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

The isoquinoline alkaloids found in Amaryllidaceae are attracting attention due to attributes that can be harnessed for the development of new drugs. The possible molecular mechanisms by which montanine exerts its inhibitory effects against cancer cells have not been documented. In the present study, montanine, manthine and a series of 15 semisynthetic montanine analogues originating from the parent alkaloid montanine were screened at a single test dose of 10 μM to explore their cytotoxic activities against a panel of eight cancer cell lines and one non-cancer cell line. Among montanine and its analogues, montanine and its derivatives 12 and 14 showed the highest cytostatic activity in the initial single-dose screening. However, the native montanine exhibited the greatest antiproliferative activity against cancer cells, with a lower mean IC50 value of 1.39 µM, compared to the displayed mean IC50 values of 2.08 µM for 12 and 3.57 µM for 14. Montanine exhibited the most potent antiproliferative activity with IC50 values of 1.04 µM and 1.09 µM against Jurkat and A549 cell lines, respectively. We also evaluated montanine's cytotoxicity and cell death mechanisms. Our results revealed that montanine triggered apoptosis of MOLT-4 cells via caspase activation, mitochondrial depolarisation and Annexin V/PI double staining. The Western blot results of MOLT-4 cells showed that the protein levels of phosphorylated Chk1 Ser345 were upregulated with increased montanine concentrations. Our findings provide new insights into the mechanisms underlying the cytostatic, cytotoxic and pro-apoptotic activities of montanine alkaloids in lung adenocarcinoma A549 and leukemic MOLT-4 cancer cell types.

• Klíčová slova
• Apoptosis, Cell cycle arrest, Cytotoxicity, DNA damage, Manthine, Montanine, Semisynthetic derivatives,
• MeSH
• alkaloidy amarylkovitých * farmakologie   MeSH
• alkaloidy * MeSH
• Amaryllidaceae * MeSH
• apoptóza MeSH
• cytostatické látky * MeSH
• isochinoliny farmakologie   MeSH
• lidé MeSH
• nádory plic * MeSH
• protinádorové látky * farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alkaloidy amarylkovitých * MeSH
• alkaloidy * MeSH
• cytostatické látky * MeSH
• isochinoliny MeSH
• montanine MeSH Prohlížeč
• protinádorové látky * MeSH

Alzheimeŕs disease (AD) is the most common neurodegenerative disorder, characterized by neuronal loss and cognitive impairment. Currently, very few drugs are available for AD treatment, and a search for new therapeutics is urgently needed. Thus, in the current study, twenty-eight new derivatives of montanine-type Amaryllidaceae alkaloids were synthesized and evaluated for their ability to inhibit human recombinant acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE). Three derivatives (1n, 1o, and 1p) with different substitution patterns demonstrated significant selective inhibitory potency for hAChE (IC50 < 5 µM), and one analog, 1v, showed selective hBuChE inhibition activity (IC50 = 1.73 ± 0.05 µM). The prediction of CNS availability, as disclosed by the BBB score, suggests that the active compounds in this survey should be able pass through the blood-brain barrier (BBB). Cytotoxicity screening and docking studies were carried out for the two most pronounced cholinesterase inhibitors, 1n and 1v.

• Klíčová slova
• Acetylcholinesterase, Alzheimeŕs disease, Amaryllidaceae alkaloid, Butyrylcholinesterase, Docking studies, Montanine-type,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• alkaloidy chemická syntéza   chemie   farmakologie   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• hematoencefalická bariéra účinky léků   metabolismus   MeSH
• isochinoliny chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• simulace molekulového dockingu * MeSH
• vztah mezi dávkou a účinkem léčiva 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
• isochinoliny MeSH
• montanine MeSH Prohlížeč

Pancracine, a montanine-type Amaryllidaceae alkaloid (AA), is one of the most potent compounds among natural isoquinolines. In previous studies, pancracine exhibited cytotoxic activity against diverse human cancer cell lines in vitro. However, further insight into the molecular mechanisms that underlie the cytotoxic effect of pancracine have not been reported and remain unknown. To fill this void, the cell proliferation and viability of cancer cells was explored using the Trypan Blue assay or by using the xCELLigence system. The impact on the cell cycle was determined by flow cytometry. Apoptosis was evaluated by Annexin V/PI and by quantifying the activity of caspases (-3/7, -8, and -9). Proteins triggering growth arrest or apoptosis were detected by Western blotting. Pancracine has strong antiproliferative activity on A549 cells, lasting up to 96 h, and antiproliferative and cytotoxic effects on MOLT-4 cells. The apoptosis-inducing activity of pancracine in MOLT-4 cells was evidenced by the significantly higher activity of caspases. This was transmitted through the upregulation of p53 phosphorylated on Ser392, p38 MAPK phosphorylated on Thr180/Tyr182, and upregulation of p27. The pancracine treatment negatively altered the proliferation of A549 cells as a consequence of an increase in G1-phase accumulation, associated with the downregulation of Rb phosphorylated on Ser807/811 and with the concomitant upregulation of p27 and downregulation of Akt phosphorylated on Thr308. This was the first study to glean a deeper mechanistic understanding of pancracine activity in vitro. Perturbation of the cell cycle and induction of apoptotic cell death were considered key mechanisms of pancracine action.

• Klíčová slova
• Amaryllidaceae alkaloids, antiproliferative activity, apoptosis, cell cycle arrest, cytotoxicity, pancracine,
• MeSH
• adenokarcinom plic patologie   MeSH
• alkaloidy izolace a purifikace   farmakologie   MeSH
• Amaryllidaceae chemie   MeSH
• apoptóza účinky léků   MeSH
• buňky A549 MeSH
• buňky Hep G2 MeSH
• fytogenní protinádorové látky izolace a purifikace   farmakologie   MeSH
• heterocyklické sloučeniny tetra- a více cyklické izolace a purifikace   farmakologie   MeSH
• leukemie patologie   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• nádorové buněčné linie MeSH
• nádory plic patologie   MeSH
• proliferace buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alkaloidy MeSH
• fytogenní protinádorové látky MeSH
• heterocyklické sloučeniny tetra- a více cyklické MeSH
• pancracine MeSH Prohlížeč

In this detailed phytochemical study of Narcissus cv. Professor Einstein, we isolated 23 previously known Amaryllidaceae alkaloids (1-23) of several structural types and one previously undescribed alkaloid, 7-oxonorpluviine. The chemical structures were identified by various spectroscopic methods (GC-MS, LC-MS, 1D, and 2D NMR spectroscopy) and were compared with literature data. Alkaloids which had not previously been isolated and studied for cytotoxicity before and which were obtained in sufficient amounts were assayed for their cytotoxic activity on a panel of human cancer cell lines of different histotype. Above that, MRC-5 human fibroblasts were used as a control noncancerous cell line to determine the general toxicity of the tested compounds. The cytotoxicity of the tested alkaloids was evaluated using the WST-1 metabolic activity assay. The growth of all studied cancer cell lines was inhibited by pancracine (montanine-type alkaloid), with IC50 values which were in the range of 2.20 to 5.15 µM.

• Klíčová slova
• 7-oxonorpluviine, Amaryllidaceae, Narcissus cv. Professor Einstein, cytotoxicity, pancracine,
• Publikační typ
• časopisecké články MeSH