Tetrahydroprotoberberine Alkaloids Research Articles

A highly enantioselective acyl-Mannich reaction of isoquinolines with aldehydes promoted by proline derivatives: an approach to 13-alkyl-tetrahydroprotoberberine alkaloids

The highly stereoselective addition of aldehydes to isoquinolines, promoted by the Hayashi–Jorgensen secondary amine catalyst, is described. The procedure has a wide scope, with CbzCl or Boc2O used to activate isoquinoline to nucleophilic addition, allowing for the facile generation of useful synthetic intermediates in high enantiomeric excesses. The products obtained are synthetic intermediates for the synthesis of tetrahydroprotoberberine alkaloids. This methodology has been applied in the first enantioselective synthesis of 13-methyl tetrahydroprotoberberine, as reported herein.

Facile synthesis of tetrahydroprotoberberine and protoberberine alkaloids from protopines and study on their antibacterial activities

A series of isoquinoline alkaloids including tetrahydroprotoberberines, N-methyl tetrahydroprotoberberines and protoberberines were facile synthesised with protopines as the starting material. All compounds were evaluated for their antibacterial activities against four pathogenic bacteria Escherichia coli, Staphyloccocus aureus, Staphylococcus gallinarum and Salmonella choleraesuis. Experimental results indicated that protoberberines were the most active compounds to the target bacteria among the tested alkaloids. It was suggested that planar molecule with high aromatisation level (e.g. coptisine 5 and berberine 6) or a positive charge of the molecules (e.g. N-methyl tetrahydroprotoberberines 11 and 12) had a positive influence on the antibacterial effects.

Aporphine and Tetrahydroprotoberberine Alkaloids from the Leaves ofGuatteria friesiana(Annonaceae) and their Cytotoxic Activities

Phytochemical investigation of the leaves of Guatteria friesiana (Annonaceae) afforded three new isoquinoline alkaloids, 13-hydroxy-discretinine, 6,6a-dehydroguatteriopsiscine and 9-dehydroxy-1-methoxy-dihydroguattouregidine. Eight known alkaloids were also isolated, 13-hydroxy-2,3,9,10-tetramethoxyprotoberberine, guatteriopsiscine, lysicamine, liriodenine, atherospermidine, lanuginosine, 7,8-dihydro-8-hydroxypalmatine and palmatine. 13-Hydroxy-2,3,9,10-tetramethoxyprotoberberine was only obtained by synthesis and is being reported as a natural product for the first time. The structures of the isolated alkaloids were established by extensive analysis of 1D and 2D nuclear magnetic resonance (NMR) and mass spectrometric (MS) data, as well as by comparison with data reported in the literature. The in vitro cytotoxic activity of the major alkaloids was evaluated against tumor and non-tumor cell lines. All of the alkaloids evaluated were determined to be inactive based on National Cancer Institute (NCI/USA) criteria. However, the alkaloid palmatine exhibited a cytostatic effect on MCF-7 (breast) and U251 (glioma) human tumor cell lines, with GI50 values lower than 20.0 µmol L-1 (10.5 and 16.2 µmol L-1, respectively), suggesting a selective cytotoxic action.

(+/-)-Govadine and (+/-)-THP, two tetrahydroprotoberberine alkaloids, as selective alpha 1-adrenoceptor antagonists in vascular smooth muscle cells.

(+/-)-Govadine and (+/-)-THP ((+/-)-2,3,10,11-tetrahydroxytetrahydroprotoberberine HBr) have been shown to inhibit noradrenaline-induced contraction of rat thoracic aortae. The pharmacological activity of the compounds was determined in thoracic aortae and cardiac tissue isolated from the rat and in trachea isolated from the guinea-pig to determine the selectivity of the compounds towards different types of receptor. (+/-)-Govadine and (+/-)-THP were found to be alpha 1-adrenoceptor blocking agents in rat thoracic aorta as revealed by their competitive antagonism of vasoconstriction induced by noradrenaline (pA2 = 6.57 +/- 0.07 and 5.93 +/- 0.06, respectively) or phenylephrine (pA2 = 6.74 +/- 0.08 and 6.06 +/- 0.10, respectively). Removal of endothelium did not affect the antagonistic potencies of (+/-)-govadine (pA2 = 6.83 +/- 0.09) and (+/-)-THP (pA2 = 6.25 +/- 0.06) on phenylephrine-induced vasoconstriction. They were more potent than yohimbine (pA2 = 6.05 +/- 0.05), but less so than phentolamine (pA2 = 7.54 +/- 0.11) and prazosin (pA2 = 9.27 +/- 0.12). (+/-)-Govadine and (+/-)-THP, furthermore, inhibited [3H]inositol monophosphate formation caused by noradrenaline (3 microM) in rat thoracic aorta. (+/-)-Govadine and (+/-)-THP were also alpha 2-adrenoceptor blocking agents with pA2 values 5.50 +/- 0.13 and 5.41 +/- 0.11, respectively. A high concentration of (+/-)-govadine (30 microM) or (+/-)-THP (30 microM) did not, however, affect the contraction induced by the thromboxane receptor agonist U46619, prostaglandin F2 alpha (PGF2 alpha), 5-hydroxytryptamine (5-HT), angiotensin II, endothelin or high K+ in rat aorta denuded of endothelium. Neither the cyclic AMP nor cyclic GMP content of rat thoracic aorta was, furthermore, changed by (+/-)-govadine or (+/-)-THP. Contraction of guinea-pig trachea caused by carbachol, histamine, leukotriene C4 or neurokinin A was not affected by (+/-)-govadine or (+/-)-THP. (+/-)-Govadine or (+/-)-THP also did not block beta 1- or beta 2-adrenoceptor-mediated responses induced by isoprenaline in rat right atria and guinea-pig trachea. It is concluded that (+/-)-govadine and (+/-)-THP are selective alpha 1-adrenoceptor antagonists in vascular smooth muscle.

L‐Stepholidine‐induced excitation of dopamine neurons in rat ventral tegmental area is associated with its 5‐HT1A receptor partial agonistic activity

l-Stepholidine (l-SPD), a tetrahydroprotoberberine alkaloid, possesses a pharmacological profile of a D₁/5-HT(1A) agonist and a D₂ antagonist. This unique pharmacological profile makes it a promising novel antipsychotic candidate. Preliminary clinical trials and animal experiments suggest that l-SPD improves both positive and negative symptoms of schizophrenia without producing significant extrapyramidal side effects. To further explore the antipsychotic mechanisms of the drug, we studied the effects of l-SPD on the activity of dopamine (DA) neurons in the ventral tegmental area (VTA) using in vivo single-unit recording technique in rats. We found that l-SPD increased VTA DA neurons firing rate and induced slow oscillation in firing pattern. Moreover, l-SPD, not clozapine, reversed d-amphetamine-induced inhibition which induced an excitation of VTA DA neurons. Furthermore, our data indicated that the excitatory effect of l-SPD is associated with its partial agonistic action for the 5-HT(1A) receptor since the 5-HT(1A) receptor antagonist WAY100635 could block the l-SPD-induced excitatory effect. However, activation of 5-HT(1A) receptor alone by specific agonist (±)-8-Hydroxy-2-(dipropylamino) tetralin (8-OH-DPAT) was insufficient to elicit excitation of VTA DA neurons, but the excitation of 8-OH-DPAT on VTA DA neurons was elicited in the presence of D₂-like receptors antagonist raclopride. Collectively, these results indicate that l-SPD excited VTA DA neurons requiring its D₂-like receptors antagonistic activity and 5-HT(1A) receptor agonistic activity. The present data demonstrate that D₂ receptor antagonist/5-HT(1A) receptor agonistic dual properties modulate dopaminergic transmission in a unique pattern that may underlie the different therapeutic responses between l-SPD and other atypical antipsychotic drugs.

Simultaneous characterization of quaternary alkaloids, 8-oxoprotoberberine alkaloids, and a steroid compound in Coscinium fenestratum by liquid chromatography hybrid ion trap time-of-flight mass spectrometry

Simultaneous characterization of quaternary alkaloids, 8-oxoprotoberberine alkaloids, and a steroid compound in Coscinium fenestratum was successfully performed by liquid chromatography hybrid ion trap time-of-flight mass spectrometry (LC/IT-TOF MS). A total of 32 compounds, including 2 benzylisoquinoline alkaloids, 3 aporphine alkaloids, 12 quaternary protoberberine alkaloids, 10 8-oxoprotoberberine alkaloids, 3 tetrahydroprotoberberine alkaloids, and a steroid compound were simultaneously separated and characterized by matching the empirical molecular formulae with those published in literature and the multi-stage mass spectrometry (MS n ) data obtained using structural information from IT, accurate mass measurement obtained from TOF MS, and HPLC separation. A total of 20 compounds, including 4 novel natural products were identified or tentatively identified for the first time from Coscinium fenestratum. In the positive-ion mode, 8-oxoprotoberberines produced [M + H] + and [M + Na] +; the fragmentation of 8-oxodihydroprotoberberines produced [M + H– CH 3] + , [M + H– CH 3– CH 3] +, and [M + H– CH 3– CH 3–CO] +, while 8-oxotetrahydroprotoberberines generated [M + H– CH 3] + , [M + H– CH 3– CH 3] +, [M + H– CH 3– H] +, and iminium ions from the cleavage of the protoberberine skeleton. The method can be applied for the analysis of 8-oxoberberine and other alkaloids in Coptis japonica, Phellodendron amurense, and other herbal medicines.

Revision of the Structure of Escholidine

The structure of the quaternary tetrahydroprotoberberine alkaloid escholidine is revised on the basis of 2D NMR spectroscopy and X-ray diffraction. In contrast to the originally reported constitution, escholidine bears an -OH group at C-9 and an -OCH3 group at C-10. The 1H and 13C NMR data and long-range 1H-13C and NOE interactions of escholidine are compared with those of thalifendine and tetrahydroberberrubine. The 15N NMR data of escholidine obtained by using long-range 1H-15N correlation experiments at natural abundance are also reported.

Bio-guided isolation of the cytotoxic corytenchine and isocoreximine from roots of Annona cherimolia

The roots of Annona cherimolia have been shown to contain the known tetrahydroprotoberberine alkaloids corytenchine ( 1) and isocoreximine ( 2), investigated for their cytotoxic properties.

Effects of l-Stepholidine on Forebrain Fos Expression: Comparison with Clozapine and Haloperidol

l-Stepholidine (SPD) is a tetrahydroprotoberberine alkaloid and a mixed dopamine D1 agonist/D2 antagonist. Preliminary clinical trials suggest that SPD improves both positive and negative symptoms of schizophrenia without producing significant extrapyramidal side effects. Here, we report that SPD mimics the effect of the atypical antipsychotic drug clozapine, preferentially increasing Fos expression in corticolimbic areas. Thus, at 10 mg/kg (i.p.), SPD induced Fos expression in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and lateral septal nucleus (LSN) without significantly affecting the dorsolateral striatum (DLSt). At higher doses (20-40 mg/kg), SPD also increased Fos expression in the DLSt. The increase, however, was less pronounced than the increase seen in the NAc. Within the NAc, SPD also induced more Fos expression in the shell than in the core. In all subcortical areas examined, the Fos expression induced by SPD was mimicked by the D2 antagonist sulpiride and reversed by the D2 agonist quinpirole, suggesting that the effect is due to blockade of D2-like receptors by SPD. In the mPFC, however, the effect was not mimicked by sulpride or reversed by quinpirole. It was also not mimicked by the D1 agonist SKF38393 or SKF38393 plus sulpride, and not reversed by the D1 antagonist SCH23390. These results suggest that, in the mPFC, SPD may induce Fos expression through a non-DA mechanism. Whether the mechanism involves an interaction of SPD with other neurotransmitters such as 5-HT and norepinephrine remains to be determined.

Alkaloid production by somatic embryo cultures of Corydalis ambigua

Somatic embryos of Corydalis ambigua (Papaveraceae), which were cultured in liquid Linsmaier and Skoog medium supplemented with 0.1 mM IAA and 3% sucrose, produced two tetrahydroprotoberberine alkaloids, corydaline (0.03% of dry cell weight) and cavidine (1.09%). Among various plant growth regulators tested, two phenylurea derivatives, thidiazuron and N-(2-chloro-4-pyridyl)-N� -phenylurea enhanced the alkaloid production. Addition of 1 mM thidiazuron to the medium gave the maximum alkaloid content, 0.12% corydaline and 1.91% cavidine, after 21 days incubation. These results were compared with those from callus cultures and various intact organs. Corydaline and cavidine were accumulated in leaf, tuber and somatic embryos, whereas corybulbine was detected only in tubers. Callus cultures and immature seeds, which lack embryos, contained only trace amounts of these alkaloids, suggesting the necessity for organ differentiation for alkaloid production in C. ambigua.

Alkaloids from Croton flavens l. and their affinities to GABA-receptors

Phytochemical investigation of several plants of Croton flavens L. from Barbados has led to the isolation of the tetrahydroprotoberberine alkaloids scoulerine and coreximine, as well as the morphinanedienones salutaridine and its racemic form salutarine, sebiferine, norsinoacutine and flavinantine. In a screening for 3H-GABA displacing activity coreximine showed the highest affinity to the GABAA receptor.

Biosynthesis and synthesis of biologically active alkaloids of Indian medicinal plants

The structure and stereochemistry of biologically active alkaloids isolated from Croton sparsiflorus, Cocculus taurifolius, C. pendulus, Corydalis meifolia and Stephania glabra were established. Biosynthetic studies were carried out on preaporphine and dihydroproaporphine alkaloids, crotsparine and crotsparinine, and abnormal aporphine alkaloid sparsiflerine; abnormal Erythrina alkaloid isococculidine; morphinan-dienone alkaloid sebiferine; quaternary aporphine bases magnoflorine and laurifoline; bisbenzylisoquinoline alkaloids, pendulin, cocsulinin, (′)-hayatin, (S,R)-hayatidin, (R,R)-isochondrodendrine and (R,R)-bebeerine; biphenylbisbenzylisoquinoline alkaloids tiliacorine, tiliacorinine and tiliageine; aporphine-1-benzylisoquinoline alkaloid thalicarpine; aporphine alkaloid glaucine; and lpecac-β-carboline alkaloid tubulosine. Synthesis of (+)-ophicarpinone, crotsparine, sparsiflorine, tetrahydroprotoberberine alkaloids, (′) scoulerine, (′)-tetrahydropalmatine and their bromo derivatives and biogenetic type synthesis of phenanthroindolizidine alkaloid, tylophorine, seco-phenanthroindolizidine alkaloid, septicin, antofine and alkaloid C, are presented.

ChemInform Abstract: Enantiomeric Separation by Cyclodextrin Modified Capillary Zone Electrophoresis (CD‐CZE) of Quaternary Tetrahydroprotoberberine Alkaloids.

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A tosyliminium ion-based total synthesis of (±)-schefferine

The synthesis of the phenolic tetrahydroprotoberberine alkaloid (±)-schefferine is reported, featuring as key steps a tosyliminium ion-mediated Friedel-Crafts alkylation of eugenol dimethyl ether and an intramolecular Mitsunobu-type amination.Key words: total synthesis, (±)-schefferine, natural product, tosyliminium ion, Mitsunobu amination.

The first tetrahydroprotoberberine alkaloid from the genus Rollinia

The first tetrahydroprotoberberine alkaloid from the genus Rollinia

Enantiomeric separation by cyclodextrin modified capillary zone electrophoresis (CD-CZE) of quaternary tetrahydroprotoberberine alkaloids.

A cyclodextrin modified capillary zone electrophoresis (CD-CZE) for the enantiomeric separation of tetrahydroprotoberberine N-metho salts was established. The resolution was optimized by changing the concentration of the electrolyte solution, hydroxypropyl-beta-CD (0.02 M, 0.07 M, or 0.14 M) or dimethyl-beta-CD (0.05 M or 0.15 M) in phosphate buffer (pH 2.5 or 3) containing 10% acetonitrile with an applied voltage of 20 kV. This method was applied toward the enantioselective bio-conversion of quaternary tetrahydroprotoberberine N-metho salts in cultured cells of Corydalis species.

A tetrahydroprotoberberine alkaloid from Croton hemiargyreus

A new tetrahydroprotoberberine alkaloid, 2,10-dihydroxi-3,10-dimethoxy-8β-methyldibenzo[a,g]quinolizidine (hemiargyrine), was isolated from Croton hemiargyreus. Other bases present were glaucine, oxoglaucine, salutaridine and norsalutaridine. Their structures were elucidated using spectroscopic techniques.

High Affinity and Selectivity of Some Tetrahydroprotoberberine Alkaloids for Rat Striatal3H-raclopride Binding Sites

Abstract Four tetrahydroprotoberberine alkaloids isolated from Guatteria ouregou and Guatteria schomburgkiana were tested for their ability to displace 3H-SCH23390 and 3H-raclopride from their specific dopaminergic striatal binding sites and to inhibit 3H-dopamine uptake by striatal synaptosomes. All of them displaced 3H-raclopride binding with a high affinity and a great selectivity. These data suggest that the tetrahydroprotoberberine skeleton could be very interesting for developing selective ligands of D2 dopamine receptors.

Formation of (R)-configurated tetrahydroprotoberberine alkaloids [formula omitted][formula omitted] and [formula omitted][formula omitted

A highly stereoselective and reversible enzyme system, using NADPH and protoberberine alkaloids, was discovered in Corydalis cava bulbs catalyzing the formation of (R)-configured tetrahydroprotoberberine alkaloids; the hitherto assumed precursor role of (R)-reticuline for these alkaloids is incorrect.

Partial purification and properties of S-adenosyl-l-methionine: (S)-tetrahydroprotoberberinecis-N-methyltransferase from suspension-cultured cells of Eschscholtzia and Corydalis

An enzyme has been found in different species of isoquinoline alkaloid-producing plant cell cultures which specifically N-methylates certain (S)-tetrahydroprotoberberine alkaloids such as (S)-canadine and (S)-stylopine at the expense of S-adenosyl-l-methionine (SAM). It was partially purified (90-fold from Eschscholtzia californica cell suspension cultures and characterized. The enzyme has a pH optimum of 8.9, a temperature optimum at 40° and a Mr of about 78 000 ± 10%. The Km for (S)-canadine was determined to be 6.4,μM, for (S)-stylopine 3.1 μM and for SAM 12,μM. The enzyme is inhibited by S-adenosyl-l-homocysteine (SAH with a Ki of 24 μM.