Pavine Alkaloid Research Articles

A novel phenylisoquinoline alkaloid with cardioprotective effect from Aconiti Lateralis Radix Praeparata

Macroporous resin chromatography, silica gel column chromatography, preparative thin layer chromatography, and semi-preparative high performance liquid chromatography were performed to isolate two compounds from the acid extract of the lateral roots of Aconitum carmichaelii: a new 9-phenylisoquinoline alkaloid(1) and a known pavine alkaloid(2). Their structures were elucidated by spectroscopy. The absolute configuration of compound 1 was identified by electronic circular dichroism(ECD) and it was determined to be(aS)-7,8-dimethoxy-9-(2-carboxy-4,5-dimethoxyphenyl)-3,4-dihydroisoquinoline-1(2H)-one(1). The cardioprotective effects of 1 and 2 against doxorubicin-induced toxicity in H9 c2 cells were evaluated. Both of the isoquinoline alkaloids showed cardioprotective activity.

Two new isoquinoline alkaloids from Cryptocarya wrayi and their biological activities

Two new isoquinoline alkaloids, cryptowrayines A (1) and B (2), along with one known pavine alkaloid (-)-12-hydroxyeschscholtzidine (3), were isolated from the twigs of Cryptocarya wrayi. The structures of new compounds were elucidated by extensive spectroscopic data analysis and electronic circular dichroism (ECD) calculations. Both compounds 1 and 2 exhibited moderate quinone reductase inducing activity in Hepa 1c1c7 cells.

First Total Synthesis of the Pavine Alkaloid (±)-Neocaryachine and Its Optical Resolution

The first total synthesis of (±)-neocaryachine (1) was achieved using a radical cyclization to produce the dibenzo-9-azabicyclo[3.3.1]nonane pavine skeleton, following a Bischler-Napieralski reaction to construct an intermediate benzylisoquinoline. The resulting racemic mixture was separated by chiral column chromatography to provide pure (+)- and (-)-1.

Extremely Facile Formation of the Pavine Alkaloid Skeleton by the Photoreaction between Isoquinoline and Benzyltrifluoroborate

Appling the photo-benzylation of isoquinoline with benzyltrifluoroborate, an extremely facile method for the construction of a pavine alkaloid skeleton was developed. When 3-methoxybenzylboron reag...

Cholinesterase and Prolyl Oligopeptidase Inhibitory Activities of Alkaloids from Argemone platyceras (Papaveraceae).

Alzheimer’s disease is an age-related, neurodegenerative disorder, characterized by cognitive impairment and restrictions in activities of daily living. This disease is the most common form of dementia with complex multifactorial pathological mechanisms. Many therapeutic approaches have been proposed. Among them, inhibition of acetylcholinesterase, butyrylcholinesterase, and prolyl oligopeptidase can be beneficial targets in the treatment of Alzheimer’s disease. Roots, along with aerial parts of Argemone platyceras, were extracted with ethanol and fractionated on an alumina column using light petrol, chloroform and ethanol. Subsequently, repeated preparative thin-layer chromatography led to the isolation of (+)-laudanosine, protopine, (–)-argemonine, allocryptopine, (–)-platycerine, (–)-munitagine, and (–)-norargemonine belonging to pavine, protopine and benzyltetrahydroisoquinoline structural types. Chemical structures of the isolated alkaloids were elucidated by optical rotation, spectroscopic and spectrometric analysis (NMR, MS), and comparison with literature data. (+)-Laudanosine was isolated from A. platyceras for the first time. Isolated compounds were tested for human blood acetylcholinesterase, human plasma butyrylcholinesterase and recombinant prolyl oligopeptidase inhibitory activity. The alkaloids inhibited the enzymes in a dose-dependent manner. The most active compound (–)-munitagine, a pavine alkaloid, inhibited both acetylcholinesterase and prolyl oligopeptidase with IC50 values of 62.3 ± 5.8 µM and 277.0 ± 31.3 µM, respectively.

(-)-Neocaryachine, an Antiproliferative Pavine Alkaloid from Cryptocarya laevigata, Induces DNA Double-Strand Breaks.

Twelve benzylisoquinoline alkaloids, including pavine and phenanthroindolizidine types, were isolated from a MeOH/CH2Cl2 extract of Cryptocarya laevigata (stem bark) through bioactivity-guided fractionation for antitumor effects. Selected compounds were evaluated for antiproliferative activity against five human tumor cell lines, including a multidrug-resistant subline. Since more common 2,3,8,9-tetrasubstituted pavine alkaloids, such as crychine (3), exhibit very mild or no cytotoxicity, this compound type has not been well investigated for antitumor activity. Thus, this report is the first discovery of a 7-hydroxylated pavine alkaloid, (-)-neocaryachine (1), to demonstrate strong antiproliferative activity, with IC50 values of 0.06 to 0.41 μM against five tested tumor cell lines, including an MDR subline. Further mechanism of action studies revealed that 1 impacts the cellular S-phase by inducing DNA double-strand breaks.

Cytotoxic and Anti-HIV Phenanthroindolizidine Alkaloids from Cryptocarya chinensis†

Bioassay-guided fractionation of the cytotoxic ethanol extract of Cryptocarya chinensis has led to the isolation of 11 compounds, including two phenanthroindolizidine alkaloids [(-)-antofine (1) and dehydroantofine (2)], five pavine alkaloids (3-7), and four proaporphine alkaloids (8-11). The structures of the isolated compounds were determined by means of NMR spectroscopic methods, and supported by HRMS and optical rotation data. Compounds 1 and 2 showed cytotoxic activity against four cancer cell lines, L1210, P388, A549, and HCT-8, with 1 being the most potent against A549 and HCT-8 with EC50 values of 0.002 and 0.001 microg/mL, respectively. In addition, 2 is first reported to exhibit significant anti-HIV activity.

ChemInform Abstract: A New Regioselective Synthesis of Isopavine and Pavine Alkaloids via Double Cyclization of N-(1,2-Diarylethyl)-N-(2-phenylsulfinylethyl)formamide.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Targeted metabolite and transcript profiling for elucidating enzyme function: isolation of novel N‐methyltransferases from three benzylisoquinoline alkaloid‐producing species

An integrated approach using targeted metabolite profiles and modest EST libraries each containing approximately 3500 unigenes was developed in order to discover and functionally characterize novel genes involved in plant-specialized metabolism. EST databases have been established for benzylisoquinoline alkaloid-producing cell cultures of Eschscholzia californica, Papaver bracteatum and Thalictrum flavum, and are a rich repository of alkaloid biosynthetic genes. ESI-FTICR-MS and ESI-MS/MS analyses facilitated unambiguous identification and relative quantification of the alkaloids in each system. Manual integration of known and candidate biosynthetic genes in each EST library with benzylisoquinoline alkaloid biosynthetic networks assembled from empirical metabolite profiles allowed identification and functional characterization of four N-methyltransferases (NMTs). One cDNA from T. flavum encoded pavine N-methyltransferase (TfPavNMT), which showed a unique preference for (+/-)-pavine and represents the first isolated enzyme involved in the pavine alkaloid branch pathway. Correlation of the occurrence of specific alkaloids, the complement of ESTs encoding known benzylisoquinoline alkaloid biosynthetic genes and the differential substrate range of characterized NMTs demonstrated the feasibility of bilaterally predicting enzyme function and species-dependent specialized metabolite profiles.

Molecular Cloning and Characterization of Tetrahydroprotoberberine cis-N-Methyltransferase, an Enzyme Involved in Alkaloid Biosynthesis in Opium Poppy

S-Adenosyl-l-methionine:tetrahydroprotoberberine cis-N-methyltransferase (EC 2.1.1.122) catalyzes the conversion of (S)-stylopine to the quaternary ammonium alkaloid, (S)-cis-N-methylstylopine, as a key step in the biosynthesis of protopine and benzophenanthridine alkaloids in plants. A full-length cDNA encoding a protein exhibiting 45 and 48% amino acid identity with coclaurine N-methyltransferase from Papaver somniferum (opium poppy) and Coptis japonica, respectively, was identified in an elicitor-treated opium poppy cell culture expressed sequence tag data base. Phylogenetic analysis showed that the protein belongs to a unique clade of enzymes that includes coclaurine N-methyltransferase, the predicated translation products of the Arabidopsis thaliana genes, At4g33110 and At4g33120, and bacterial S-adenosyl-L-methionine-dependent cyclopropane fatty acid synthases. Expression of the cDNA in Escherichia coli produced a recombinant enzyme able to convert the protoberberine alkaloids stylopine, canadine, and tetrahydropalmatine to their corresponding N-methylated derivatives. However, the protoberberine alkaloids tetrahydroxyberbine and scoulerine, and simple isoquinoline, benzylisoquinoline, and pavine alkaloids were not accepted as substrates, demonstrating the strict specificity of the enzyme. The apparent K(m) values for (R,S)-stylopine and S-adenosyl-L-methionine were 0.6 and 11.5 microm, respectively. TNMT gene transcripts and enzyme activity were detected in opium poppy seedlings and all mature plant organs and were induced in cultured opium poppy cells after treatment with a fungal elicitor. The enzyme was detected in cell cultures of other members of the Papaveraceae but not in species of related plant families that do not accumulate protopine and benzophenanthridine alkaloids.

Alkaloids from Eschscholzia californica and Their Capacity to Inhibit Binding of [3H]8-Hydroxy-2-(di-N-propylamino)tetralin to 5-HT1A Receptors in Vitro

A 70% ethanol extract of California poppy (Eschscholzia californica) was able to bind to 5-HT(1A) and 5-HT(7) receptors at 100 mug/mL. The subsequent isolation procedure yielded the known alkaloids californidine (1), escholtzine (2), N-methyllaurotetanine (3), caryachine (4), and O-methylcaryachine (5), along with a new pavine alkaloid, 6S,12S-neocaryachine-7-O-methyl ether N-metho salt (7). The structure of 7 was determined by spectroscopic data interpretation, while the absolute stereochemistry was determined by means of circular dichroism. From the results obtained from the radioligand-binding assay of the pure compounds, including the commercially available protopine (6), it was evident that the activity on the 5-HT(1A) receptor was at least partly due to the presence of the aporphine alkaloid 3, which showed the highest inhibition of [(3)H]8-hydroxy-2-(di-N-propylamino)tetralin ([(3)H]8-OH-DPAT) binding with an EC(50) value of 155 nM and a K(i) of 85 nM.

In vitro anti-influenza virus activity of the pavine alkaloid (-)-thalimonine isolated from Thalictrum simplex L.

The pavine alkaloid (-)-thalimonine (Thl), isolated from the Mongolian plant Thalictrum simplex inhibited markedly the reproduction of influenza virus A/Germany/27, str. Weybridge (H7N7) and A/Germany/34, str. Rostock (H7N1) in cell cultures of chicken embryo fibroblasts. In a number of assays at a non-toxic concentration range of 0.1-6.4 microM the alkaloid inhibited viral reproduction in a selective and specific way (selectivity index = 640, 106.6, respectively). Expression of viral glycoproteins haemagglutinin (HA), neuraminidase (NA) and nucleoprotein (NP) on the surface of infected cells, virus-induced cytopathic effect, infectious virus yields, HA production and virus-specific protein synthesis were all reduced. The inhibition was dose-related and depended on virus inoculum. The time of addition experiments indicated that viral reproduction was markedly inhibited when Thl was added at 4-5 h of infection. No inactivating effect on extracellular virus was found.

Cardiac electrophysiologic and antiarrhythmic actions of a pavine alkaloid derivative, O-methyl-neocaryachine, in rat heart.

1. O-methyl-neocaryachine (OMNC) suppressed the ischaemia/reperfusion-induced ventricular arrhythmias in Langendorff-perfused rat hearts (EC50=4.3 microM). Its electrophysiological effects on cardiac myocytes and the conduction system in isolated hearts as well as the electromechanical effects on the papillary muscles were examined. 2. In rat papillary muscles, OMNC prolonged the action potential duration (APD) and decreased the maximal rate of depolarization (V(max)). As compared to quinidine, OMNC exerted less effects on both the V(max) and APD but a positive inotropic effect. 3. In the voltage clamp study, OMNC decreased Na+ current (I(Na)) (IC50=0.9 microM) with a negative-shift of the voltage-dependent inactivation and a slowed rate of recovery from inactivation. The voltage dependence of I(Na) activation was, however, unaffected. With repetitive depolarizations, OMNC blocked I(Na) frequency-dependently. OMNC blocked I(Ca) with an IC(50) of 6.6 microM and a maximum inhibition of 40.7%. 4. OMNC inhibited the transient outward K+ current (I(to)) (IC50=9.5 microM) with an acceleration of its rate of inactivation and a slowed rate of recovery from inactivation. However, it produced little change in the steady-state inactivation curve. The steady-state outward K+ current (I(SS)) was inhibited with an IC50 of 8.7 microM. The inward rectifier K+ current (I(K1)) was also reduced by OMNC. 5. In the perfused heart model, OMNC (3 to 30 microM) prolonged the ventricular repolarization time, the spontaneous cycle length and the atrial and ventricular refractory period. The conduction through the AV node and His-Purkinje system, as well as the AV nodal refractory period and Wenckebach cycle length were also prolonged (30 microM). 6. In conclusion, OMNC blocks Na+, I(to) and I(SS) channels and in similar concentrations partly blocks Ca2+ channels. These effects lead to a modification of the electromechanical function and may likely contribute to the termination of ventricular arrhythmias. These results provide an opportunity to develop an effective antiarrhythmic agent with modest positive inotropy as well as low proarrhythmic potential.

Alkaloids of the wood of Cryptocarya chinensis.

Four new pavine alkaloids, (+)-eschscholtzidine-N-oxide (1), (-)-12-hydroxycrychine (2), (-)-12-hydroxy-O-methylcaryachine (3), and (-)-N-demethylcrychine (4), and four new proaporphine alkaloids, isocryprochine (5), prooxocryptochine (6), isoamuronine (7), and (+)-8,9-dihydrostepharine (8), together with nine known compounds were isolated from an ethanol extract of the wood of Cryptocarya chinensis. Their structures were elucidated by spectral analysis (NMR and MS), and the structures of 2 and 5 were confirmed by X-ray crystallography.

An efficient synthesis of argemonine, a pavine alkaloid

A method for the synthesis of 1,2-dihydroisoquinoline derivatives is described and the conversion of the 1,2-dihydroisoquinoline intermediate to a pavine alkaloid via palladium-induced intramolecular hydroarylation reaction and radical cyclization is presented.

ChemInform Abstract: Aryl Radical Cyclizations: One-Pot Syntheses of Protoberberine and Pavine Alkaloids.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Aryl radical cyclizations: one-Pot syntheses of protoberberine and pavine alkaloids.

Treatment of 2-(2'-bromo-beta-phenethyl)isocarbostyrils 7 with AIBN-Bu(3)SnH in boiling benzene gave 8-oxoberbines 3 in good yields. A similar treatment of 2-(2'-bromo-beta-phenethyl)isoquinolinium bromides 6 and their nor- and homoanalogues (10,11) induced 6-, 5-, and 7-exo radical closures in a one-pot manner to give protoberberines 2, dibenzo[b,g]indolizidine 14a and, dibenzo[a, h]-1-azabicyclo[5.4.0]undecane 15a, respectively. A one-pot radical cyclization of 1-(2'-bromobenzyl)isoquinoline methiodide 18a gave a pavine alkaloid, (+/-)-algemonine (19a).

Increased Efficacy of Zinc Complexes With Picolinic and Aspartic Acids Against Herpes Simplex Virus (HSV) Infection When Combined With the Pavine Alkaloid (‐)‐Thalimonine

Complexes of zinc with picolinic and aspartic acids inhibit key steps of HSV-1 replication affecting different virus-specific targets. As was recently demonstrated by us, the pavine alkaloid (-)-thalimonine irreversibly inhibits HSV-1 infection in cultured cells. The aim of the present study was the evaluation of the combined effect of zinc complexes and (-)-thalimonine on uninfected and HSV-1 infected cells. The data obtained have shown that zinc complexes and the alkaloid exert decreased cytotoxicity (antagonistic effect) and significantly increased anti-HSV-1 activity (synergistic effect) when applied in dual chess-board combinations as compared to the individual effects of compounds tested. These combinations are also effective against the infection caused by a resistant to acyclovir (ACV) HSV-1 mutant and the effect has been recognised as synergistic.

A comparative investigation on alkaloid composition in different populations of Eschscholtzia californica cham.

The alkaloid compositions of different populations of Eschscholtzia californica Cham. grown under controlled conditions and of some samples of the commercial drug have been examined using a reversed-phase HPLC method. Seven compounds have been detected (O-methylcaryachine, protopine, α-allocryptopine, eschscholtzine, californidine, sanguinarine and chelerytrine). In all samples the major components were the pavine alkaloids eschscholtzine and californidine, although their content varied to a large extent (from 1 to 10-fold). The commericial drug contained a significantly lower concentration of alkaloids. Copyright © 1999 John Wiley & Sons, Ltd.

Formation of pavine alkaloids by callus culture of Cryptocarya chinensis

Three quaternary pavine alkaloids, caryachine N-metho salt, neocaryachine N-metho salt and crychine N-metho salt were isolated from a callus culture of Cryptocarya chinensis. Neocaryachine N-metho salt is reported for the first time as a natural product. The effect of various culture media components on the growth of callus, and the production of caryachine N-metho salt were also investigated.