Polycyclic compounds with N-methyl substitution, structurally related to Amaryllidaceae alkaloids, have been synthesised, together with their analogues bearing a quaternary nitrogen atom. To prevent the lone electron pair of the nitrogen from interfering with the reaction sequence, two approaches to the synthesis were investigated: N-oxidation and Boc protection of the nitrogen. The second method was more successful due to the limited stability of N-oxides in the halocyclisation step. An asymmetric version of the synthesis was also developed for this type of compounds. The prepared products were tested in vitro for their cholinesterase inhibitory activity and the results were rationalised by molecular docking studies with human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE). In general, our products were more active against BuChE than against AChE, and it was noted that larger ligands should be prepared for future studies, since in some cases acetylcholine can still fit into the active site along with the bound ligand.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• alkaloidy amarylkovitých * chemie   farmakologie   MeSH
• alkaloidy * chemie   MeSH
• Amaryllidaceae * chemie   metabolismus   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemie   MeSH
• dusík MeSH
• lidé MeSH
• simulace molekulového dockingu MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• alkaloidy amarylkovitých * MeSH
• alkaloidy * MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• dusík MeSH

Twenty known Amaryllidaceae alkaloids of various structural types, and one undescribed alkaloid of narcikachnine-type, named narcieliine (3), have been isolated from fresh bulbs of Zephyranthes citrina. The chemical structures of the isolated alkaloids were elucidated by a combination of MS, HRMS, 1D and 2D NMR, and CD spectroscopic techniques, and by comparison with literature data. The absolute configuration of narcieliine (3) has also been determined. Compounds isolated in a sufficient quantity were evaluated for their in vitro acetylcholinesterase (AChE; E.C. 3.1.1.7), butyrylcholinesterase (BuChE; E.C. 3.1.1.8), and prolyl oligopeptidase (POP; E.C. 3.4.21.26) inhibition activities. Significant human AChE/BuChE (hAChE/hBuChE) inhibitory activity was demonstrated by the newly described alkaloid narcieliine (3), with IC50 values of 18.7 ± 2.3 µM and 1.34 ± 0.31 µM, respectively. This compound is also predicted to cross the blood-brain barrier (BBB) through passive diffusion. The in vitro data were further supported by in silico studies of 3 in the active site of hAChE/hBuChE.

• Klíčová slova
• Alkaloids, Alzheimer's disease, Amaryllidaceae, Docking studies, Narcieliine, Zephyranthes citrina,
• MeSH
• acetylcholinesterasa chemie   metabolismus   MeSH
• alkaloidy chemie   izolace a purifikace   farmakologie   terapeutické užití   MeSH
• Alzheimerova nemoc farmakoterapie   patologie   MeSH
• Amaryllidaceae chemie   metabolismus   MeSH
• butyrylcholinesterasa chemie   metabolismus   MeSH
• cholinesterasové inhibitory chemie   metabolismus   farmakologie   terapeutické užití   MeSH
• hematoencefalická bariéra účinky léků   metabolismus   MeSH
• katalytická doména MeSH
• kinetika MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie MeSH
• molekulární konformace MeSH
• simulace molekulového dockingu MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• alkaloidy MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH

A novel series of aromatic esters (1a-1m) related to the Amaryllidaceae alkaloid (AA) haemanthamine were designed, synthesized and tested in vitro with particular emphasis on the treatment of neurodegenerative diseases. Some of the synthesized compounds revealed promising acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory profile. Significant human AChE (hAChE) inhibition was demonstrated by 11-O-(3-nitrobenzoyl)haemanthamine (1j) with IC50value of 4.0 ± 0.3 µM. The strongest human BuChE (hBuChE) inhibition generated 1-O-(2-methoxybenzoyl)haemanthamine (1g) with IC50 value 3.3 ± 0.4 µM. Moreover, 11-O-(2-chlorbenzoyl)haemanthamine (1m) was able to inhibit both enzymes in dose-dependent manner. The mode of hAChE and hBuChE inhibition was minutely inspected using enzyme kinetic analysis in tandem with in silico experiments, the latter elucidating crucial interaction in 1j-, 1m-hAChE and 1g-, 1m-hBuChE complexes. The blood-brain barrier (BBB) permeability was investigated applying the parallel artificial membrane permeation assay (PAMPA) to predict the CNS availability of the compounds.

• Klíčová slova
• Acetylcholinesterase, Alzheimer’s disease, Amaryllidaceae, Butyrylcholinesterase, Docking studies, Haemanthamine,
• MeSH
• acetylcholinesterasa chemie   metabolismus   MeSH
• alkaloidy amarylkovitých chemie   metabolismus   terapeutické užití   MeSH
• Alzheimerova nemoc farmakoterapie   patologie   MeSH
• Amaryllidaceae chemie   metabolismus   MeSH
• butyrylcholinesterasa chemie   metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   metabolismus   terapeutické užití   MeSH
• estery chemie   MeSH
• fenantridiny chemie   metabolismus   terapeutické užití   MeSH
• hematoencefalická bariéra účinky léků   metabolismus   MeSH
• kinetika MeSH
• lidé MeSH
• simulace molekulového dockingu MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• alkaloidy amarylkovitých MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• estery MeSH
• fenantridiny MeSH
• hemanthamine MeSH Prohlížeč

Plants of the Amaryllidaceae family are promising therapeutic tools for human diseases and have been used as alternative medicines. The specific secondary metabolites of this plant family, called Amaryllidaceae alkaloids (AA), have attracted considerable attention due to their interesting pharmacological activities. One of them, galantamine, is already used in the therapy of Alzheimer's disease as a long acting, selective, reversible inhibitor of acetylcholinesterase. One group of AA is the montanine-type, such as montanine, pancracine and others, which share a 5,11-methanomorphanthridine core. So far, only 14 montanine-type alkaloids have been isolated. Compared with other structural-types of AA, montanine-type alkaloids are predominantly present in plants in low concentrations, but some of them display promising biological properties, especially in vitro cytotoxic activity against different cancerous cell lines. The present review aims to summarize comprehensively the research that has been published on the Amaryllidaceae alkaloids of montanine-type.

• Klíčová slova
• Amaryllidaceae, alkaloids, biological activity, derivatives, montanine, montanine-type, pancracine,
• MeSH
• alkaloidy amarylkovitých chemie   izolace a purifikace   farmakologie   MeSH
• Amaryllidaceae chemie   metabolismus   MeSH
• antiprotozoální látky chemie   izolace a purifikace   farmakologie   MeSH
• cholinesterasové inhibitory chemie   izolace a purifikace   farmakologie   MeSH
• fenantridiny chemie   izolace a purifikace   farmakologie   MeSH
• fytogenní protinádorové látky chemie   izolace a purifikace   farmakologie   MeSH
• galantamin chemie   izolace a purifikace   farmakologie   MeSH
• heterocyklické sloučeniny tetra- a více cyklické chemie   izolace a purifikace   farmakologie   MeSH
• inhibiční koncentrace 50 MeSH
• isochinoliny chemie   izolace a purifikace   farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nootropní látky chemie   izolace a purifikace   farmakologie   MeSH
• rostlinné extrakty chemie   MeSH
• sekundární metabolismus MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• alkaloidy amarylkovitých MeSH
• antiprotozoální látky MeSH
• cholinesterasové inhibitory MeSH
• fenantridiny MeSH
• fytogenní protinádorové látky MeSH
• galantamin MeSH
• hemanthamine MeSH Prohlížeč
• heterocyklické sloučeniny tetra- a více cyklické MeSH
• isochinoliny MeSH
• montanine MeSH Prohlížeč
• nootropní látky MeSH
• pancracine MeSH Prohlížeč
• rostlinné extrakty MeSH

Twelve derivatives 1a-1m of the β-crinane-type alkaloid haemanthamine were developed. All the semisynthetic derivatives were studied for their inhibitory potential against both acetylcholinesterase and butyrylcholinesterase. In addition, glycogen synthase kinase 3β (GSK-3β) inhibition potency was evaluated in the active derivatives. In order to reveal the availability of the drugs to the CNS, we elucidated the potential of selected derivatives to penetrate through the blood-brain barrier (BBB). Two compounds, namely 11-O-(2-methylbenzoyl)-haemanthamine (1j) and 11-O-(4-nitrobenzoyl)-haemanthamine (1m), revealed the most intriguing profile, both being acetylcholinesterase (hAChE) inhibitors on a micromolar scale, with GSK-3β inhibition properties, and predicted permeation through the BBB. In vitro data were further corroborated by detailed inspection of the compounds' plausible binding modes in the active sites of hAChE and hBuChE, which led us to provide the structural determinants responsible for the activity towards these enzymes.

• Klíčová slova
• Alzheimer’s disease, Amaryllidaceae, acetylcholinesterase, butyrylcholinesterase, docking studies, glycogen synthase kinase-3β inhibition, haemanthamine,
• MeSH
• alkaloidy amarylkovitých chemie   metabolismus   MeSH
• Alzheimerova nemoc metabolismus   MeSH
• Amaryllidaceae chemie   metabolismus   MeSH
• fenantridiny chemie   metabolismus   MeSH
• hematoencefalická bariéra metabolismus   MeSH
• kinasa glykogensynthasy 3beta metabolismus   MeSH
• lidé MeSH
• ligandy MeSH
• molekulární konformace MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• permeabilita MeSH
• simulace molekulového dockingu MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alkaloidy amarylkovitých MeSH
• fenantridiny MeSH
• hemanthamine MeSH Prohlížeč
• kinasa glykogensynthasy 3beta MeSH
• ligandy MeSH

Scadoxus puniceus (Amaryllidaceae), a medicinal plant of high value in South Africa, is used as a component of a traditional herbal tonic prescribed to treat several ailments. Ultra-high performance liquid chromatography-tandem mass spectrometry quantified the phenolic compounds in different organs of S. puniceus. Gravity column chromatography was used to separate fractions and active compounds. The structure of these compounds was determined using 1D and 2D nuclear magnetic resonance and mass spectroscopic techniques. A microplate technique was used to determine the acetylcholinesterase inhibitory activity of the pure compounds. Metabolite profiling revealed a greater profusion of hydroxycinnamic acids (69.5%), as opposed to hydroxybenzoic acids (30.5%). Chlorogenic acid was the most abundant (49.6% of hydroxycinnamic acids) compound. In addition to chlorogenic acid, the study is the first to report the presence of sinapic, gallic, and m-hydroxybenzoic acids in the Amaryllidaceae. Chromatographic separation of S. puniceus led to the isolation of haemanthamine (1), haemanthidine (2), and a rare chlorinated amide, metolachlor (3), the natural occurrence of which is described for the first time. Haemanthamine, haemanthidine, and metolachlor displayed strong acetylcholinesterase inhibitory activity (IC50 ; 23.1, 23.7, and 11.5 μM, respectively). These results substantiate the frequent use of S. puniceus as a medicinal plant and hold much promise for further pharmaceutical development.

• Klíčová slova
• Amaryllidaceae, NMR, alkaloids, chromatography, paintbrush lily, phenolics,
• MeSH
• acetamidy chemie   izolace a purifikace   metabolismus   farmakologie   MeSH
• alkaloidy amarylkovitých chemie   izolace a purifikace   metabolismus   farmakologie   MeSH
• Amaryllidaceae chemie   metabolismus   MeSH
• cholinesterasové inhibitory chemie   izolace a purifikace   farmakologie   MeSH
• fenantridiny chemie   izolace a purifikace   metabolismus   farmakologie   MeSH
• kyseliny kumarové chemie   izolace a purifikace   metabolismus   farmakologie   MeSH
• léčivé rostliny chemie   MeSH
• rostlinné extrakty chemie   izolace a purifikace   metabolismus   farmakologie   MeSH
• tandemová hmotnostní spektrometrie MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Jihoafrická republika MeSH
• Názvy látek
• acetamidy MeSH
• alkaloidy amarylkovitých MeSH
• cholinesterasové inhibitory MeSH
• fenantridiny MeSH
• hemanthamine MeSH Prohlížeč
• hemanthidine MeSH Prohlížeč
• kyseliny kumarové MeSH
• metolachlor MeSH Prohlížeč
• rostlinné extrakty MeSH

In this study, twenty-two Amaryllidaceae alkaloids were screened for their anticancer potential. All isolates were evaluated for antiproliferative activities on a panel of 17 human cell types of different tissue origin using WST-1 assay. In addition, we determined the antiproliferative effect with a real-time cell analysis xCELLigence system. Thereafter, to evaluate the barely known in vivo anticancer potential of the most potent molecule haemanthamine, a preliminary study was performed using an Ehrlich tumor-bearing mice model. The results showed that haemanthamine, lycorine and haemanthidine exerted the highest antiproliferative activity. The mean growth percent (GP) value after a single-dose 10 μM treatment was for haemanthamine 21%, for lycorine 21% and for haemanthidine 27% that of untreated control cells (100%). Furthermore, haemanthamine, lycorine and haemanthidine exhibited significant cytotoxicities against all the tested cell lines with individual IC50 values in the micromolar range. Dynamic real-time measures of impedance by xCELLigence indicated that these three compounds suppress cell proliferation after 10 h of treatment at a concentration of 10 μM or higher. Regrettably, in a follow-up in vivo antitumor activity study, haemanthamine showed no statistically significant reduction in the tumor size with no prolongation of survival time of Ehrlich tumor-bearing mice. Taken together, these results provide a new clue and guidance for exploiting Amaryllidaceae alkaloids as anticancer agents.

• Klíčová slova
• Alkaloids, Amaryllidaceae, Antiproliferative activity, In vitro, In vivo,
• MeSH
• alkaloidy chemie   farmakologie   terapeutické užití   MeSH
• Amaryllidaceae chemie   metabolismus   MeSH
• apoptóza účinky léků   MeSH
• Ehrlichův tumor farmakoterapie   mortalita   patologie   MeSH
• fytogenní protinádorové látky chemie   farmakologie   terapeutické užití   MeSH
• Kaplanův-Meierův odhad MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• screeningové testy protinádorových léčiv MeSH
• transplantace heterologní MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alkaloidy MeSH
• fytogenní protinádorové látky MeSH

This update covers the syntheses of Amaryllidaceae alkaloids since the publication of the last major review in 2008. A short summary of past syntheses and their step count is provided for the major constituents; pancratistatin, 7-deoxypancratistatin, narciclasine, lycoricidine, lycorine, and for other natural constituents, as well as for unnatural derivatives. Discussion of biological activities is provided for unnatural derivatives. Future prospects and further developments in this area are covered at the end of the review. The literature is covered to the end of August 2015.

• Klíčová slova
• Amaryllidaceae alkaloids, anticancer drugs, biological activity, structure-activity relationship, total synthesis,
• MeSH
• alkaloidy amarylkovitých chemická syntéza   chemie   MeSH
• alkaloidy chemická syntéza   chemie   MeSH
• Amaryllidaceae chemie   metabolismus   MeSH
• fenantridiny chemická syntéza   chemie   MeSH
• fytogenní protinádorové látky chemická syntéza   chemie   MeSH
• isochinoliny chemická syntéza   chemie   MeSH
• stereoizomerie MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• alkaloidy amarylkovitých MeSH
• alkaloidy MeSH
• fenantridiny MeSH
• fytogenní protinádorové látky MeSH
• isochinoliny MeSH
• lycoricidine MeSH Prohlížeč
• lycorine MeSH Prohlížeč
• narciclasine MeSH Prohlížeč
• pancratistatin MeSH Prohlížeč