or mouse). The effect of these selected compounds on the expression of pro-inflammatory cytokines TNF-α, IL-1α, IL-1ß, and IL-6 of the NF-κB signaling pathway were examined in macrophage cell lines, revealing dose-dependent effects. Additionally, paraxylines A, C, D, and G also presented modest cytotoxic activity against MCF-7 and HeLa cell lines with IC50 values ranging from 23.1 to 43.5 µM.

Unusual Vilasinin-Class Limonoids from Trichilia rubescens.

Eight vilasinin-class limonoids, including the unusually chlorinated rubescins K-M (1-3), the 2,3-epoxylated rubescin N (4), and rubescins O-R (5-8), were newly isolated from Trichilia rubescens. The structures of the isolated compounds were determined through spectroscopic and spectrometric analyses, as well as ECD calculations. The natural occurrence of chlorinated limonoids 1-3 was confirmed by chemical methods and HPLC analysis of a roughly fractionated portion of the plant extract. Eight selected limonoids, including previously known and new compounds, were evaluated for antiproliferative activity against five human tumor cell lines. All tested limonoids, except 8, exhibited significant potency, with IC50 values of <10 µM; in particular, limonoid 14 strongly inhibited tumor cell growth, with IC50 values of 0.54-2.06 µM against all tumor cell lines, including multi-drug-resistant cells.

In Vitro Anti-Inflammatory Study of Limonoids Isolated from Chisocheton Plants.

Chisocheton plants from the family Meliaceae have traditionally been used to treat several diseases; however, scientific evidence is limited. The most abundant chemical constituents of this plant are the limonoids, which are known for their various biological activities, including anti-inflammatory effects. However, the anti-inflammatory effects and underlying mechanisms of action of the constituents of Chisocheton plants have not been fully explored. In this report, we evaluated the anti-inflammatory activity of 17 limonoid compounds from Chisocheton plant primarily by measuring their inhibitory effects on the production of pro-inflammatory cytokines, including TNF-α, IL-6, IL-1ß, and MCP-1, in LPS-stimulated THP-1 cells using an ELISA assay. Compounds 3, 5, 9, and 14-17 exhibited significant activity in inhibiting the evaluated pro-inflammatory markers, with IC50 values less than 20 µM and a high selectivity index (SI) range. Compounds 3, 5, 9, and 15 significantly suppressed the expression of phosphorylated p38 MAPK in THP-1 cells stimulated with LPS. These findings support the use of limonoids from Chisocheton plants as promising candidates for anti-inflammatory therapy.

Unusual triterpenoids and steroids from Cipadessa baccifera and their biological activities.

Five undescribed triterpenoids and steroids (1-5), as well as ten known compounds, were purified from the branches and leaves of Cipadessa baccifera. Notably, 1 and 2 are rare cipadesin-type limonoids with an unusual 8,30-epoxide ring and 1,8-ether linkage, respectively. Compound 5 possessed pregnane steroid skeleton with an uncommon 5/6/6/6/5-fused ring system. Their structures were constructed by extensive spectroscopic analysis (NMR, IR, UV, and HRESIMS), and their absolute configurations were confirmed by ECD calculations and quantum chemical calculations. All the isolates were in vitro assayed for their antimicrobial potentials against 6 pathogenic microorganisms and antiproliferation activities against five human cancer cell lines. As a result, compounds 5, 12, 13, and 14 exhibited moderate antibacterial activities (MIC: 25-50 µg/mL). Moreover, 5 showed cytotoxicity against five cancer cell lines with IC50 values ranging from 8.0 to 19.9 µM.

Swietenolide isolated from Swietenia macrophylla King in Hook seeds shows in vitro anti-colorectal cancer activity through inhibition of mouse double minute 2 (MDM2) homolog.

Swietenia macrophylla King in Hook (SM) is known to have several medicinal properties. Chloroform extracts of SM seeds (SMCE) as well as two isolated limonoids swietenine (1) and swietenolide (2) showed significant in vitro anti-CRC activity in human colon carcinoma (HCT116) cell line. 2 (IC50 = 5.6 µM) was found to be two times more potent than 1 (IC50 = 10 µM). Both compounds showed anti-CRC activity through inhibition of the Mouse Double Minute 2 homolog (MDM2) of the MDM2-p53 pathway. The Selectivity Index (S.I.) of isolated compounds 1 and 2 for cancer cells were about 6.6 and 12.8 fold respectively which was significantly better than the S.I. of the extract (S.I. ∼1.5).

Phragmalin-Type Limonoids from the Fruits of Chukrasia tabularis and Their Anti-Inflammatory Activity.

Phytochemical investigation on the fruits of C. tabularis led to the isolation of five new phragmalin-type limonoids (1-5) and four known ones (6-9). The structures of the new compounds 1-5, named chuktabamalins A-E, were elucidated via spectroscopic techniques (HRESIMS, 1D and 2D NMR) and were comparable with the literature data of known compounds. In addition, new compounds were evaluated for in vitro anti-inflammatory activity. Compounds 1, 2, 3 and 5 showed moderate anti-inflammatory activity with IC50 values of 21.72 ± 2.79, 23.29 ± 1.00, 47.08 ± 3.47 and 66.67 ± 2.89 µM, respectively.

The pharmacological and pharmacokinetic properties of obacunone from citrus fruits: A comprehensive narrative review.

Limonoids are a class of oxygenated terpenoids that exist mainly in citrus fruits. As a kind of limonoid, obacunone has attracted more and more researchers' attention because of its extensive pharmacological activities. The purpose of the narrative review is to systematically review relevant studies on the pharmacological effects and pharmacokinetic characteristics of obacunone to provide researchers with the latest and useful information. Pharmacological studies have shown that obacunone has a variety of pharmacological activities, such as anticancer, antioxidant, anti-inflammatory, anti-diabetes, neuroprotection, antibiosis, and antivirus. Among them, the anticancer effect is the most prominent. Pharmacokinetic studies have shown that the oral bioavailability of obacunone is low. This indicates the presence of high first-pass metabolism. We hope that this paper can help relevant scholars understand the progress in pharmacological and pharmacokinetic research of obacunone and help the further development of obacunone as a functional food.

Xylomolins O-X: New limonoids from the Thai mangrove Xylocarpus moluccensis.

Ten new limonoids, named xylomolins O-X, were isolated from seeds of the mangrove Xylocarpus moluccensis, collected in the mangrove swamp of Trang Province, Thailand. Their structures were elucidated on the basis of comprehensive spectroscopic data analysis. The absolute configurations of five compounds (1, 3, 8-10) were unequivocally determined by single-crystal X-ray diffraction analyses, conducted with Cu Kα radiation. Xylomolins OU (1-7) are structurally intriguing mexicanolides, and xylomolin V (8) is a derivative of azadirone. Xylomolin W (9) is the first phragmalin 1,8,9-orthoester with report on X-ray crystallography from the genus Xylocarpus. In addition, xylomolin X (10) is the fifth member of the khayalactone class of limonoids with a hexahydro-2H-2,5-propanocyclopenta[b]furan motif. Compounds 1-10 inhibited NO production in LPS-activated RAW 264.7 macrophages in the range of 10.45-95.47% at the concentration of 100.0 µM. Xylomolin X (10) and xylomolin V (8), exhibited the most potent activity with IC50 values of 9.90 ± 1.84 µM and 14.66 ± 2.33 µM, respectively.

Limonoids from the fruits of Chisocheton lasiocarpus (Meliaceae).

Two new azadirone-type limonoids, namely lasiocarpine A (1) and lasiocarpine B (2) were isolated from the fruit of Chisocheton lasiocarpus along with three known limonoids (3-5). UV, IR, one- and two- dimensional NMR, and mass spectrometry were used to determine the chemical structure of the isolated compounds. Furthermore, their cytotoxic activity against breast cancer cell line MCF-7 was evaluated using PrestoBlue reagent. From these compounds, lasiocarpine A (1) showed the strongest activity with an IC50 value of 43.38 µM.

Meliaceae genomes provide insights into wood development and limonoids biosynthesis.

Meliaceae is a useful plant family owing to its high-quality timber and its many limonoids that have pharmacological and biological activities. Although some genomes of Meliaceae species have been reported, many questions regarding their unique family features, namely wood quality and natural products, have not been answered. In this study, we provide the whole-genome sequence of Melia azedarach comprising 237.16 Mb with a contig N50 of 8.07 Mb, and an improved genome sequence of Azadirachta indica comprising 223.66 Mb with a contig N50 of 8.91 Mb. Moreover, genome skimming data, transcriptomes and other published genomes were comprehensively analysed to determine the genes and proteins that produce superior wood and valuable limonoids. Phylogenetic analysis of chloroplast genomes, single-copy gene families and single-nucleotide polymorphisms revealed that Meliaceae should be classified into two subfamilies: Cedreloideae and Melioideae. Although the Meliaceae species did not undergo additional whole-genome duplication events, the secondary wall biosynthetic genes of the woody Cedreloideae species, Toona sinensis, expanded significantly compared to those of A. indica and M. azedarach, especially in downstream transcription factors and cellulose/hemicellulose biosynthesis-related genes. Moreover, expanded special oxidosqualene cyclase catalogues can help diversify Sapindales skeletons, and the clustered genes that regulate terpene chain elongation, cyclization and modification would support their roles in limonoid biosynthesis. The expanded clans of terpene synthase, O-methyltransferase and cytochrome P450, which are mainly derived from tandem duplication, are responsible for the different limonoid classes among the species. These results are beneficial for further investigations of wood development and limonoid biosynthesis.

Hainanxylogranolides A-F: New Limonoids isolated from the seeds of Hainan mangrove plant Xylocarpus granatum.

Six new limonoids, named hainanxylogranolides A-F (1-6), together with nineteen known ones (7-25) were isolated from the seeds of a Hainan mangrove Xylocarpus granatum. The structures of the new compounds were established by extensive NMR spectroscopic data combined with the DFT and TDDFT calculated electronic circular dichroism spectra. Hainanxylogranolide A (1) is the aromatic B-ring limonoid containing a central pyridine ring and a C-17 substituted γ(21)-hydroxybutenolide moiety. Hainanxylogranolide B (2) belongs to the small group of mexicanolides containing a C3-O-C8 bridge, whereas hainanxylogranolides C and D (3 and 4) are mexicanolides comprising a C1-O-C8 bridge. Compounds 9 and 25 posed obvious inhibition effect on the tube formation of HUVECs. There are only about 25% tube-like structures were observed at the concentration of 40.0 µM of compound 25. The antiviral activities of the isolates against herpes simplex virus-1 (HSV-1) and severe fever with thrombocytopenia syndrome virus (SFTSV) were tested in vitro. Compound 23 exhibited moderate anti-SFTSV activity with the IC50 value of 29.58 ± 0.73 µM. This is the first report of anti-angiogenic effect and anti-SFTSV activity of limonoids from the genus Xylocarpus.

A Gedunin-Type Limonoid, 7-Deacetoxy-7-Oxogedunin, from Andiroba (Carapa guianensis Aublet) Reduced Intracellular Triglyceride Content and Enhanced Autophagy in HepG2 Cells.

The seed oil of Carapa guianensis Aublet (Andiroba) has been used in folk medicine for its insect-repelling, anti-inflammatory, and anti-malarial activities. This study aimed to examine the triglyceride (TG) reducing effects of C. guianensis-derived limonoids or other commercially available limonoids in human hepatoblastoma HepG2 cells and evaluate the expression of lipid metabolism or autophagy-related proteins by treatment with 7-deacetoxy-7-oxogedunin (DAOG; 1), a principal limonoid of C. guianensis. The gedunin-type limonoids, such as DAOG (% of control at 20 µM: 70.9 ± 0.9%), gedunin (2, 74.0 ± 1.1%), epoxyazadiradione (4, 73.4 ± 2.0%), 17ß-hydroxyazadiradione (5, 79.9 ± 0.6%), 7-deacetoxy-7α-hydroxygedunin (6, 61.0 ± 1.2%), andirolide H (7, 87.4 ± 2.2%), and 6α-hydroxygedunin (8, 84.5 ± 1.1%), were observed to reduce the TG content at lower concentrations than berberine chloride (BBR, a positive control, 84.1 ± 0.3% at 30 µM) in HepG2 cells pretreated with high glucose and oleic acid. Andirobin-, obacunol-, nimbin-, and salannin-type limonoids showed no effect on the intracellular TG content in HepG2 cells. The TG-reducing effect of DAOG was attenuated by the concomitant use of compound C (dorsomorphin), an AMPK inhibitor. Further investigation on the detailed mechanism of action of DAOG at non-cytotoxic concentrations revealed that the expressions of autophagy-related proteins, LC3 and p62, were upregulated by treatment with DAOG. These findings suggested that gedunin-type limonoids from Andiroba could ameliorate fatty liver, and that the action of DAOG in particular is mediated by autophagy.

Limonoids with anti-inflammatory activity: A review.

The natural limonoids distributed mainly in the Meliaceae and Rutaceae plants are known for their unique and complex structure with high degree oxidation and cyclic rearrangement. However, these compounds exhibit a broad range of biological activities such as insecticidal, antibacterial, antifungal, antimalarial, antioxidant, anticancer, antiviral, and anti-inflammatory. There is still limited report about the biological activity of the anti-inflammatory effect of limonoids isolated from plants. Therefore, this study aimed to examine the effect of intact, deformed and rearranged limonoids as anti-inflammatory agents. The majority of anti-inflammatory investigations were evaluated by in vitro and in vivo assays of the isolated pure compounds and their derivatives. For the in vitro study, intact and C-ring seco limonoids showed a potent inhibitory effect against NO production. The in vivo analysis of Intact, C-seco, and AD-seco limonoids showed a potent effect based on the inhibition of pro-inflammatory cytokines expression, indicating their potency as anti-inflammatory agents.

Coumarins, furocoumarins and limonoids of Citrus trifoliata and their effects on human colon adenocarcinoma cell lines.

Citrus trifoliata L. (Chinese or Japanese bitter orange) is a medicinal plant with furocoumarins and limonoids as characteristic secondary metabolites. The bitter taste of the fruit limits its use as food, however, it is applied in Asian traditional medicine for its antiphlogistic effect, to treat digestive ulcers and different gastrointestinal disorders and cancer. The phytochemical composition and pharmacological characteristics of this species have not been fully discovered, nevertheless its potential antiproliferative or cytotoxic effects might be related to furocoumarins or limonoids. Our aim was to isolate and identify secondary metabolites from C. trifoliata peel and seeds and to investigate their bioactivities that might be related to the supposed anticancer effect of the plant. By using different chromatographic methods, six pure compounds (phellopterin (2), scoparone (3), myrsellin (4), triphasiol (6), umbelliferone (7) and citropten (5,7-dimethoxycoumarin (8)) were isolated from the peel and four (imperatorin (1), auraptene (5), limonin (9) and deacetyl nomilin (10)) from the seeds of C. trifoliata fruits. These compounds are furocoumarin (1, 2), coumarin (3-8), and limonoid derivatives (9, 10). Scoparone (3) has been detected in this species for the first time. The furocoumarins (1-2) showed moderate activity on the human colorectal adenocarcinona tumor cell line COLO 320 in antiproliferative assays and 2 also had remarkable P-glycoprotein inhibitory activity and synergistic effect with doxorubicin. The coumarin 5 showed significant activity on the COLO 320 cell line in antiproliferative assays and P-glycoprotein inhibitory activity in the FACS (fluorescence activated cell sorting) assay.

Chemical constituents of Entandrophragma angolense and their anti-inflammatory activity.

From the stem bark of Entandrophragma angolense, six undescribed compounds were isolated, including seco-tirucallane type triterpenoids, limonoids, and a catechin glucoside, along with nineteen known structures. All structures were determined by interpretation of spectroscopic and HRMS data, and absolute configuration was confirmed with the aid of electronic circular dichroism. The isolated compounds were tested for LPS-induced NO inhibition in RAW 264.7 macrophages and EC50 values for moluccensin O and (-)-catechin were 81 µM and 137 µM, respectively.

Anti-TMV activity and effects of three prieurianin-type limonoids from Munronia henryi.

Three prieurianin-type limonoids (1-3), including two new compounds (1 and 2) and one known compound (3) were isolated from Munronia henryi. These compounds were tested for their activities against tobacco mosaic virus (TMV) by the conventional half-leaf method and the outcomes were analyzed by western blotting and RT-PCR assays. The three tested compounds, at 100 µg/mL, showed strong antiviral activities in the pretreated tobacco plants with inhibition rates ranging from 70.5% to 81.3%, which were significantly higher than that of the positive control, ningnanmycin (55.6%). Their potential of inducing systemic acquired resistance (SAR) was also evaluated, in which compound 1 showed excellent induction activities. Furthermore, it was found that potentiation of defense-related enzyme activity and the contents of SA was increased. Compound 1 could also inhibit the expression of TMV CP and up-regulate the expression of defense-related genes. This work revealed that these limonoids, especially compound 1 could induce resistance in tobacco plants against the viral pathogen TMV. Meanwhile, compounds 1-3 could down-regulate the expression of NtHsp70-1 and Nthsp70-261 genes, indicating that these limonoids possibly inhibit TMV infection by suppressing NtHsp70-1 and Nthsp70-261 expression. This study is the first to report antiviral compounds with two different mechanisms of action.