piperidines and securinine

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.. 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.. 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.. 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.. 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.

Topics: Alkaloids; Azepines; Cell Line, Tumor; Heterocyclic Compounds, Bridged-Ring; Humans; Janus Kinases; Lactones; Leukemia; Lysine; Male; Phosphatidylinositols; Piperidines; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases; Tyrosine

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.

Topics: Alkaloids; Anti-Infective Agents; Antineoplastic Agents, Phytogenic; Azepines; Chemistry Techniques, Synthetic; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Humans; Indolizines; Lactones; Leukemia, Myeloid, Acute; Molecular Structure; Parasympatholytics; Piperidines; Plants, Medicinal; Rutin; Tropanes

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.

Topics: Alkaloids; Animals; Azepines; Drugs, Chinese Herbal; Euphorbiaceae; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Phytotherapy; Piperidines; Plants, Medicinal

Topics: Alkaloids; Anaphylaxis; Azepines; Drug Eruptions; Drugs, Chinese Herbal; Gossypol; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Neuromuscular Depolarizing Agents; Piperidines

To explore the effective method in treating infantile chronic aplastic anemia (ICAA) by using traditional Chinese medicine (TCM).. Seventy-eight cases of ICAA were observed, 48 of them were treated with Tiaoxue Yisui recipe (treated group), 30 cases were treated with SSL regimen (control group).. The remission rate and total effective rate in treated group were 52.08% and 81.25% respectively, they were higher than those in control group (P < 0.05). After one year treatment the ratio of hemopoietic and non-hemopoietic cells in treated group was higher than that in control group (P < 0.05). The number of megakaryocyte in treated group was more than those in control group (P < 0.05).. Tiaoxue Yisui recipe could improve the quality of the patient's life. The therapeutical mechanism of the Tiaoxue Yisui recipe might promote the proliferation of hemopoietic stem cells and regulate the immune function.

Topics: Adolescent; Alkaloids; Anemia, Aplastic; Azepines; Bone Marrow Examination; Child; Child, Preschool; Drug Therapy, Combination; Drugs, Chinese Herbal; Female; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Levamisole; Male; Piperidines; Prospective Studies; Stanozolol

Function-oriented molecular editing of the polycyclic scaffold of securinine led to the preparation of a library of simplified analogs that have been evaluated for their cytotoxicity potential against HCT116 and HL60 human cell lines. Chemical diversity at the C14 position (securinine numbering) was generated through the site-selective γ-iodination followed by Pd-catalyzed Sonogashira and Suzuki-Miyaura reactions. To explain the selectivity in the iodination step, a reaction mechanism has been proposed. Surprisingly, the piperidine ring (ring A) of the securinine skeleton has been found to be irrelevant for the cytotoxic activity. Based on this finding, the pharmacophoric core of securinine could be simplified to the key BCD motif. The nature of the substituent at the nitrogen can vary from a methyl or an isobutyl group to a benzyl or a carbamate moiety. Interestingly, the N-benzyl substituted simplified analog exhibited the same cytotoxic activity as the parent compound securinine. This functional group tolerance paves the way for the installation of reactive handles for the synthesis of molecular probes for target identification.

Topics: Antineoplastic Agents; Azepines; Cell Proliferation; Cell Survival; Density Functional Theory; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HCT116 Cells; Heterocyclic Compounds, Bridged-Ring; HL-60 Cells; Humans; Lactones; Molecular Conformation; Piperidines; Structure-Activity Relationship; Tumor Cells, Cultured

Securinega alkaloids have fascinated the synthetic chemical community for over six decades. Historically, major research foci in securinega alkaloid synthesis have been on the efficient construction of the fused tetracyclic framework that bears a butenolide moiety and tertiary amine-based heterocycles. These "basic" securinega alkaloids have evolved to undergo biosynthetic oxidative diversifications, especially on the piperidine core. However, a general synthetic solution to access these high-oxidation state securinega alkaloids is lacking. In this study, we have completed the total synthesis of various C4-oxygenated securinine-type alkaloids including securingines A, C, D, securitinine, secu'amamine D, phyllanthine, and 4-epi-phyllanthine. Our synthetic strategy features stereocontrolled oxidation, rearrangement, and epimerization at N1 and C2-C4 positions of the piperidine core within (neo)securinane scaffolds. Our discoveries provide a fundamental synthetic solution to all known securinine-type natural products with various oxidative and stereochemical variations around the central piperidine ring.

Topics: Alkaloids; Azepines; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Lactones; Piperidines; Stereoisomerism

Acute myeloid leukemia is characterized by abnormal differentiation of hematopoietic stem cells, leading to the accumulation of immature myeloid cells. Differentiation therapy has been a successful treatment option for acute promyelocytic leukemia but suffers from adverse effects. Therefore, search for novel differentiation-inducing agents with minimal side effects is desirable. Securinine, a naturally-occurring alkaloid, induces differentiation in various leukemic cells and apoptosis in other types of cancers. However, the underlying molecular mechanism(s) remain elusive. Our study aimed to elucidate the possible molecular mechanism(s) and signaling events involved in securinine-induced differentiation of HL-60 cells. Securinine inhibited proliferation in a time- and dose-dependent manner and triggered differentiation. A higher CD14+ population indicated maturation toward monocytic lineage. Securinine caused cell cycle arrest at the G0/G1 phase and enhanced ROS generation. Quantitative gene expression analysis showed significant down-regulation of

Topics: Azepines; Cell Differentiation; Heterocyclic Compounds, Bridged-Ring; HL-60 Cells; Humans; Lactones; MAP Kinase Signaling System; Piperidines

Impaired differentiation of newborn neurons or abnormalities at the synapses resulted from stress maladaptation could be the key etiology of depression. Recent studies have shown that mTOR, a crucial factor for neuronal differentiation and synapse development, acts as a common factor that mediates the rapid antidepression effects of several new-class antidepressants. In this study, the antidepressant-like activity of securinine, an alkaloid that has central nervous system stimulation ability, was investigated. Both securinine and its enantiomer virosecurinine exhibited potent

Topics: Animals; Antidepressive Agents; Azepines; Cell Differentiation; Heterocyclic Compounds, Bridged-Ring; Lactones; Mice; Piperidines; TOR Serine-Threonine Kinases

Analysis of the anticancer and antimitotic activity of the plant derived alkaloid securinine along with its effect on the organization of cellular microtubules as well as its binding with purified goat brain tubulin in-vitro.. The cytotoxicity of securinine on different cell lines was conducted using SRB assay. The effect of securinine on the cellular microtubules was analyzed using immunofluorescence microscopy. The binding of securinine on purified goat brain tubulin was evaluated using fluorescent spectroscopy.. Securinine effectively prevented the proliferation of cervical, breast and lung cancer cells with an IC. Considering the strong anticancer and anti-metastatic property and low toxicity in non-malignant cell lines, we suggest that securinine can be used as a chemotherapeutic drug either alone or in combination with other known anticancer molecules.

Topics: A549 Cells; Antineoplastic Agents; Azepines; Dose-Response Relationship, Drug; HEK293 Cells; HeLa Cells; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; MCF-7 Cells; Microtubules; Mitosis; Neoplasms; Piperidines; Tubulin

Atherosclerosis is a chronic vascular disease and characterized by accumulation within the intima of inflammatory cells, smooth muscle cells, lipid, and connective tissue.. The purpose of the present study was to identify natural agents that commonly reverse advanced atherosclerotic plaque to early atherosclerotic plaque.. 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.. 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.. Securinine may be a potential natural candidate for the treatment of atherosclerosis because it attenuates vascular inflammation and dysfunction as well as vascular lesion.

Topics: Animals; Aorta; Atherosclerosis; Azepines; Endothelial Cells; Endothelium, Vascular; Gene Expression Regulation; Heterocyclic Compounds, Bridged-Ring; Human Umbilical Vein Endothelial Cells; Humans; Lactones; Male; Mice, Inbred C57BL; Mice, Knockout; Mice, Knockout, ApoE; Myocytes, Smooth Muscle; NF-kappa B; Piperidines; Plaque, Atherosclerotic; Protective Agents; Vasodilation

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.

Topics: Animals; Azepines; Bone Diseases, Metabolic; Cell Differentiation; Herbal Medicine; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Mice; Osteogenesis; Piperidines

Multidrug resistance (MDR) is a main cause of chemotherapy failure and patient death. This situation usually involves a glycoprotein (P-gp) mediated drug efflux, resulting in a low cellular drug concentration and insensitivity. Here we report the design, synthesis and evaluation of novel (+/-)-securinine bivalents as P-gp inhibitors in vitro and in vivo. MTT assays reflected that bivalent mimetics of securinine particularly the virosecurinine bivalent mimetic 8C showed promissing MDR reversal potential in both P-gp highly expressed cell line HepG2/DOX and MCF-7/ADM. At a 10 μM concentration, 8C can entirely reverse the resistance of HepG2/DOX to doxorubicin (DOX), and is more effective than the positive control verapamil (VRP). Fluorescence, flow cytometry, and DOX efflux assays demonstrated that 8C can facilitate the accumulation and diminish the efflux of intracellular DOX. Molecular docking analysis and western blot assays indicated that 8C accomplished this by competitively inhibiting the activity of P-gp rather than by affecting its expression. Compound 8C was also observed to reverse drug resistance effectively in xenograft models when combined with DOX. This study lays a foundation for the discovery of (+/-)-securinine ramifications as P-gp inhibitors and provides a promising lead compound 8C as a P-gp mediated MDR reversal agent.

Topics: Alkaloids; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Azepines; Cell Line, Tumor; Cell Survival; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Male; Mice, Inbred BALB C; Mice, Nude; Piperidines; Verapamil

The present study aims to evaluate the anticancer effect of L-securinine on androgen-independent prostate cancer (AIPC) DU145 cells. L-securinine (2.5, 5, and 10 μM) treatment for 24, 48 and 72 h displayed strong growth inhibitory effect on DU145 cells in a concentration and time-dependent fashion but has less toxicity toward normal androgen-dependent LNCaP cells. Hoechst 332582 staining of DU145 cells and Annexin V-FITC/ PI dual-labeling followed by flow cytometry assay identified that this growth inhibition by L-securinine would be due to the induction of apoptosis. Moreover Transwell assay revealed that L-securinine significantly inhibited the cell migration/invasion ability of DU145 cells. Furthermore, results of western blotting showed that the involvement of mitochondrial apoptotic pathway in the L-securinine-induced apoptosis of DU145 cell, as evidenced by an increase in the protein expression of Bax, cleaved caspase-9, cleaved caspase-3, cytosolic cytochrome c, and cleaved PARP, together with a unchanged cleaved caspase-8 and decreased Bcl-2 protein expression. Also, L-securinine-induced antimetastatic activity in DU145 cells was associated with decreased protein expression of MMP-2 and MMP-9 and concurrent reduction of VEGF. In addition, further studies revealed that L-securinine may inhibit the protein expression of AGTR1, p-MEK1/2, p-ERK1/2, p-STAT3, PAX2, and p-PAX2, while the expression of ERK1/2, MEK1/2, and STAT3 protein retains intact. These findings suggest that L-securinine may be a promising chemopreventive agent against AIPC.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Azepines; bcl-2-Associated X Protein; Caspase 3; Caspase 9; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Mitochondria; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; PAX2 Transcription Factor; Piperidines; Prostatic Neoplasms, Castration-Resistant; Receptor, Angiotensin, Type 1; Signal Transduction; STAT3 Transcription Factor

Lung cancer remains the leading cause of cancer-related death worldwide. It is important to explore the biomarkers of diagnosis and prognosis in lung cancer. To evaluate the cytotoxicity of L-securinine and the expression and methylation of secreted frizzled-related proteins (SFRPs) genes in the human lung adenocarcinoma cells, cell counting kit-8 (CCK-8) assay was used to assess the proliferation of lung adenocarcinoma cells treated with L-securinine. Quantitative real-time PCR (qRT-PCR) and bisulfite sequencing PCR were used to detect the expression and the DNA methylation of SFRPs genes, respectively. L-securinine inhibited the proliferation of lung adenocarcinoma cells and induced the upregulation of SFRP1 gene expression and the methylation changes at CpG sites in the SFRP1 promoter region. L-securinine was a potential agent in the treatment of lung cancer by upregulation of SFRP1 gene expression and changing the SFRP1 gene methylation.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Azepines; Cell Line, Tumor; DNA Methylation; Heterocyclic Compounds, Bridged-Ring; Humans; Intracellular Signaling Peptides and Proteins; Lactones; Lung Neoplasms; Molecular Structure; Piperidines; Promoter Regions, Genetic; Proteins; Stereoisomerism

Flueggeacosines A-C (1-3), three dimeric securinine-type alkaloid analogues with unprecedented skeletons, were isolated from Flueggea suffruticosa. Compounds 1 and 2 are the first examples of C-3-C-15' connected dimeric securinine-type alkaloids. Compound 3 is an unprecedented heterodimer of securinine-type and benzoquinolizidine alkaloids. Biosynthetic pathways for 1-3 were proposed on the basis of the coexisting alkaloid monomers as the precursors. Compound 2 exhibited significant activity in promoting neuronal differentiation of Neuro-2a cells.

Topics: Animals; Azepines; Cell Differentiation; Cell Line, Tumor; Dimerization; Dose-Response Relationship, Drug; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Lactones; Mice; Molecular Conformation; Piperidines; Structure-Activity Relationship

Glial activation and subsequent release of neurotoxic proinflammatory factors are believed to play an important role in the pathogenesis of several neurological disorders including Parkinson's disease (PD). Inhibition of glial activation and inflammatory processes may represent a therapeutic target to alleviate neurodegeneration. Securinine, a major natural alkaloid product from the root of the plant

Topics: Animals; Anti-Inflammatory Agents; Astrocytes; Azepines; Blotting, Western; Cell Survival; Heterocyclic Compounds, Bridged-Ring; Interferon-Stimulated Gene Factor 3; Lactones; Lipopolysaccharides; Mice; Microglia; Mitogen-Activated Protein Kinases; Neuroprotective Agents; NF-kappa B; Nitric Oxide Synthase Type II; Nitrites; Parkinson Disease; Phosphorylation; Piperidines; Polymerase Chain Reaction

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.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Azepines; Cell Line, Tumor; Enzyme Inhibitors; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Neoplasms; Oxidation-Reduction; Oxidative Stress; Piperidines; Reactive Oxygen Species; Thioredoxin-Disulfide Reductase

Oxidative stress and amyloid deposition are tightly interconnected pathological features of Alzheimer disease. In this respect, both amyloid production and aggregation may be stimulated by oxidative stress and also the increase of pathogenic β-amyloid and its aggregated form lead to oxidative stress progression. Therefore, the search for potential drugs with both antioxidant and antiaggregation properties are of great interest.. In this study, we described the stereospecific synthesis of alkaloid securinine aminoderivatives.. We showed that the newly synthesized compounds possess antioxidant and metal-chelating properties. Indeed, we report that one compound has inhibitory effects towards μ-amyloid aggregation.. Based on these results, aminoderivatives of securinine scaffold are promising compounds for development of new drugs for the treatment of neurodegenerative diseases.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Animals; Antioxidants; Azepines; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Male; Oxidative Stress; Peptide Fragments; Piperidines; Rats

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by the degeneration of motor neurons in the spinal cord, leading to muscular atrophy. SMA is caused by deletions or mutations in the survival motor neuron gene (SMN1) on chromosome 5q13. A second copy of the SMN gene (SMN2) also exists on chromosome 5, and both genes can produce functional protein. However, due to alternative splicing of the exon 7, the majority of SMN protein produced by SMN2 is truncated and unable to compensate for the loss of SMN1. Increasing full-length SMN protein production by promoting the exon 7 inclusion in SMN2 mRNA or increasing SMN2 gene transcription could be a therapeutic approach for SMA. In this study, we screened for the compounds that enhance SMN2 exon 7 inclusion by using SMN2 minigene-luciferase reporter system. We found that securinine can increase luciferase activity, indicating that securinine promoted SMN2 exon 7 inclusion. In addition, securinine increased full-length SMN2 mRNA and SMN protein expression in SMA patient-derived lymphoid cell lines. To investigate the mechanism of securinine effect on SMN2 splicing, we compared the protein levels of relevant splicing factors between securinine-treated and untreated cells. We found that securinine downregulated hnRNP A1 and Sam68 and upregulated Tra2-β1 expression. However, securinine, unlike HDAC inhibitors, did not enhance tra2-β1 gene transcription, indicating a post-transcriptional mechanism for Tra2-β1 upregulation. Furthermore, we treated SMA-like mice with securinine by i.p. injection and found that securinine treatment increased SMN2 exon 7 inclusion and SMN protein expression in the brain and spinal cord. According to our results, securinine might have the potential to become a therapeutic drug for SMA disease.

Topics: Animals; Azepines; Cell Line; Central Nervous System Stimulants; Exons; Heterocyclic Compounds, Bridged-Ring; Heterogeneous-Nuclear Ribonucleoproteins; Lactones; Lymphoid Tissue; Mice; Muscular Atrophy, Spinal; Piperidines; Protein Splicing; RNA, Messenger; Serine-Arginine Splicing Factors; Survival of Motor Neuron 2 Protein

Oxidative stress and mitochondrial disturbances are the common and important causative factors of aging, and play an important role in the late onset of sporadic neurodegenerative diseases, including Alzheimer disease (AD). Furthermore, emerging evidence from in vitro and in vivo disease models suggests that oxidative stress and increased vulnerability to induction of mitochondrial permeability transition leads to the pathogenesis of the neurological disorders. Towards the goals of developing effective neuroprotectors, this article describes the synthesis and neuroprotective studies of various derivatives of the naturally occurring alkaloid securinine, based on which a lead compound, allomargaritarine (a diastereomer of margaritarine), was identified as an effective therapeutic for neuroprotection. Allomargaritarine exhibits high antioxidant activity, and has significant mitoprotective effect on cellular models of neurodegeneration.

Topics: Aging; Animals; Animals, Newborn; Azepines; Cell Survival; Cells, Cultured; Cerebral Cortex; Heterocyclic Compounds, Bridged-Ring; Lactones; Male; Mitochondria; Neuroprotective Agents; Oxidative Stress; Piperidines; Rats

A series of new securinine analogues was prepared by Heck reaction from readily accessible securinine and commercially available iodoarenes. The in vitro cytotoxicity of the prepared compounds was assayed against a panel of four cancer cell lines: A375, A549, HCT-116 and HL-60 showing promising growth inhibition with excellent IC50 values in the nanomolar range. The plasmatic stability of the most potent analogue was also investigated demonstrating that they might serve as valuable leads for the development of anticancer drugs.

Topics: Antineoplastic Agents; Apoptosis; Azepines; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Neoplasms; Piperidines

DNA topoisomerase I (Topo I) has been validated as a target for anticancer agents. In this study, a series of novel securinine derivatives bearing β'-hydroxy-α,β-unsaturated ketone moiety were designed and synthesized via a Baylis-Hillman reaction for screening as Topo I inhibitors and antitumor agents. Their topoisomerase I inhibitory activity as well as their cytotoxicity against four human cancer cell lines (A549, HeLa, HepG2, SH-SY5Y) were evaluated, and two pairs of diastereomers 4a-1 and 4a-6 with significant Topo I inhibitory activity and potent anti-proliferative activity against cancer cell lines were identified. The diastereomers were separated, and absolute configurations of five pairs of diastereomers were identified based on X-ray crystallographic analysis and circular dichroism (CD) spectra analysis. Further mechanism studies of the most active compounds 4a-1-R and 4a-1-S indicated that this kind of securinine derivative exhibits a different inhibitory mechanism from that of camptothecin, an established Topo I inhibitor. Unlike camptothecin, compounds 4a-1-R and 4a-1-S specifically inhibits the combination of Topo I and DNA rather than forming the drug-enzyme-DNA covalent ternary complex. In addition, molecular docking and molecular dynamic studies revealed the binding patterns of these compounds with Topo I.

Topics: Antineoplastic Agents; Azepines; Cell Line, Tumor; Cell Proliferation; DNA Cleavage; DNA Topoisomerases, Type I; Drug Design; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Models, Molecular; Piperidines; Protein Conformation; Structure-Activity Relationship; Topoisomerase I Inhibitors

Topics: Animals; Azepines; Blotting, Western; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cell Enlargement; Cell Line, Tumor; Drug Design; Drug Evaluation, Preclinical; Extracellular Signal-Regulated MAP Kinases; Heterocyclic Compounds, Bridged-Ring; Immunohistochemistry; Lactones; MAP Kinase Signaling System; Mice; Molecular Structure; Neurites; Neuroprotective Agents; Phosphorylation; Piperidines; Proto-Oncogene Proteins c-akt

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.. 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.. 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.. 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.

Topics: Apoptosis; Azepines; Cell Cycle; Cell Proliferation; HeLa Cells; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Membrane Potential, Mitochondrial; Phyllanthus; Piperidines; Plant Extracts; Real-Time Polymerase Chain Reaction

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.

Topics: Alkaloids; Azepines; Biomass; Bioreactors; Biotechnology; Culture Media; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Indolizidines; Lactones; Light; Piperidines; Plant Shoots; Tissue Culture Techniques

The asymmetric total synthesis of (-)-14,15-dihydrosecurinine and the formal total synthesis of (-)-securinine were accomplished starting from an easily available malimide. A concise SmI2-mediated radical coupling strategy has been developed to construct the bridged α-hydroxy 6-azabicyclo[3.2.1]octanone in four steps with high diastereoselectivity.

Topics: Alkaloids; Azabicyclo Compounds; Azepines; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Indicators and Reagents; Lactones; Piperidines; Stereoisomerism

Time-dependant density functional theory-electronic circular dichroism spectra prediction was carried out to study the absolute configuration of phyllanthidine-type derivatives 5 and 6, derived from securinine (1) and its enantiomer virosecurinine (2), respectively. This method demonstrated to be very reliable in this alkaloid series. Thus, 5 and 6 shared the same stereochemistry as their parent precursors, confirming the retentive nature of the oxidation sequence. In addition, this study highlighted the key role of the methylene bridge (BC ring) in the chiroptical activity of these compounds. These results fully clarified the stereochemical relationships between the phyllanthidine and the securinine subgroups.

Topics: Alkaloids; Azepines; Circular Dichroism; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Lactones; Models, Molecular; Molecular Structure; Piperidines; Plant Components, Aerial; Stereoisomerism

Preliminary results related to the development of [2 + 2 + 1]-oxa-hetero-Pauson-Khand cycloaddition strategy toward the Securinega alkaloids are reported. The critical tricyclic BCD-ring core was assembled in only nine linear steps from cheap 4-hydroxy-l-proline. The study provides valuable insight into the scope of a rare hetero-Pauson-Khand reaction, a powerful tool for the rapid construction of butenolide-containing natural products.

Topics: Alkaloids; Azepines; Biological Products; Cycloaddition Reaction; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Hydroxyproline; Lactones; Piperidines

The Securinega alkaloids are a class of natural products isolated from plants of the Euphorbiaceae family. L-securinine induces apoptosis in the human promyelocytic leukemia cell line HL-60 indicating its potential as an efficient natural antitumor drug with low toxicity. The aim of the present study was to investigate the apoptotic effects of L-securinine on HL-60 cells and to explore its potential underlying molecular mechanism(s) as an antitumor agent. HL-60 cells were cultured with L-securinine. The proliferation and changes in cell morphology were evaluated by cell counting Kit-8 (CCK-8) assay and electron microscopy, respectively. Induction of apoptosis and cell cycle progression were investigated by flow cytometry. The PI3K/AKT/mTOR pathway gene expression was measured by quantitative PCR (qPCR). L-securinine decreased the viability of HL-60 cells in a dose- and time-dependent manner, with IC50 values at 24, 48 and 72 h post-treatment of 47.88, 23.85 and 18.87 µmol/l, respectively. Numerous apoptotic bodies were observed in the HL-60 cells treated with 25 µmol/l L-securinine for 48 h. L-securinine at 12.5, 25 and 50 µmol/l increased the rate of apoptosis in HL-60 cells, and G1/S phase progression was retarded. Furthermore, L-securinine induced downregulation of PI3K, AKT and mTOR gene expression and upregulation of PTEN gene expression in a dose-dependent manner. In conclusion, L-securinine induces apoptosis and inhibition of cell cycle progression in HL-60 cells by modulation of the PI3K/AKT/mTOR pathway gene expression. These observations indicate the potential of L-securinine as an antitumor agent.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Azepines; Cell Line, Tumor; Cell Proliferation; Cell Survival; Gene Expression; Heterocyclic Compounds, Bridged-Ring; HL-60 Cells; Humans; Lactones; Leukemia, Promyelocytic, Acute; MAP Kinase Signaling System; Phosphatidylinositol 3-Kinases; Piperidines; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; S Phase Cell Cycle Checkpoints; TOR Serine-Threonine Kinases

Natural products have been discovered to be valuable sources of antitumor drugs. L-Securinine is a natural product extracted from the leaves or roots of Securinega suffruticosa Pall Rehd. The current study was done to investigate the molecular mechanisms of antitumor effects of L-securinine. The inhibitory activities of L-securinine on human breast cancer MCF-7 cells were studied in vitro by a Cell Counting Kit-8(cck8) assay. Flow cytometry was used to analyze the apoptotic ratio and cell cycle distribution of control and treated MCF-7 cells with L-Securinine. Real-time quantitative PCR was conducted to evaluate expression levels of apoptosis related genes P53, Bax, Bcl-2, Mtor, P70s6k. L-Securinine exhibited remarkable antiproliferation activities on MCF-7 cells in dose- and time-dependent manner (24, 48 and 72 h of incubation). A 48 h exposure to L-securinine at a concentration ranging from 0 to 40 microM resulted in a significant increase in apoptotic ratio. At both low and high concentrations, L-securinine preferably perturbed the cell cycle in MCF-7 cells by arrest of G1 phase. These results were further confirmed by the increased expression of bax, p53 and the decreased expression of bcl-2, mtor, p70s6k in a dose-dependent manner. In summary, these findings suggest that L-securinine has an anti-tumor effect against MCF-7 cells and could be further exploited as a potential lead in antitumor drug development.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Azepines; bcl-2-Associated X Protein; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Female; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Piperidines; Proto-Oncogene Proteins c-bcl-2; Real-Time Polymerase Chain Reaction

(-)-Securinine (SE) is a major alkaloid found in plant Securinega suffruticosa, which has a wide range of pharmacological activities including anticancer, anti-parasitic and central nervous system stimulating effects, etc. To aid the pharmacological study of SE, we developed an LC-MS/MS method for quantitative determination of SE in mouse plasma. In this method, plasma samples were first prepared with salting-out assisted liquid-liquid extraction using cold acetonitrile (-20°C) and 2.00 M ammonium acetate. Separation of SE and the internal standard (IS) from sample matrix was achieved on a Gemini Nx C18 column using 40% acetonitrile and 60% 10.0mM ammonium acetate at a flow rate of 0.200 mL min(-1). Quantification of SE was accomplished with positive electrospray ionization tandem mass spectrometry using mass transitions m/z 218.1→84.1 for SE, and m/z 204.1→70.2 for the IS. This method has a lower limit of quantitation (LLOQ) of 0.600 ng mL(-1) and a linear calibration range up to 600 ng mL(-1) in mouse plasma. The intra- and inter-run accuracy (%RE) and precision (%CV) were ≤ ± 6% and 6%, respectively. The IS normalized matrix factors from six lots of plasma matrices ranged 0.92-1.07, and the recoveries of plasma SE were 99-109%. The validated method has been applied to the measurement of SE in plasma samples of a mouse study.

Topics: Animals; Azepines; Chromatography, Reverse-Phase; Heterocyclic Compounds, Bridged-Ring; Lactones; Linear Models; Liquid-Liquid Extraction; Mice; Mice, Inbred BALB C; Piperidines; Reproducibility of Results; Sensitivity and Specificity; Solubility; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

Fragment-based screening is commonly used to identify compounds with relatively weak but efficient localized binding to protein surfaces. We used mass spectrometry to study fragment-sized three-dimensional natural products. We identified seven securinine-related compounds binding to Plasmodium falciparum 2'-deoxyuridine 5'-triphosphate nucleotidohydrolase (PfdUTPase). Securinine bound allosterically to PfdUTPase, enhancing enzyme activity and inhibiting viability of both P. falciparum gametocyte (sexual) and blood (asexual) stage parasites. Our results provide a new insight into mechanisms that may be applicable to transmission-blocking agents.

Topics: Alkaloids; Antimalarials; Azepines; Biological Products; Deoxyuracil Nucleotides; Dose-Response Relationship, Drug; Heterocyclic Compounds, Bridged-Ring; Kinetics; Lactones; Life Cycle Stages; Piperidines; Plasmodium falciparum; Protozoan Proteins; Recombinant Fusion Proteins; Small Molecule Libraries; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship

Total syntheses of (±)-securinine and (±)-allosecurinine that employ a tandem rhodium carbenoid-initiated Claisen/α-ketol rearrangement sequence as a key step are described.

Topics: Alkaloids; Azepines; Cyclization; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Lactones; Molecular Structure; Piperidines; Rhodium; Stereoisomerism

Securinine, a GABA(A) receptor antagonist, has been reported to enhance monocyte cell killing of Coxiella burnetii without obvious adverse effects in vivo. We employed multiplex 2D gel electrophoresis using Zdyes, a new generation of covalently linked fluorescent differential protein detection dyes to analyze changes in the monocyte proteome in response to Securinine. Securinine antagonism of GABA(A) receptors triggers the activation of p38. We used the differential protein expression results to guide a search of the literature and network analysis software to construct a systems biology model of the effect of Securinine on monocytes. The model suggests that various metabolic modulators (fatty acid binding protein 5, inosine 5'-monophosphate dehydrogenase, and thioredoxin) are at least partially reshaping the metabolic landscape within the monocytes. The actin bundling protein L-plastin, and the Ca(2+) binding protein S100A4 also appear to have important roles in the immune response stimulated by Securinine. Fatty acid binding protein 5 (FABP5) may be involved in effecting lipid raft composition, inflammation, and hormonal regulation of monocytes, and the model suggests that FABP5 may be a central regulator of metabolism in activated monocytes. The model also suggests that the heat shock proteins have a significant impact on the monocyte immune response. The model provides a framework to guide future investigations into the mechanisms of Securinine action and with elaboration may help guide development of new types of immune adjuvants.

Topics: Adjuvants, Immunologic; Antigen Presentation; Azepines; Computational Biology; Electrophoresis, Gel, Two-Dimensional; GABA-A Receptor Antagonists; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Lactones; Metabolic Networks and Pathways; Models, Biological; Monocytes; p38 Mitogen-Activated Protein Kinases; Piperidines; Proteome; Proteomics; Receptors, GABA-A; Signal Transduction

Securinine, an alkaloid originally isolated from Securinega suffruticosa, exhibits a wide range of biological activities, including anti-malarial activity. Along with securinine, 10 pyrrolidine derivatives, generated via the retrosynthesis of (-)-securinine, were selected and tested for their inhibitory activity against Toxoplasma gondii growth in vitro. Anti-Toxoplasma activity correlated to hydrophobicity of the tested compounds. Three pyrrolidine derivatives along with securinine inhibit Toxoplasma proliferation at the micromolar range. These compounds act on parasite proliferation in different capacities, either by slowing the growth rate or inhibiting invasion of host cells. Securinine induces bradyzoite differentiation at comparable levels to treatment with alkali media in vitro.

Topics: Antiprotozoal Agents; Azepines; Cells, Cultured; Fibroblasts; Foreskin; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Male; Piperidines; Pyrimethamine; Pyrrolidines; Toxoplasma

As the defining feature of Acute Myeloid Leukemia (AML) is a maturation arrest, a highly desirable therapeutic strategy is to induce leukemic cell maturation. This therapeutic strategy has the potential of avoiding the significant side effects that occur with the traditional AML therapeutics. We identified a natural compound securinine, as a leukemia differentiation-inducing agent. Securinine is a plant-derived alkaloid that has previously been used clinically as a therapeutic for primarily neurological related diseases. Securinine induces monocytic differentiation of a wide range of myeloid leukemia cell lines as well as primary leukemic patient samples. Securinine's clinical potential for AML can be seen from its ability to induce significant growth arrest in cell lines and patient samples as well as its activity in significantly impairing the growth of AML tumors in nude mice. In addition, securinine can synergize with currently employed agents such as ATRA and decitabine to induce differentiation. This study has revealed securinine induces differentiation through the activation of DNA damage signaling. Securinine is a promising new monocytic differentiation inducing agent for AML that has seen previous clinical use for non-related disorders.

Topics: Animals; Azepines; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; DNA Damage; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; HL-60 Cells; Humans; Lactones; Leukemia, Myeloid, Acute; Mice; Mice, Nude; Monocytes; Myeloid Cells; Piperidines; Receptors, GABA; Reproducibility of Results; Signal Transduction; Xenograft Model Antitumor Assays

To investigate the anti-tumor effects of L-securinine inducing colon cancer SW480 cell autophagy and explore its potential molecular mechanism.. 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).. 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.. 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.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Azepines; Beclin-1; Cell Cycle; Cell Line, Tumor; Colonic Neoplasms; Euphorbiaceae; Flow Cytometry; Gene Expression; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Membrane Proteins; Phytotherapy; Piperidines; Plant Extracts; Up-Regulation; Vacuoles

The identification of agents that preferentially kill cancer cells while protecting normal cells offers the potential to overcome toxicities found in many existing chemotherapeutic agents. Because p53 is frequently inactivated in cancer, agents that preferentially kill p53-null cells and protect wild-type p53-expressing cells are highly desirable chemotherapeutic agents. By using pairs of isogenic colon cancer cell lines that differ only in p53 expression (RKO and HCT116), securinine was found to exhibit these properties. Securinine (30 microM) induces apoptosis in 73% of p53-null HCT116 cells (LD(50) 17.5 microM) as opposed to 17.6% of HCT116 parental cells (LD(50) 50 microM) at 72 h after treatment. The mechanism of securinine-mediated death in p53-deficient cells involves the induction of the p53 family member, p73. Interestingly, the proapoptotic protein p73 is down-regulated in colon cancer cells expressing p53. This differential regulation of p73 in a p53-dependent fashion reveals a novel pathway for preferentially targeting cancer cells. In contrast to p53-deficient cells, cells expressing p53 are protected from cell death through the p53-mediated up-regulation of p21. These studies reveal a novel approach to specifically target colon cancer cells lacking p53 as well as identify a novel clinically relevant pathway to selectively induce p73 in p53-null cells.

Topics: Apoptosis; Azepines; Blotting, Western; Caspase Inhibitors; Caspases; Cell Adhesion; Cell Cycle; Cell Proliferation; Colonic Neoplasms; DNA Damage; DNA-Binding Proteins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Nuclear Proteins; Piperidines; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured; Tumor Protein p73; Tumor Suppressor Protein p53; Tumor Suppressor Proteins

The alkaloid (-)-securinine was synthesized in 18 steps and 16% overall yield from trans-4-hydroxy-l-proline.

Topics: Azepines; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Lactones; Piperidines; Stereoisomerism

The most representative securinega alkaloids have been synthesized through a new strategy involving the palladium-catalyzed enantioselective allylation of a cyclic imide, a vinylogous Mannich reaction, and a ring-closing metathesis process, as the key steps. The diastereoselectivity of the vinylogous Mannich reaction was in partial agreement with DFT theoretical calculations performed in a model system. The synthesis of (-)-norsecurine has been accomplished in nine steps from succinimide and 14% overall yield and that of securinine in 10 steps from glutarimide and 20% overall yield. Both syntheses compare favorably with those previously described. The three key transformations have been performed in a synthetically useful scale (more than 500 mg). Moreover, since the enantioselectivity was originated by a chiral phosphine ligand, the antipode of which is readily available, the same route is expected to give access to (+)-norsecurinine and virosecurinine.

Topics: Alkaloids; Azepines; Catalysis; Euphorbiaceae; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Imides; Lactones; Palladium; Piperidines; Quantum Theory; Stereoisomerism; Substrate Specificity

Topics: Alkaloids; Azepines; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Lactones; Piperidines; Pyrrolidines

A new and versatile synthetic route to Securinega alkaloids is reported. The first synthesis of allosecurinine has been accomplished in seven steps and 40% yield, starting from (+)-menisdaurilide, using a vinylogous Mannich reaction as the key transformation. Similarly, viroallosecurinine has been synthesized from (-)-menisdaurilide.

Topics: Alkaloids; Azepines; Benzofurans; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Lactones; Piperidines; Stereoisomerism

Investigations on callus cultures of Securinega suffruticosa indicated that the cell line of S. suffruticosa callus was able to accumulate four known Securinega alkaloids with dextro rotation but not levo rotation as reported before: virosecurinine (1), viroallosecurinine (2), 14,15-dihydrovirosecurinine (3) and ent-phyllanthidine (4). Time course studies on the growth of callus cultures were carried out. The effects of different plant growth regulators, sucrose concentrations on callus growth and virosecurinine production were also reported.

Topics: Alkaloids; Azepines; Cell Division; Cell Line; Chromatography, High Pressure Liquid; Culture Media; Cytokinins; Euphorbiaceae; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Indoleacetic Acids; Lactones; Magnetic Resonance Spectroscopy; Piperidines; Plant Stems; Stereoisomerism

Innate immune cell stimulation represents a complementary approach to vaccines and antimicrobial drugs to counter infectious disease. We have used assays of macrophage activation and in vitro and in vivo phase II Coxiella burnetii infection models to compare and contrast the activity of a novel innate immune cell agonist, securinine, with known TLR agonists. As expected, TLR agonists, such as LPS (TLR4) and fibroblast-stimulating lipopeptide-1 (FSL-1; TLR2), induced macrophage activation and increased macrophage killing of phase II C. burnetii in vitro. FSL-1 also induced accelerated killing of C. burnetii in vivo. Securinine, a gamma-aminobutyric acid type A receptor antagonist, was found to induce TLR-independent macrophage activation in vitro, leading to IL-8 secretion, L-selectin down-regulation, and CD11b and MHC Class II antigen up-regulation. As seen with the TLR agonists, securinine also induced accelerated macrophage killing of C. burnetii in vitro and in vivo. In summary, as predicted by the literature, TLR agonists enhance macrophage killing of phase II C. burnetii in vitro, and at least for TLR2 agonists, this activity occurs in vivo as well. Securinine represents a novel macrophage agonist, which has similar effects as TLR agonists in this model yet apparently, does not act through known TLRs. Securinine has minimal toxicity in vivo, suggesting it or structurally similar compounds may represent novel, therapeutic adjuvants, which increase resistance to intracellular pathogens.

Topics: Alkaloids; Animals; Azepines; Cell Survival; Cells, Cultured; Coxiella burnetii; Diglycerides; Female; Fluorescent Antibody Technique; GABA-A Receptor Antagonists; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Humans; Interleukin-8; Lactones; Lipopolysaccharides; Macrophage Activation; Macrophages; Mice; Mice, Inbred BALB C; Monocytes; Oligopeptides; Piperidines; Receptors, GABA-A; Toll-Like Receptors

[reaction: see text] A model study to support the intermediacy of the aziridinium ion in the proposed biogenetic origin of secu'amamine A from allosecurinine is described.

Topics: Alkaloids; Azepines; Aziridines; Crystallography, X-Ray; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Hydrogenation; Lactones; Models, Biological; Molecular Conformation; Molecular Structure; Piperidines

A new isolate of Aspergillus sp. hydrogenated the gamma,delta-double bond of securinine (143 mg l(-1)) to give 14,15-dihydrosecurinine at over 98% (w/w) yield after 8 h. It also hydrogenated the C11(13) double bond of 3-hydroxy-1(10),3,11(13)-guaiatriene-12,6-olide-2-one (HGT) (200 mg l(-1)) to give 3-hydroxy-1(10),3-guaiadiene-12,6-olide-2-one with over 98% (w/w) conversion after 24 h.

Topics: Alkaloids; Aspergillus; Azepines; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Hydrogen; Hydrogen Bonding; Hydrogenation; Lactones; Piperidines; Species Specificity

[reaction: see text] A diastereoselective total synthesis of securinine in optically pure form was achieved by employing ring-closing metathesis of the corresponding dienyne compound as a key step.

Topics: Alkaloids; Azepines; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Lactones; Models, Chemical; Molecular Structure; Pipecolic Acids; Piperidines; Stereoisomerism

The syntheses of securinine and (-)-allonorsecurinine have been achieved starting from easily available alpha-amino acid derivatives and using as key steps a RCM and a Heck reaction for the formation of rings D and C, respectively. [reaction: see text]

Topics: Alkaloids; Azepines; Euphorbiaceae; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Lactones; Magnetic Resonance Spectroscopy; Molecular Structure; Piperidines

The effects of (+) securinine on behavior and morphological changes after intracerebral ventricle injection of beta-amyloid (25-35) (Abeta(25-35)) in rats were investigated. A single high dose of Abeta(25-35) could impair the spatial cognitive function. The latency of locating the platform was longer in the model group than in the sham-operated group. While chronic administration of D-securinine (40 mg kg(-1)) could significantly shorten the latency. After Morris water maze, the activity of choline acetyltransferase (ChAT) and acetylcholinesterase (AchE) were detected. The results showed that D-securinine could decrease the AchE activity significantly and have no effect on ChAT. Meanwhile, immunohistochemistry analysis revealed that D-securinine could reduce the glial inflammatory responses induced by beta-amyloid protein. These results suggest that the effect of D-securinine in improving the cognitive deficits and neurodegeneration in betaAP(25-35)-treated rats may involve direct and indirect actions on targets. The GABA receptor plays a key role in these therapeutic effects and may be helpful in the treatment of Alzheimer's disease.

Topics: Acetylcholinesterase; Alkaloids; Amyloid beta-Peptides; Animals; Azepines; Behavior, Animal; Brain; Choline O-Acetyltransferase; Dose-Response Relationship, Drug; Drug Interactions; Glial Fibrillary Acidic Protein; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Immunohistochemistry; Lactones; Male; Maze Learning; Neuroprotective Agents; Neurotoxicity Syndromes; Peptide Fragments; Peptides; Piperidines; Rats; Rats, Sprague-Dawley; Time Factors

The effect of nimodipine on securinine-induced long-term potentiation in rat hippocampus was studied. The rise of intracellular calcium during the induction of long-term potentiation was measured using Fura-2/AM--a Ca (2+) fluorescent chelator. Results showed that intracerebroventricular injection of nimodipine (4 nmol) blocked the induction of long-term potentiation elicited by securinine (0.4 pmol) and high-frequency stimulation (p < 0.05), but 2-amino-5-phosphonovaleric acid (5 nmol) had no inhibitory effect on securinine-induced long-term potentiation. In addition, securinine-induced intracellular calcium increment was inhibited by nimodipine (10(-6) mol. L(-1), p < 0.01), but not by 2-amino-5-phosphonovaleric acid (10(-6) mol. L(-1), p > 0.05).

Topics: Alkaloids; Anesthesia; Animals; Azepines; Calcium; Calcium Channel Blockers; Dentate Gyrus; Drug Interactions; Euphorbiaceae; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Lactones; Long-Term Potentiation; Male; Molecular Structure; Nimodipine; Piperidines; Plants, Medicinal; Rats; Rats, Sprague-Dawley; Time Factors

To study the in vitro and in vivo metabolism of (-)-securinine.. The metabolic transformation of (-)-securinine was studied by using phenobarbital-induced rat liver microsomal incubate containing the NADPH-generating system in vitro and the constitution of the system was optimized. A reversed phase HPLC method was established to analyze the parent drug and its metabolites. The major metabolites were isolated and purified by liquid-liquid extraction, preparative TLC and HPLC, and their structures were elucidated as 6-hydroxyl securinine, 6-carbonyl securinine, 5 beta-hydroxyl securinine and 5 alpha-hydroxyl securinine by 1HNMR, 13CNMR and MS spectral analysis. An HPLC method was developed to analyze securinine and its metabolites in biofluids (bile, urine) of rat. The bile, urine and their enzymatic hydrolyzed samples of the rat i.p. administrated with (-)-securinine were determined by using this method.. Four main metabolites of (-)-securinine in rat hepatic microsome incubation were obtained and their structures were elucidated. Metabolites from in vitro study were confirmed in biofluids (bile, urine) which were collected from rats given securinine i.p. It was suggested that 6-hydroxyl securinine was excreted in conjugated form as well by analyzing enzymatic hydrolyzed bile.. The main metabolic pathway of (-)-securinine in vitro and in vivo is basically elucidated.

Topics: Alkaloids; Animals; Azepines; Bile; Euphorbiaceae; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; In Vitro Techniques; Lactones; Male; Microsomes, Liver; Piperidines; Plants, Medicinal; Rats; Rats, Wistar; Stereoisomerism

To establish a high-performance capillary electrophoresis (HPCE) chiral separation method for d-securinine and l-securinine, and use this method to investigate the stereoselective metabolism process of d- and l-securinine in Wistar rats.. The electrophoretic condition and parameters were investigated and the optimized conditions were as following: the electrophoretic medium was 40 mmol.L-1 Tris-H3PO4 buffer (pH adjusted to 6.0 with H3PO4) containing 32 mmol.L-1 HP-beta-CD as chiral selector. Determination was carried out with a UV detector at 254 nm. The separations were performed at 16 degrees C with a positive voltage of 15 kV. Samples were injected into the capillary by pressure for 6 s. The biological samples (urine, bile, plasma and feces) of rats were alkalized and extracted with ethyl acetate.. The experimental results showed that the concentration of HP-beta-CD, the concentration of the running buffer and the pH value of the buffer were the main important factors which effected the resolution. d-Securinine and l-securinine were separated at baseline level under the determination conditions. The determination was not interfered by endogenous components and metabolites. After i.p. administration, the rats excreted more d-securinine than l-securinine through bile, urine and feces. The metabolism process in rats was stereoselective.. This method is simple, reliable and suitable for studying the stereoselective metabolism of securinine in rats.

Topics: Alkaloids; Animals; Azepines; Bile; Electrophoresis, Capillary; Euphorbiaceae; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Lactones; Male; Molecular Structure; Piperidines; Plants, Medicinal; Rats; Rats, Wistar; Stereoisomerism

To study the effects of (+) and (-) securinine on the basic synaptic transmission and long-term potentiation (LTP) induced by high-frequency stimulation in the dentate gyrus of anesthetized rats and its possible mechanism.. The population spike (PS) was recorded by electrophysiological techniques.. The results showed that at the concentration of 2 x 10(-9) mol.L-1, (+), (-) securinine showed no effect on either the basal PS or LTP. At high cocentrations (2 x 10(-8), 2 x 10(-7) mol.L-1), (+), (-) securinine not only potentiated the basal PS but also enhanced the magnitude of LTP. (+), (-) Securinine showed similar effects; and the effects were completely inhibited by the inhibitory amino acid GABA.. These results suggest that the effects of (+), (-) securinine on induction and maintenance of LTP may be related to its blockade of GABA receptor.

Topics: Alkaloids; Animals; Azepines; Dentate Gyrus; GABA Antagonists; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Lactones; Long-Term Potentiation; Male; Piperidines; Rats; Rats, Sprague-Dawley; Stereoisomerism; Synaptic Transmission

Pharmacological activities of virosecurinine (Vse) and securinine (Sec) were studied. The results showed that acute toxicity of Vse was 1/13.6 that of Sec, and Vse had no convulsive effects on rats or frogs, while Sec had. The results also showed that Vse and Sec could elevate blood pressure and excite respiration in cats.

Topics: Alkaloids; Animals; Azepines; Blood Pressure; Cats; Drugs, Chinese Herbal; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Lactones; Piperidines; Ranidae; Rats; Respiration

[structure: see text]. The concise total synthesis of securinine in nine steps from readily available starting materials is described. Key steps of the synthesis include an addition of a silyloxyfuran to an in situ generated iminium ion and a novel ring closing metathesis reaction.

Topics: Alkaloids; Azepines; Central Nervous System Stimulants; Crystallization; GABA Antagonists; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Indicators and Reagents; Lactones; Models, Molecular; Molecular Conformation; Piperidines; Plants, Medicinal; Stereoisomerism

To investigate cardiovascular effects of changed GABAergic tonic activation in periventricular forebrain, arterial pressure (AP), heart rate (HR) and renal sympathetic nerve discharge (RSND) were recorded in anesthetized rats when L-securinine (L-Sec) was administered into the lateral intracerebroventricle. L-Sec elicited dose-dependent increases in RSND, AP and HR, which were much weaker than those of bicuculline. L-Sec antagonized the sympatho-inhibitory and depressor effects evoked by both muscimol and baclofen. These results indicate that GABAergic inhibition originating from periventricular forebrain may suppress tonically sympathetic outflow to cardiovascular system which is disinhibited by L-Sec, and L-Sec is likely an unselective GABA receptor antagonist.

Topics: Alkaloids; Animals; Azepines; Blood Pressure; Electrophysiology; GABA Antagonists; Heart Rate; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Injections, Intraventricular; Kidney; Lactones; Male; Piperidines; Rats; Rats, Sprague-Dawley; Sympathetic Nervous System

To study whether securinine might induce apoptosis in human leukemia HL-60 cells.. Inhibition of proliferation was measured using MTT assay. The amount of apoptotic cells was measured by flow cytometry. DNA fragmentation was visualized by DNA agarose gel electrophoresis and the cellular changes were observed by electron microscope.. Securinine 5-80 mg.L-1 elicited typical apoptosis morphological changes and DNA fragmentation in a concentration-dependent manner in HL-60 cells. Securinine inhibited HL-60 cell proliferation in a time- and concentration-dependent manner. The IC50 and 95% confidence limits were 27 (15-47) mg.L-1 after 12-h treatment with securinine.. Securinine induced apoptosis in HL-60 cells.

Topics: Alkaloids; Antineoplastic Agents, Phytogenic; Apoptosis; Azepines; Cell Division; DNA Fragmentation; DNA, Neoplasm; Dose-Response Relationship, Drug; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; HL-60 Cells; Humans; Lactones; Piperidines

The hydroxide ion-catalyzed hydrolysis of securinine involves the ring opening of the lactone moiety. The rate of hydrolysis is insensitive to the ionic strength. The observed pseudo-first-order rate constants reveal a decrease of approximately 4-fold due to the increase in the MeCN content from 4 to 50% (v/v) in mixed aqueous solvent. The temperature dependence of the rate of hydrolysis follows the Eyring equation, which yields delta H* and delta S* as 11.0 kcal mol-1 and -34.5 cal deg-1 mol-1, respectively. The hydroxyl carboxylate product of the alkaline hydrolysis of securinine is shown to undergo cyclization in acidic medium to yield securinine. The observed pseudo-first-order rate constants for cyclization increase linearly with an increase in [H+]. The change in the content of MeCN from 3.8 to 47.2% (v/v) in mixed aqueous solvents does not show an effect on the rate of the cyclization reaction. The most plausible mechanisms for alkaline hydrolysis and acid cyclization reactions are also discussed.

Topics: Alkaloids; Azepines; Central Nervous System Stimulants; Cyclization; Half-Life; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Hydrolysis; Kinetics; Lactones; Piperidines; Sodium Hydroxide; Spectrophotometry, Ultraviolet; Temperature

The recently described potent and selective GABAA antagonist SR 95531 (gabazine) is compared to six other GABAA antagonists: (+)-bicuculline, (-)-securinine, (+)-tubocurarine, iso-THAZ, R-5135, and pitrazepine. Starting from ab initio molecular orbital calculations performed on crystal atomic coordinates, attempts were made to identify in each structure the functional groups that are involved in receptor recognition and binding. A molecular modeling study revealed that (a) all compounds possess accessible cationic and anionic sites separated by an 4.6-5.2 A intercharge distance, (b) the antagonistic nature of the compounds can be explained by the presence of additional binding sites, (c) the correct spatial orientation of the additional binding sites is crucial for GABAA selectivity, and (d) the criteria determining the potency of the antagonist effect are an accurate intercharge distance (greater than 5 A) and the existence of hydrogen-bonding functionalities on one of the additional ring system. The presented pharmacophore accounts also for the inactivity of closely related compounds such as (-)-bicuculline, adlumidine, virosecurinine, allosecurinine, and the 4,6-diphenyl analogue of gabazine.

Topics: Alkaloids; Androstanes; Azasteroids; Azepines; Bicuculline; Crystallization; Dibenzazepines; GABA-A Receptor Antagonists; gamma-Aminobutyric Acid; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Isoxazoles; Lactones; Models, Molecular; Molecular Conformation; Molecular Structure; Piperidines; Pyridazines; Receptors, GABA-A; Structure-Activity Relationship; Tubocurarine; X-Ray Diffraction

Securinine, an alkaloid having strychnine-like action was synthesized using 1,4-cyclohexanedione as the starting material through the following sequence of reactions: condensation with piperidine, reduction, cyclization catalyzed by mercuric acetate and intramolecular condensation, totally in eleven steps. The IR, 1HNMR and melting point of the synthetic product is identical with those of natural securinine.

Topics: Alkaloids; Azepines; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Lactones; Piperidines

The present experiments investigated changes in beta-adrenoceptor binding and noradrenaline stores in mouse cerebral cortex after single treatments with drugs which bind to the GABAA receptor but which attenuate the actions of GABA. Neither the GABA antagonist, securinine, nor the picrotoxin/Cl- channel ligand, picrotoxin, affected noradrenaline levels or beta-adrenoceptor binding. However, both the benzodiazepine inverse agonist, DMCM, and pentylenetetrazole increased noradrenaline levels 24 h after injection. Only pentylenetetrazol modified beta-adrenoceptor binding: there was a significant increase in receptor number 4 days after injection, but a significant decrease after 7 days. The anxiogenic, proconvulsant drug, yohimbine, was without effect. The changes induced by DMCM and pentylenetetrazole do not seem to be related to the behavioural effects of these drugs or to their affinity for binding to benzodiazepine receptors. The possibility that these compounds have actions in addition to those at the GABAA receptor is discussed.

Topics: Alkaloids; Animals; Azepines; Cerebral Cortex; Chlorides; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Ion Channels; Kinetics; Lactones; Male; Mice; Neuromuscular Depolarizing Agents; Norepinephrine; Pentylenetetrazole; Picrotoxin; Piperidines; Receptors, Adrenergic, beta; Receptors, GABA-A; Yohimbine

Topics: Alkaloids; Azepines; Central Nervous System Stimulants; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Lactones; Piperidines

Topics: Alkaloids; Animals; Azepines; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Lactones; Male; Membrane Potentials; Piperidines; Rana catesbeiana; Rats; Rats, Inbred Strains; Receptors, GABA-A; Receptors, Neurotransmitter; Spinal Cord

Topics: Alkaloids; Animals; Azepines; Central Nervous System Stimulants; Diazepam; Drug Synergism; gamma-Aminobutyric Acid; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Male; Mice; Piperidines; Seizures

Topics: Alkaloids; Animals; Azepines; Erythrocytes; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Intestine, Small; Lactones; Male; Mice; Mice, Inbred Strains; Piperidines; Rats; Rats, Inbred Strains; Spinal Cord

Experiments were undertaken to determine the site of action of securinine and related convulsant indolizidines. All of these compounds induced tonic seizures in mice, with CD50 values ranging from 11 to 87 mg/kg. The CD50 for bicuculline was found to be 8 mg/kg. Equilibrium binding assays revealed that securinine and dihydrosecurinine inhibit [3H]GABA binding to rat brain membranes with an IC50 of approximately 50 microM, which is some 7 times less potent than bicuculline. Allosecurinine and virosecurinine have IC50 values greater than 1 mM. Both dihydrosecurinine and securinine inhibited GABA-stimulated benzodiazepine binding in rat brain membranes, though they were somewhat weaker than bicuculline in this respect. Other binding assays revealed that securinine and its analogs were inactive as inhibitors of bicuculline-insensitive GABA binding, benzodiazepine, cholinergic muscarinic, and beta-adrenergic receptor binding. In addition, while thiocyanate ion increased the apparent binding potency of bicuculline 10-fold, it had little effect on that of securinine. Extracellular electrophysiological studies on neurons in the cat spinal cord indicated that securinine and dihydrosecurinine blocked the inhibitory action of GABA while having no effect on that of glycine. Allo- and virosecurinine were much less active as GABA receptor antagonists in this test. These results suggest that, like bicuculline, securinine and dihydrosecurinine are selective antagonists of GABA recognition sites on mammalian central neurons.

Topics: Alkaloids; Animals; Azepines; Bicuculline; Cats; Central Nervous System; Convulsants; Female; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Lactones; Mice; Mice, Inbred ICR; Piperidines; Receptors, GABA-A; Seizures; Stimulation, Chemical

Topics: Adolescent; Adult; Alkaloids; Anemia, Aplastic; Azepines; Central Nervous System Stimulants; Child; Child, Preschool; Chronic Disease; Drug Therapy, Combination; Female; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Male; Middle Aged; Piperidines; Stanozolol

Topics: Adolescent; Adult; Aged; Alkaloids; Anemia, Aplastic; Azepines; Central Nervous System Stimulants; Child; Chronic Disease; Female; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Male; Middle Aged; Piperidines

Topics: Alkaloids; Animals; Azepines; Cats; Dogs; Erythrocytes; Female; Haplorhini; Heterocyclic Compounds, Bridged-Ring; Hydrogen-Ion Concentration; Kidney; Lactones; Liver; Male; Mice; Myocardium; Organ Specificity; Oxygen; Piperidines; Rabbits; Rats

Topics: Alkaloids; Animals; Anura; Azepines; Cats; Cattle; Central Nervous System; Dogs; Heterocyclic Compounds, Bridged-Ring; Horses; Lactones; Mice; Piperidines; Rabbits; Sheep; Veterinary Medicine

Topics: Alkaloids; Azepines; Glaucoma; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Myasthenia Gravis; Ophthalmology; Optic Atrophy; Piperidines; Retina; Vision Tests; Visual Fields

Topics: Alkaloids; Azepines; Heterocyclic Compounds, Bridged-Ring; Lactones; Piperidines; Polarography

Topics: Alkaloids; Azepines; Chemical Phenomena; Chemistry, Pharmaceutical; Chemistry, Physical; Circular Dichroism; Heterocyclic Compounds, Bridged-Ring; Lactones; Optical Rotatory Dispersion; Piperidines; Research

Topics: Alkaloids; Azepines; Chemistry Techniques, Analytical; Chemistry, Pharmaceutical; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Lactones; Piperidines; Research; Stereoisomerism

Topics: Alkaloids; Azepines; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Piperidines

Topics: Alkaloids; Azepines; Chemistry, Pharmaceutical; Heterocyclic Compounds, Bridged-Ring; Lactones; Piperidines; Research

Topics: Alkaloids; Azepines; Bridged-Ring Compounds; Chemistry, Pharmaceutical; Heterocyclic Compounds, Bridged-Ring; Lactones; Piperidines; Research

Topics: Alkaloids; Azepines; Chemistry, Pharmaceutical; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Lactones; Piperidines; Research

Topics: Adsorption; Alkaloids; Azepines; Carbon; Chemistry, Pharmaceutical; Euphorbiaceae; Heterocyclic Compounds, Bridged-Ring; Lactones; Piperidines; Research

Topics: Alkaloids; Azepines; Galantamine; Heterocyclic Compounds, Bridged-Ring; Lactones; Piperidines

Topics: Alkaloids; Azepines; Heterocyclic Compounds, Bridged-Ring; Humans; Hypotension; Lactones; Piperidines

Topics: Alkaloids; Azepines; Heterocyclic Compounds, Bridged-Ring; Lactones; Piperidines