Molecular Mechanisms of Medicinal Plant Securinega suffruticosa-derived Compound Securinine against Spinal Muscular Atrophy based on Network Pharmacology and Experimental Verification.

BACKGROUND: Spinal Muscular Atrophy (SMA) is a severe motor neuronal disorder with high morbidity and mortality. Securinine has shown the potential to treat SMA; however, its anti-SMA role remains unclear. OBJECTIVE: This study aims to reveal the anti-SMA mechanisms of securinine. METHODS: Securinine-associated targets were acquired from Herbal Ingredients' Targets (HIT), Similarity Ensemble Approach (SEA), and SuperPred. SMA-associated targets were obtained from GeneCards and Dis- GeNET. Protein-protein Interaction (PPI) network was constructed using GeneMANIA, and hug targets were screened using cytoHubba. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using ClusterProfifiler. Molecular docking was conducted using Pymol and Auto- Dock. In vitro assays were used to verify the anti-SMA effects of securinine. RESULTS: Twenty-six intersection targets of securinine and SMA were obtained. HDAC1, HDAC2, TOP2A, PIK3R1, PRMT5, JAK2, HSP90AB1, TERT, PTGS2, and PAX8 were the core targets in PPI network. GO analysis demonstrated that the intersecting targets were implicated in the regulation of proteins, steroid hormones, histone deacetylases, and DNA transcription. KEGG analysis, pathway-pathway, and hub target-pathway networks revealed that securinine might treat SMA through TNF, JAK-STAT, Ras, and PI3K-Akt pathways. Securinine had a favorable binding affinity with HDAC1, HSP90AB, JAK2, PRMT5, PTGS2, and TERT. Securinine rescued viability suppression, mitochondria damage, and SMN loss in the SMA cell model. Furthermore, securinine increased HDAC1 and PRMT5 expression, decreased PTGS2 expression, suppressed the JAK2-STAT3 pathway, and promoted the PI3K-Akt pathway. CONCLUSION: Securinine might alleviate SMA by elevating HDAC1 and PRMT5 expression and reducing PTGS2 via JAK2-STAT3 suppression and PI3K-Akt activation.

Potential anticancer activities of securinine and its molecular targets.

BACKGROUND: Securinine is an alkaloid identified from the roots and leaves of the shrub Flueggea suffruticosa (Pall.) Baill. The molecular structure of securinine consists of four rings, including three chiral centers. It has been suggested that securinine can be chemically synthesized from tyrosine and lysine. Securinine has long been used to treat central nervous system diseases. In recent years, more and more evidence shows that securinine also has anticancer activity, which has not been systematically discussed and analyzed. PURPOSE: This study aims to propose an overall framework to describe the molecular targets of securinine in different signal pathways, and discuss the current status and prospects of each pathway, so as to provide a theoretical basis for the development securinine as an effective anticancer drug. METHODS: The research databases on the anticancer activity of securinine from PubMed, Scopus, Web of Science and ScienceDirect to 2021 were systematically searched. This paper follows the Preferred Reporting Items and Meta-Analysis guidelines. RESULTS: Securinine has the ability to kill a variety of human cancer cells, including, leukemia as well as prostate, cervical, breast, lung, and colon cancer cells. It can regulate the signal pathways of phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin, Wnt and Janus kinase-signal transducer and activator of transcription, promote cancer cell apoptosis and autophagy, and inhibit cancer cell metastasis. Securinine also has the activity of inducing leukemia cell differentiation. CONCLUSION: Although there has been some experimental evidence indicating the anticancer effect of securinine and its possible pharmacology, in order to design more effective anticancer drugs, it is necessary to study the synergy of intracellular signaling pathways. More in vivo experiments and even clinical studies are needed, and the synergy between securinine and other drugs is also worth studying.

Identification of securinine as vascular protective agent targeting atherosclerosis in vascular endothelial cells, smooth muscle cells, and apolipoprotein E deficient mice.

BACKGROUND: Atherosclerosis is a chronic vascular disease and characterized by accumulation within the intima of inflammatory cells, smooth muscle cells, lipid, and connective tissue. PURPOSE: The purpose of the present study was to identify natural agents that commonly reverse advanced atherosclerotic plaque to early atherosclerotic plaque. METHODS: Differentially expressed genes (DEGs) were analyzed in silico. The differentially expressed genes from 9 intimal thickening and 8 fibrous cap atheroma tissue which were collected from GEO data were assessed by the connectivity map. Natural candidate securinine, a main compound from Securinega suffruticosa, was selected and administrated 1, 5 mg/kg/day in apolipoprotein-E-deficient (ApoE KO) mice for 18 weeks. RESULTS: Securinine significantly showed lowered blood pressure and improvement of metabolic parameters with hyperlipidemia. The impairment in vasorelaxation was remarkably decreased by treatment with securinine. H&E staining revealed that treatment with securinine reduced atherosclerotic lesions. Securinine suppressed the expression of adhesion molecules and matrix metalloproteinase-2/-9 in both ApoE KO and vascular endothelial cells (HUVEC). In HUVEC pretreatment with securinine significantly inhibited ROS generation and NF-κB activation. Growth curve assays using the real-time cell analyzer showed that securinine significantly decreased TNF-α-induced aortic smooth muscle cell proliferation and migration in a dose-dependent manner. CONCLUSION: Securinine may be a potential natural candidate for the treatment of atherosclerosis because it attenuates vascular inflammation and dysfunction as well as vascular lesion.

Securinine suppresses osteoclastogenesis and ameliorates inflammatory bone loss.

Securinine (Sec) is a naturally derived compound separated from the roots of Securinega suffruticosa, which has long been used as a herbal medicine. Sec is widely known as a GABA receptor antagonist, it is also known as an innate immune cell agonist and has been reported to increase macrophage activity and promote monocyte maturation. On the basis of these studies, we investigated the effect of Sec on osteoclast differentiation and bone resorbing function. We have found that Sec inhibits RANKL-induced osteoclast differentiation, fusion, actin ring formation, and bone resorbing function by the inhibition of gene expression associated with each stage. Moreover, Sec significantly suppressed osteoclastogenesis by decreasing the phosphorylation of p38, Akt, JNK, IκB, and PLCγ2, in pathways involved in early osteoclastogenesis as well as through the subsequent suppression of c-Fos and NFATc1. Finally, Sec effectively protected bone loss induced by the excessive inflammatory responses and activity of osteoclasts in vivo by a micro-CT and histological analysis. In conclusion, our findings suggest that Sec may be a promising drug for bone metabolic diseases such as osteoporosis, which is associated with the excessive activity of osteoclasts.

The combination of Ilexhainanoside D and ilexsaponin A1 reduces liver inflammation and improves intestinal barrier function in mice with high-fat diet-induced non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is becoming a major health concern worldwide. Ilex hainanensis Merr. extract was proved to have anti-inflammation effect on NAFLD, and Ilexhainanoside D (IhD) and ilexsaponin A1 (IsA) were the main triterpenoid saponins extracted from it. PURPOSES: To investigate the hepatoprotective effect of the combination of IhD and IsA (IIC) against NAFLD and discuss the potential mechanisms. METHODS: Male C57BL/6 mice were fed a high-fat diet (HFD) to induce NAFLD and were treated with IIC (60, 120 or 240 mg/kg) for 8 weeks. Growth parameters, abdominal fat content, serum biochemical markers, hepatic lipid accumulation and insulin tolerance were assessed. Quantitative real-time PCR was used to determine the hepatic gene expression of TLR2, TLR4, TNF-α, IL-6, and IL-1ß. Western blot analysis was performed to determine the expression of the epidermal tight junction proteins ZO-1 and occludin. Gut microbiota profiles were established via high-throughput sequencing of the V3-V4 region of the bacterial 16S rRNA gene. RESULTS: IIC significantly reduced the severity of NAFLD induced by HFD in a dose-dependent manner. IIC decreased the ratio of Firmicutes/Bacteroidetes, reduced the relative abundance of Desulfovibrio and increased the relative abundance of Akkermansia. The intestinal barrier was improved as evidenced by the upregulation of the expression of ZO-1 and occludin in the ileum. IIC thus reduced the entry of LPS into the circulation and decreased the hepatic gene expression levels of proinflammatory cytokines. CONCLUSION: This approach demonstrated the positive effects of IIC in a mouse model of NAFLD, indicating that it possibly acts by reducing inflammation and improving the intestinal barrier function.

A combination of astragaloside I, levistilide A and calycosin exerts anti-liver fibrosis effects in vitro and in vivo.

Liver fibrosis is excessive accumulation of extracellular matrix proteins that results from various chronic liver diseases. Hepatic stellate cells (HSCs) play an essential role in the pathogenesis of liver fibrosis. Danggui Buxue Tang (DBT) is a classic formula of Chinese traditional medicine. We previously showed that DBT could ameliorate liver fibrosis in rats. However, the bioactive components of DBT in the treatment of liver fibrosis remain unknown. In this study we evaluated 14 ingredients from DBT in human hepatic stellate cell line LX-2, and found that astragaloside I (A), levistilide A (L) and calycosin (C) produced synergistic proliferation inhibition on LX-2 cells and TGF-ß1-activated LX-2 cells. Thus, we prepared a mixture of them, and named this combination as ALC formula. Using high-content screening and Western blot assay we revealed that the ALC formula significantly reduced the expression of α-SMA and collagen I in LX-2 cells. The in vivo anti-fibrosis effects of ALC formula were evaluated in a liver fibrosis model in C57BL/6 mice established through injection of dimethylnitrosamine (DMN 2 mg/kg, ip) for 4 weeks. In the third week, the nice were injected with ALC formula (astragaloside I 44.21 mg/kg per day, levistilide A 6 mg/kg per day and calycosin 3.45 mg/kg per day; ip) or sorafenib, a positive control drug (6 mg/kg per day, ip) for 2 weeks. We found that administration of the ALC formula markedly decreased collagen deposition, hydroxyproline (Hyp) content and α-SMA expression levels in the liver tissues compared to the model mice. In conclusion, the present study demonstrates for the first time that astragaloside I, levistilide A and calycosin may be the 3 main bioactive components in DBT; their combination exerts anti-liver fibrosis effects in vitro and in vivo.

A Tri-O-Bridged Diels-Alder Adduct from Cortex Mori Radicis.

Sanggenon X, an unusual tri-O-bridged Diels-Alder adduct, was isolated from Cortex Mori Radicis. Its structure was established by spectroscopic analysis, including NMR and HR-MS (High Resolution Mass Spectrometry). Sanggenon X contained three O-bridged rings, where the oxygenated bridgeheads were all quaternary carbons. Chemical methylation was carried out to deduce the linkages of the three O-bridges. The absolute configuration was determined by calculating the ECD (Electronic Circular Dichroism) using the TDDFT (Time-Dependent Density Functional Theory) method. Sanggenon X showed significant antioxidant activity against Fe2+-Cys-induced lipid peroxidation in rat liver microsomes, and was as effective as the positive control, curcumin.

Polyprenylated acylphloroglucinols from Hypericum scabrum.

Fourteen phloroglucinols, named hyperciumoxide A-N, and a known compound were isolated from air-dried aerial parts of Hypericum scabrum. The structures of these compounds were deduced on the basis of extensive 1D- and 2D-NMR experiments. Hepatoprotective properties against D-galactosamine-induced HL-7702 cell damage of isolated compounds were evaluated. Meanwhile, these compounds were also tested for antidepressant activity by inhibiting reuptake of tritiated serotonin ([3H]-5-HT) and Noradrenalinet ([3H]-NE) in rat brain synaptosomes.

Levistilide A inhibits angiogenesis in liver fibrosis via vascular endothelial growth factor signaling pathway.

Levistilide A (C24H28O4, molecular weight = 380.48) derived from Angelica sinensis (Danggui) has been reported to inhibit hepatic stellate cell proliferation. This study investigated the effects of levistilide A on liver fibrosis relating to angiogenesis, particularly on the characteristic change in liver sinusoidal endothelial cells. LX-2 cells were activated by TGF-ß1, and the human hepatic sinusoidal endothelial cells (HHSECs) were induced by endothelial cell growth supplement. Cell viability was detected using a methylthiazoldiphenyl-tetrazolium bromide assay; F-actin was visualized through the fluorescence probe method; cell proliferation was examined using the EdU kit; antiangiogenesis activity was assessed using the tube formation assay and transgenic zebrafish model. To verify the results in vivo, rats were subcutaneously injected with CCl4 twice a week for six weeks to duplicate the liver fibrosis model and then treated with 10 mL/kg of normal saline, 4 mg/kg of sorafenib, and 3 and 6 mg/kg of levistilide A for three weeks from the fourth week. Collagen deposition was detected through Sirius Red staining; liver microvasculature was examined through vWF labeling and X-ray 2D imaging; sinusoidal fenestrations were observed through scanning electron microscopy; collagen I, α-SMA, CD31, vascular endothelial growth factor (VEGF), and VEGF-R2 were detected through Western blotting. Our results indicated that levistilide A attenuated LX-2 cell activation and HHSEC proliferation. The ability of HHSECs to form tubelike structures in Matrigel was inhibited, and the number of functional vessels in transgenic zebrafish decreased. In in vivo experiments, levistilide A reduced collagen deposition and the number of new microvessels; ameliorated sinusoid capillarization; and downregulated the expression of CD31, VEGF, and VEGF-R2. These findings suggest that levistilide A can inhibit liver fibrosis through antiangiogenesis by alleviating sinusoid capillarization via the VEGF signaling pathway. Impact statement Levistilide A has been reported to inhibit hepatic stellate cell (HSC) proliferation. In this study, we further investigated the mechanisms of levistilide A on liver fibrosis relating to angiogenesis, particularly on the characteristic change in liver sinusoidal endothelial cells. The cell models of HSC and liver sinusoidal endothelial cell and CCl4 induced liver fibrosis model were used. These results suggest that levistilide A can inhibit liver fibrosis through antiangiogenesis by alleviating sinusoid capillarization via the vascular endothelial growth factor signaling pathway. The effect of levistilide A on liver fibrosis was confirmed, and its detailed mechanism was also discussed. These findings suggest that levistilide A may be a great potential drug for treating liver fibrosis through antiangiogenesis, and this effect will be verified in other fibrotic animal model studies or by clinical trials.

Securinine disturbs redox homeostasis and elicits oxidative stress-mediated apoptosis via targeting thioredoxin reductase.

Thioredoxin reductase (TrxR) and thioredoxin (Trx) are two major components of the thioredoxin system, which plays essential roles in regulating cellular redox signaling. Mammalian TrxRs are essential seleno-flavoenzymes with a conserved penultimate selenocysteine (Sec) residue at the C-terminus, and have attracted considerable interests as promising targets for anticancer drugs. Securinine (SCR), a major active alkaloid lactone from the Chinese herbal medicine Securinega suffruticosa, has been established clinical success in treatment of neurological disorders. Recently, increasing evidence demonstrates that SCR has potential cytotoxicity to various types of tumor cells, which enables this old central nervous system drug as a potential cancer therapeutic agent. However, the mechanism underlying the anticancer activity of SCR is not well defined. We reported here that SCR inhibits both the purified TrxR and the enzyme in intact cells. SCR elicits accumulation of reactive oxygen species (ROS), elevation of oxidized glutathione and Trx, disturbs redox homeostasis, and eventually leads to oxidative stress-mediated HeLa cell apoptosis. Importantly, pharmacological inhibition or knockdown of TrxR sensitizes the cells to SCR treatment, underpinning the physiological significance of targeting TrxR by SCR. Our discovery discloses a novel mechanism underlying the anticancer activity of SCR and provides basic data for further development of SCR as a cancer chemotherapeutic drug.

Securinine from Phyllanthus glaucus Induces Cell Cycle Arrest and Apoptosis in Human Cervical Cancer HeLa Cells.

BACKGROUND: The Securinega-type alkaloids occur in plants belonging to Euphorbiaceae family. One of the most widely distributed alkaloid of this group is securinine, which was identified next to allosecurinine in Phyllanthus glaucus (leafflower). Recently, some Securinega-type alkaloids have paid attention to its antiproliferative potency towards different cancer cells. However, the cytotoxic properties of allosecurinine have not yet been evaluated. METHODS: The cytotoxicity of the extract, alkaloid fraction obtained from P. glaucus, isolated securinine and allosecurinine against HeLa cells was evaluated by real-time xCELLigence system and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was detected by annexin V and 7-amino-actinomycin (7-AAD) staining and confirmed with fluorescent Hoechst 33342 dye. The assessment of mitochondrial membrane potential (MMP), reactive oxygen species (ROS) generation, the level of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), caspase-3/7 activity and cell cycle analysis were measured by flow cytometry. The enzymatic activity of caspase-9 was assessed by a luminometric assay. The expression of apoptosis associated genes was analyzed by real-time PCR. RESULTS: The experimental data revealed that securinine and the alkaloid fraction were significantly potent on HeLa cells growth inhibition with IC50 values of 7.02 ± 0.52 µg/ml (32.3 µM) and 25.46 ± 1.79 µg/ml, respectively. The activity of allosecurinine and Phyllanthus extract were much lower. Furthermore, our study showed that the most active securinine induced apoptosis in a dose-dependent manner in the tested cells, increased the percentage of ROS positive cells and depolarized cells as well as stimulated the activity of ERK1/2, caspase-9 and -3/7. Securinine also induced cell cycle arrest in S phase. Real-time PCR analysis showed high expression of TNFRSF genes in the cells stimulated with securinine. CONCLUSIONS: Securinine induces apoptosis and activates cell cycle checkpoints in HeLa cells which is associated with oxidative stress. The results indicate that the mitochondrial pathway is involved in the programmed cell death.

Design and Synthesis of Dimeric Securinine Analogues with Neuritogenic Activities.

Neurite outgrowth is crucial during neuronal development and regeneration, and strategies that aim at promoting neuritogenesis are beneficial for reconstructing synaptic connections after neuronal degeneration and injury. Using a bivalent analogue strategy as a successful approach, the current study identifies a series of novel dimeric securinine analogues as potent neurite outgrowth enhancers. Compounds 13, 14, 17-19, and 21-23, with different lengths of carbon chain of N,N-dialkyl substituting diacid amide linker between two securinine molecules at C-15 position, exhibited notable positive effects on both neuronal differentiation and neurite extension of neuronal cells. Compound 14, one of the most active compounds, was used as a representative compound for mechanistic studies. Its action on neurite outgrowth was through phosphorylation/activation of multiple signaling molecules including Ca2+/calmodulin-dependent protein kinase II (CaMKII), extracellular signal-regulated kinase (ERK) and Akt. These findings collectively identify a new group of beneficial compounds for neuritogenesis, and may provide insights on drug discovery of neural repair and regeneration.

The Securinega alkaloids.

Securinega alkaloids represent a family of plant secondary metabolites known for 50 years. Securinine (1), the most abundant and studied alkaloid of this series was isolated by Russian researchers in 1956. In the following years, French and Japanese scientists reported other Securinega compounds and extensive work was done to elucidate their intriguing structures. The homogeneity of this family relies mainly on its tetracyclic chemical backbone, which features a butenolide moiety (cycle D) and an azabicyclo[3.2.1]octane ring system (rings B and C). Interestingly, after a period of latency of 20 years, the Securinega topic reemerged as a prolific source of new natural structures and to date more than 50 compounds have been identified and characterized. The oligomeric subgroup gathering dimeric, trimeric, and tetrameric units is of particular interest. The unprecedented structure of the Securinega alkaloids was the subject of extensive synthetic efforts culminating in several efficient and elegant total syntheses. The botanical distribution of these alkaloids seems limited to the Securinega, Flueggea, Margaritaria, and Breynia genera (Phyllanthaceae). However, only a limited number of plant species have been considered for their alkaloid contents, and additional phytochemical as well as genetic studies are needed. Concerning the biosynthesis, experiments carried out with radiolabelled aminoacids allowed to identify lysine and tyrosine as the precursors of the piperidine ring A and the CD rings of securinine (1), respectively. Besides, plausible biosynthetic pathways were proposed for virosaine A (38) and B (39), flueggine A (46), and also the different oligomers flueggenine A-D (48-51), fluevirosinine A (56), and flueggedine (20). The case of nirurine (45) and secu'amamine (37) remains elusive and additional studies seem necessary to understand their mode of production. The scope of biological of activities of the Securinega alkaloids was mainly centered on the CNS activity of securinine (1), although the exact mechanism of action remained in part unknown. Nevertheless, for its stimulant and antispasmodic effects securinine nitrate was marketed as a drug in the USSR until the early 1990s. Moreover, securinine (1) and several other Securinega alkaloids recently demonstrated promising anticancer properties. In particular securinine (1) demonstrated markedly benefits in the treatment of acute myeloid leukemia.

Production of therapeutically relevant indolizidine alkaloids in Securinega suffruticosa in vitro shoots maintained in liquid culture systems.

Microshoot cultures of the Chinese medicinal plant Securinega suffruticosa (Pall.) Rehd. were established and evaluated for the presence of therapeutically relevant indolizidine alkaloids securinine (S) and allosecurinine (AS). The cultures were maintained in shake flasks (SFs) and a bubble column bioreactor (BCB) using the modified Murashige's shoot multiplication medium supplemented with 1.0 mg l(-1) benzyladenine (BA), 3.0 mg l(-1) 2-isopentenyladenine (2iP), and 0.3 mg l(-1) 1-naphthaleneacetic acid (NAA). The influence of light and medium supplementation strategies with biosynthesis precursor (lysine (LY)) and nutrient formulations (casein hydrolysate (CH) and coconut water (CW)) on biomass growth and alkaloid production were investigated. SF cultures grown in the presence of light yielded up to 6.02 mg g(-1) dry weight (DW) S and 3.70 mg g(-1) DW AS, corresponding to the respective productivities of 98.39 and 60.21 mg l(-1). Among feeding experiments, CW supplementation proved most effective for SF-grown shoots, increasing biomass yield and AS productivity by 52 and 44 %, respectively. Maximum concentrations of securinine (3.25 mg g(-1) DW) and allosecurinine (3.41 mg g(-1) DW) in BCB cultures were achieved in the case of 1.0 g l(-1) LY supplementation. These values corresponded to the productivities of 42.64 and 44.47 mg per bioreactor, respectively.

L-securinine induced the human colon cancer SW480 cell autophagy and its molecular mechanism.

AIMS: To investigate the anti-tumor effects of L-securinine inducing colon cancer SW480 cell autophagy and explore its potential molecular mechanism. MAIN METHODS: MTT method was used to detect the antitumor effect of SW480 cells cultured with L-securinine in vitro. Light and electron microscopy were used to observe SW480 cells treated with L-securinine morphological changes. Flow cytometry was used to observe the apoptoticratio and cell cycle inducing with the L-securinine in SW480 cells, and the autophagic apoptosis ratio was determined by FITC-conjugated annexin V by flow cytometry (FCM). FCM was applied to analysis cell cycle; the expression of autophagy gene Beclin-1 was examined by reverse transcriptase polymerase chain reaction (RT-PCR). KEY FINDINGS: The generation depression effects of SW480 cells cultured in vitro were detected byMTT method (Pb0.05), and there were dosage-time dependent relationships. Numerous autophagic vacuoles and empty vacuoles were observed in SW480 cells treated with 2.5 µM L-securinine for 48 h by electron microscopy, and the process of cell division that got less was observed.Through flow cytometry, a number of observed autophagic cells were obviously increased, and G1/S phase was retarded. L-Securinine tended to arrest cells at the G1 phase of the cell cycle. The percentage of the apoptotic cells increased as treatment duration and concentrations increased. Beclin-1 expression enhanced with L-securinine concentration increased. SIGNIFICANCE: L-Securinine has an anti-tumor effect against colon cancer SW480 cell. The L-securinine can induce striking autophagy in SW480 cell in vitro. The autophagy induced by L-securinine is related with upregulating the expression of autophagy gene Beclin-1.

Securinega suffruticosa.

This review gives an account of the current knowledge on the chemical constituents, biological activity and pharmacological properties of Securinega suffruticosa. A wide range of chemical compounds have been isolated, mainly alkaloids, flavonoids, tannins and lipids. From the pharmacological point of view the most interesting group are the alkaloids, among which securinine, an indolizidine alkaloids containing a unique tricyclic structure.

Progress toward the synthesis of the basiliolides and transtaganolides: an intramolecular pyrone Diels-Alder entry into a novel class of natural products.

Efforts directed toward the synthesis of a basiliolide/transtaganolide model system are disclosed. A highly endo-selective intramolecular pyrone Diels-Alder (IMPDA) cycloaddition rapidly constructs the tricyclic core of the basiliolides and transtaganolides.

Securinega alkaloids from the wood of Securinega suffruticosa var. amamiensis.

Three new Securinega alkaloids, secu'amamines B-D ( 1- 3), were isolated from the wood of the Japanese medicinal plant Securinega suffruticosa var. amamiensis, together with five known analogues ( 4, 6- 9). The structures 1- 3 were elucidated by spectroscopic methods including 2D NMR, and all eight compounds were evaluated for cytotoxicity against two cancer cell lines.

Applications of multicomponent reactions for the synthesis of diverse heterocyclic scaffolds.

A four-component coupling process involving sequential reactions of aldehydes, primary amines, acid chlorides, and nucleophiles has been developed to prepare multifunctional substrates that may be employed in subsequent ring-forming reactions to generate a diverse array of functionalized heterocyclic scaffolds. This new approach to diversity-oriented synthesis was then applied to the first total synthesis of the isopavine alkaloid (+/-)-roelactamine.

[A new hetisine-type alkaloid from the stems and leaves of Aconitum coreanum].

AIM: To study the chemical constituents of the stems and leaves of Aconitum coreanum (Lèvl.) Rapaics. METHODS: The constituents of Aconitum coreanum were isolated by using various kinds of modern chromatographic methods. The new alkaloid was identified on the basis of spectral analysis. RESULTS: Two compounds were isolated and identified as: 13-dehydro-1beta-acetyl-2alpha,6beta-dihydroxyhetisine (I) and Guanfu base G (II). CONCLUSION: Compound I is a new alkaloid.