Phenanthrene Alkaloids Research Articles

Menisperdaurines A-W, structurally diverse isoquinoline alkaloids from Menispermum dauricum and their dopamine D1 receptor activities

A total of 33 structurally diverse isoquinoline alkaloids were isolated from the rhizomes of Menispermum dauricum, including seventeen benzylisoquinoline analogues (menisperdaurines A-Q, 1–17), five protoberberine analogues (menisperdaurines R-V, 18–22), a quaternary phenanthrene alkaloid (menisperdaurine W, 23) and ten known compounds (24–33). Compound structures, including absolute configurations, were determined by extensive spectroscopic methods, quantum chemical calculations of chemical shifts, and calculated and experimental electronic circular dichroism (ECD) data. Compounds 1–5 were glycosidic benzylisoquinolines with glucose moieties attached at the C-12 position. Compound 8 was the first example that was isolated from the rhizomes of Menispermum dauricum, benzylisoquinoline and an aromatic unit connected by a sugar bridge. Compounds were evaluated for their inhibitory effects on the dopamine D1 receptor. Compounds 1, 8, 21, 24 and 29 showed potent D1 antagonistic activities, with IC50 values ranging from 1.0 to 4.5 μM. Compound 1 exhibited the highest antagonistic activity with an IC50 value of 1.0 ± 0.2 μM.

First Total Syntheses of Natural Phenanthrene Alkaloids, Uvariopsamine, Noruvariopsamine, 8-Hydroxystephenanthrine, 8-Methoxyuvariopsine, Thalihazine, and Secophoebine, and Their Potential as Antimalarial Agents.

The first total syntheses of natural phenanthrene alkaloids, namely, uvariopsamine (1), noruvariopsamine (2), 8-hydroxystephenanthrine (3), 8-methoxyuvariopsine (4), thalihazine (5), and secophoebine (6), have been realized. In addition, their in vitro antimalarial activity against the multidrug-resistant K1 strain of Plasmodium falciparum and in vitro cytotoxic activity against the human nasopharynx carcinoma (KB), small cell lung cancer (NCI-H187), and breast cancer (MCF7) human cancer cell lines were investigated. All the phenanthrene alkaloids showed significant antiplasmodial activity (IC50 1.07-7.41 µM), and most compounds displayed low to no toxicity against the three cancer cell lines tested. Particularly, 3 exhibited the best antimalarial activity with an IC50 value of 1.07 µM, no toxicity to NCI-H187 (IC50 > 50 µM), and low toxicity against KB (IC50 24.53 µM) and MCF7 (IC50 42.67 µM) cell lines.

Evaluation the Protective Effect of Withania somnifera Extract on the Level of Sex Hormone in Morphine Addicted Female Rats

Morphine is one of the most types of phenanthrene alkaloid opioid used to soothe the acute and chronic pain via narcotic and analgesic medical employment. Increasingly constantly used of opioid in the public and medication practical important knowledge improve that. Morphine show pernicious has effects on numerous tissue for instance ovary, liver and lung morphine side effects instruct for existence of oxidative role due to generation of reactive oxygen species in the affected tissue. Last decades researchers proved that natural substance provides protective role against toxic effect. Thus, withania somnifera consider as antioxidant substance provide protective versus the toxic substance as morphine. The present study wase aimed to evaluate the protective role of withania somnifera extract on the level of sex hormone in morphine addicted female rats. In conclusion, the present study confirmed a truth evidence of a protective roles of withania somnifera against the morphine addiction in female rats.

Isolation and characterization of alkaloids from thalictrum minus

The aim of the present work was to continue studies on the alkaloid content of the minus and identifying major alkaloids of the above ground parts of Th. minus of Iranian origin. Thalictrum minus population of Iran, contained two major phenanthrene alkaloids that their structure were established by spectral methods. Thaliglucine has been detected for the first time in the minus. Thaliglucine N-oxide is assumed to be a new phenanthrene N-oxide.

ANTIOXIDANT PROPERTIES AND EFFECTS OF APORPHINE ALKALOIDS AND THEIR PHENANTHRENE SECO-ISOMERS ON ACETYLCHOLINESTERASE ACTIVITY

For the first time, model’s phenanthrene seco-alkaloids (seco-glaucine and seco-boldine) obtained in the medium of subcritical water SBW) from plant aporphine alkaloids were studied as antioxidants and inhibitors of acetylcholinesterase (AChE). Antioxidant activity (in vitro) of model’s aporphine and phenanthrene alkaloids: boldine, seco-boldine, glaucine and seco-glaucine, (BD, s-BD, GL and s-GL) was studied in the reaction with a stable free radical DPPH (1,1- diphenyl-2-picrylhydrazyl). In vivo, antioxidant activity was determined in a bioluminescent test system using genetically modified E. coli strains. In experiments in vitro (DPPH-test) and in vivo (biotest) phenanthrene alkaloids s-GL and s-BD demonstrate the higher antioxidant activity than their aporphine precursors GL and BD. For the study (in vitro) of the anticholinesterase activity of alkaloids and their phenanthrene seco-isomers used the “Ellman’s method” with minor modifications. The data on the inhibitory activity of the AChE enzyme with aporphine and phenanthrene alkaloids, expressed as IC50 values obtained from dose-response curves, demonstrate that the inhibitory activity for seco-boldine (IC50 = 0.21 mM) and seco-glaucine (IC50 = 0.04 mM ) is higher than for the initial aporphine alkaloids boldine (IC50 = 0.29 mM) and glaucine (IC50 = 0.44 mM), respectively. Thus, it has been shown that phenanthrene alkaloids obtained in SBW exhibit higher antioxidant activity and better inhibiting AChE-activity than their aporphine precursors.

Protective Effect of Genistein on the Morphine-Induced Kidney Disorders in Male Mice

Background: Morphine is a member of the naturally occurring phenanthrene alkaloids of opium. Genistein is a phytoestrogen, present in soy products. This study was designed to evaluate protective effects of genistein against morphine induced damages to the kidneys of mice. Methods: In this study, 48 male mice were randomly assigned to 8 groups: control (saline), morphine treated group (10 mg/kg/day); genistein groups (1, 2, 4 mg/kg/day) and morphine plus genistein treated group. Drugs were administrated intraperitoneally for 30 consequent days. Weight of animals and kidneys, glomeruli characteristics, kidney function markers and blood serum nitric oxide level has been studied. Result: The results indicated that morphine administration significantly increased Lactate dehydrogenase (LDH), Blood urea nitrogen (BUN), creatinine and nitric oxide levels compared to the control ( saline) group (P<0.05). Genistein in all doses and genistein plus morphine at the dose of 4 mg/kg significantly decreased LDH, BUN, creatinine, glomerular diameter and nitric oxide levels compared to the control and morphine groups (p<0.05). Conclusion: It seems that genistein administration improved kidney damages induced by morphine in mice.

Aporphine and phenanthrene alkaloids with antioxidant activity from the roots of Stephania tetrandra

Five new alkaloids (1–5), including three new aporphine alkaloids and two new phenanthrene alkaloids, together with 10 known compounds (6–15) were obtained from the roots of Stephania tetrandra. Their structures were elucidated by spectroscopic methods, single-crystal X-ray diffraction, and electronic circular dichroism analyses. Compounds 7–10, and 13 showed antioxidant activities with malondialdehyde (MDA) inhibitory rates of 62.50 ± 1.91 to 98.44 ± 0.34% at the concentration of 10 μM.

Synthesis of Phenanthrene Alkaloids in Subcritical Water Using Secoboldine as an Example

Synthesis of Phenanthrene Alkaloids in Subcritical Water Using Secoboldine as an Example

DARK Classics in Chemical Neuroscience: Morphine.

As the major psychoactive agent in opium and direct precursor for heroin, morphine is a historically critical molecule in chemical neuroscience. A structurally complex phenanthrene alkaloid produced by Papaver somniferum, morphine has fascinated chemists seeking to disentangle pharmacologically beneficial analgesic effects from addiction, tolerance, and dependence liabilities. In this review, we will detail the history of morphine, from the first extraction and isolation by Sertürner in 1804 to the illicit use of morphine and proliferation of opioid use and abuse disorders currently ravaging the United States. Morphine is a molecule of great cultural relevance, as the agent that single-handedly transformed our understanding of pharmacognosy, receptor dynamics, and substance abuse and dependence disorders.

Synthesis of Phenanthrene Alkaloids from Herbal Aporphine Alkaloids in Subcritical Water Using Synthesis of Seco-Glaucine as an Example

Transformation of the model aporphine alkaloid glaucine into the phenanthrene alkaloid secoglaucine (seco-GL) in subcritical water at 100–250°C without catalytic additives is studied. The maximum yield of seco-glaucine is achieved at 250°C. It is shown that under these conditions the load of the initial compound affects only slightly the yield of the target compound, which is on average 80%. The increase of the GL load up to 400 mg results in precipitation of the target seco-GL directly from the reaction mixture. The suggested method avoids the use of costly and toxic organic solvents.

Berberine-targeted miR-21 chemosensitizes oral carcinomas stem cells.

Cancer recurrence and chemoresistance are two major obstacles to the treatment of oral squamous cell carcinomas (OSCC). And cancer stem cells (CSCs) have been found to possess tumor initiating, self-renewal and metastasis abilities, resulting in the relapse and chemoresistance of OSCC. In the present study, we investigated the anti-CSCs effect of berberine, a phenanthrene alkaloid isolated from the Berberis genus. Our results demonstrated that berberine dose dependently downregulated the oncogenicity in vitro, including ALDH1 activity, self-renewal property, and colony formation and invasion abilities as well as potentiated chemosensitivity of OSCC-CSCs. In addition, tumor growth in mice was attenuated after oral gavage treatment of berberine. We showed that the expression of miR-21 was suppressed following administration of berberine in OSCC-CSCs. And inhibition of endogenous miR-21 reduced the characteristics of CSCs, including self-renewal, migration, invasion capabilities and ALDH1 activity. Taken together, we demonstrated the anti-CSC effect of berberine in oral cancer and its potential to serve as adjuvant to traditional chemotherapy to improve treatment effect.

Beilschglabrines A and B: Two new bioactive phenanthrene alkaloids from the stem bark of Beilschmiedia glabra

Two new phenanthrene alkaloids, beilschglabrines A (1) and B (2) were isolated from the stem bark of Beilschmiedia glabra, together with lupeol, taraxerol, and 24-methylenelanosta-7,9-diene-3β-15α-diol. The structures of the isolated compounds were elucidated by extensive spectroscopic data analysis and comparison with respective literature data. The compounds were tested for DPPH radical scavenging, acetylcholinesterase and lipoxygenase inhibitory activities. Compound 1 displayed considerable activity in the acetylcholinesterase (IC50 50.4μM), the DPPH radical scavenging (IC50 115.9μM) and the lipoxygenase (IC50 32.8μM) assays.

Dicentrine Analogue-Induced G2/M Arrest and Apoptosis through Inhibition of Topoisomerase II Activity in Human Cancer Cells.

Lindera megaphylla has been traditionally used as an antineoplastic and wound healing remedy. We previously demonstrated the antitumor effects of D-dicentrine, a natural aporphine alkaloid from the root of L.megaphylla. To generate analogues, series of phenanthrene alkaloids from D-dicentrine were synthesized by degradation with ethyl chloroformate in pyridine, base hydrolysis, and N-alkylation. In this study, we demonstrated that one of the synthesized D-dicentrine analogues (here after designated as analogue 1) exhibited more potent cytotoxic effects than D-dicentrine in colon adenocarcinoma, hepatoma, leukemia, and epidermoid carcinoma cells. We performed cell cycle and apoptotic analysis by flow cytometry, an apoptotic DNA detection ELISA assay, and topoisomerase II activity by the kinetoplast DNA concatenation assay for studying their cytotoxic mechanisms. We found that both D-dicentrine and analogue 1 induced apoptosis and G2/M arrest in HL-60 leukemia cells. The percentage of apoptotic cells induced by analogue 1 was 4.5-fold higher than that induced by D-dicentrine as evident from measuring the amount of histone-bound DNA fragments. Moreover, we found that analogue 1 was 28-fold more potent than D-dicentrine for inhibition of topoisomerase II activity by the kinetoplast DNA concatenation assay. Our findings indicate that D-dicentrine analogue 1 is very promising as a potential antitumor agent for future study.

Deoxygenation of Phenolic Alkaloids by a Modified Pd/C-Catalyzed Hydrogenolysis Method

A modified palladium on carbon (Pd/C) catalyzed hydrogenolysis method for the removal of the phenolic-OH group in phenolic alkaloids as the 1-phenyl-1<i>H</i>-tetrazol-5-yl derivative by the addition of magnesium metal or ammonium acetate in acetic acid is described. Five different types of isoquinoline alkaloids, i.e., phenanthrene alkaloid, aporphine, pavine, protoberberine, and 1-benzyltetrahydroisoquinoline, were used as reactants. The results indicate that the addition of either magnesium metal or ammonium acetate has the advantage of decreasing the amount of Pd/C and the accelerating reaction rate over the simple Pd/C-catalyzed hydrogenolysis, thus it is practical for larger-scale preparation of de-phenolated alkaloids for pharmacological study.

Facile synthesis of 4,5,6a,7-tetrahydrodibenzo[de,g]chromene heterocycles and their transformation to phenanthrene alkaloids

Oxa-Pictet–Spengler cyclization and microwave-assisted C–H arylation have been implemented as key steps in the synthesis of new isochroman heterocycles containing a 4,5,6a,7-tetrahydrodibenzo[de,g]chromene motif. These isochromans may be easily transformed to phenanthrene alkaloids via acidic cleavage of the isochroman ring and standard synthetic manipulations thereafter. The route described is attractive in that it provides access to two biologically interesting scaffolds in simple and high yielding synthetic steps.

3,4-Dihydroxy- and 3,4-methylenedioxy- phenanthrene-type alkaloids with high selectivity for D2 dopamine receptor

Dopamine-mediated neurotransmission plays an important role in relevant psychiatric and neurological disorders. Nowadays, there is an enormous interest in the development of new drugs acting at the dopamine receptors (DR) as potential new targets for the treatment of schizophrenia or Parkinson’s disease. Previous studies have revealed that isoquinoline compounds such as tetrahydroisoquinolines (THIQs) can behave as selective D2 dopaminergic alkaloids. In the present study we have synthesized five aporphine compounds and five phenanthrene alkaloids and evaluated their potential dopaminergic activity. Binding studies on rat striatal membranes were used to evaluate their affinity and selectivity towards D1 and D2 DR. Phenanthrene type alkaloids, in particular the 3,4-dihydroxy- and 3,4-methylenedioxy derivatives, displayed high selectivity towards D2 DR. Therefore, they are potential candidates to be used in the treatment of schizophrenia (antagonists) or Parkinson’s disease (agonists) due to their scarce D1 DR-associated side effects.

Synthesis and reactive oxygen species scavenging activity of halogenated alkaloids from boldine

Six halogenated alkaloids have been semi-synthesized from natural boldine as starting material. Their antioxidant activity toward reactive oxygen species (ROS) generation by neutrophils stimulated with N-formyl-methionyl-leucyl-phenylalanine and in the hypoxanthine–xanthine oxidase system was evaluated. Most of the alkaloids synthesized inhibited ROS generation in both systems in a concentration-dependent manner. The alkaloids with phenolic substituents displayed more powerful anti-oxidative activity than those containing methoxylated groups. None of the alkaloids assayed had any effect on xanthine oxidase activity. Therefore, halogenated phenanthrene alkaloids can become in promising candidates for the development of novel and potent anti-inflammatory drugs.

Antiplatelet effects of some aporphine and phenanthrene alkaloids in rabbits and man.

Two aporphines (boldine and laurolitsine) and five phenanthrene alkaloids (litebamine, secoboldine, N-cyanosecoboldine, N-methylsecoglaucine and N-methylsecopredicentrine) were evaluated in-vitro for their ability to inhibit platelet aggregation. All seven alkaloids inhibited aggregation of rabbit platelets and inhibited the release of ATP induced by arachidonic acid and collagen in rabbit platelets. Those aggregations induced by platelet-activating factor (PAF), thrombin, U46619 and ADP were inhibited by the three N-substituted secoboldine derivatives only. Thromboxane B2 formation caused by arachidonic acid was also suppressed by these compounds. They did not affect the generation of [3H]inositol monophosphate caused by collagen, PAF and thrombin in the presence of indomethacin. Platelet cyclic AMP level was unaffected by litebamine, but was increased by N-methylsecoglaucine. Litebamine suppressed the secondary aggregation, but not the primary aggregation, induced by ADP and adrenaline in platelet-rich plasma from man, whereas N-methylsecoglaucine inhibited both primary and secondary aggregation. It is concluded that the antiplatelet effect of these seven aporphine and phenanthrene alkaloids is mainly a result of inhibition of thromboxane A2 formation; N-methylsecoglaucine has additional antiplatelet activity as a result of increasing the levels of platelet cyclic AMP.

Litebamine, a phenanthrene alkaloid from the wood of Litsea cubeba, inhibits rat smooth muscle cell adhesion and migration on collagen

Smooth muscle cells (SMCs) play an important role in the development of atherosclerosis and restenosis after angioplasty and coronary bypass grafting. The pathogenesis of these vascular diseases includes the abnormal production of extracellular matrix (ECM) proteins by SMCs and their interactions with this newly synthesized and preexisting ECM. Litebamine, a natural phenanthrene alkaloid from the wood of Litsea cubeba, has been shown to inhibit platelet aggregation and thromboxane B 2 formation, suggesting its antithrombotic activity. In the present study we examined litebamine effects on vascular SMC adhesion and migration. Our results indicated that litebamine inhibited rat aortic SMCs (RASMCs) and A10 thoracic SMCs adhesion to collagen but not to other matrix proteins, suggesting its specificity on collagen. This inhibition was possibly resulted from that litebamine attenuated immobilized collagen-induced focal adhesion kinase ( FAK) phosphorylation and actin cytoskeleton reorganization in RASMCs, as determined by Western blotting and immunofluorescence microscopy. In a functional study, litebamine also inhibited platelet-derived growth factor (PDGF)-induced RASMC migration but did not affect PDGF-induced matrix metalloproteinases (MMPs) secretion. Strikingly, among the tested kinases involved in PDGF-induced migration, only PDGF-induced phosphatidylinositol-3 kinase (PI-3K) activation was inhibited by litebamine. Taken together, we demonstrated here that litebamine can functionally inhibit vascular SMC adhesion and migration and elucidated its possible mechanisms of action. As SMC adhesion and migration are critical events in disease-related vascular remodeling, this compound may have beneficial effects in preventing cardiovascular diseases.

Synthesis of Thalicthuberine

The structure previously assigned to the phenanthrene alkaloid thalicthuberine has been confirmed by a total synthesis in which the key step involved the formation of ring C of the aporphine alkaloid (±)-nantenine by a radical-initiated cyclisation. Opening of ring B of (±)-nantenine with methyl chloroformate and subsequent reduction of the N-carbomethoxy group afforded thalicthuberine.