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Alkaloids of Papaver rhoeas L. (Papaveraceae) and their biological activity related to Alzheimerʼs disease IV.
Gergely, Eszter ; Chlebek, Jakub (advisor) ; Hradiská Breiterová, Kateřina (referee)
Gergely, E.: Alkaloids of Papaver rhoeas L. (Papaveraceae) and their biological activity related to Alzheimerʼs disease IV. Diploma thesis, Charles University, Faculty of Pharmacy in Hradec Králové, Department of Pharmacognosy and Pharmaceutical Botany, Hradec Králové 2022, 61 pages. A chloroform alkaloid extract of aerial parts of Papaver rhoeas L. (Papaveraceae) showed a significant inhibitory activity on human butyrylcholinesterase (IC50hBuChE = 3,94 ± 0,35 µg/ml) [1,2]. hBuChE represents a key enzyme playing an important role in the pathogenesis of Alzheimer's disease. The main aim of this study was to isolate pure alkaloids by bio-guided assay using flash chromatography and preparative TLC, elucidate their structures (MS, NMR, and optical rotation) and cholinesterase inhibitory activity with Ellman's spectrophotometric method. Prediction of possibility of the molecules' crossing through blood-brain barrier (BBB) via logBB was calculated. Potential non-cytotoxicity of the most active compound was screened on selected nine cancer cell lines and one non-cancer cell line MRC-5. The identified isolated alkaloid (+)-caaverine showed a promising and selective hBuChE inibition (IC50hBuChE = 4,09 ± 0,50 µM and IC50hAChE > 100 µM, respectively) and should be able to cross the BBB (logBB = 0,372) by...
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Biological activity of Peganum harmala L. alkaloids and their semi-synthetic derivatives I.
Víchová, Barbora ; Chlebek, Jakub (advisor) ; Křoustková, Jana (referee)
1 ABSTRACT Víchová Barbora: Biological activity of Peganum harmala L. alkaloids and their semi-synthetic derivatives I. Diploma thesis 2022. Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacognosy and Pharmaceutical Botany β-Carboline alkaloids are natural substances with potential use in tumor therapy. In particular harmine, which acts cytotoxically by several mechanisms. The aim of the diploma thesis was to prepare N9-derivatives of harmine derivatives, to clarify their structure based on common spectrometric and spectroscopic methods (ESI, ESI-MS, NMR) and subsequently to study their biological activity (cytotoxicity, AChE, BchE and GSk-3beta inhibition). These tests resulted in several active derivatives, suitable candidates for further study. 9-N-(2-nitrobenzyl)harmine (HMA-22) was significantly cytotoxic to the Jurkat cell line (16% cell viability after 48 hours, compared to the control, with better cytotoxicity than the standard doxorubicin at a concentration of 1 μM). Another very active derivative was found 9-N-(5-bromopentyl)harmine (HMA-30), which was more cytotoxic to most tested cell lines than doxorubicin (1 μM), similarly as most of other derivatives. HMA-30 was also found as a potent BChE inhibitor (IC 50 4.06 ± 0.48 μM). 9-N-(4-nitrobenzyl)harmine (HMA-20)...
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Alkaloids of Papaver rhoeas L. (Papaveraceae) and their biological activity related to Alzheimerʼs disease III.
Bučková, Anna ; Chlebek, Jakub (advisor) ; Suchánková, Daniela (referee)
Alkaloids of Papaver rhoeas L. (Papaveraceae) and their biological activity related to Alzheimerʼs disease III. ABSTRACT Bučková, A.: Alkaloids of Papaver rhoeas L. (Papaveraceae) and their biological activity related to Alzheimerʼs disease III.; Diploma thesis, Charles University, Faculty of Pharmacy in Hradec Králové, Department of Pharmacognosy and Pharmaceutical Botany, Hradec Králové 2022, 59 pages The aim of this diploma thesis was to fractionate the combined extract (CHCl3 +EtOAc + I- ) from Papaver rhoeas L. using flash chromatography and subsequently, to isolate alkaloids from the chosen factions by preparative TLC. The chemical structures of the isolated compounds were determined by spetrometric and spectroscopic methods (MS, NMR and optical rotation). Alkaloids were identified as (+)-rhoeadin, (+)-rhoeagenin a (+)-isorhoeagenin. After structure elucidation, the alkaloids were tested in vitro for inhibitory activity towards enzymes that are playing part in the pathogenesis of the Alzheimer's disease (acetylcholinesterase, butyrylcholinesterase a prolyloligopeptidase). Based on the results, the studied alkaloids seem to be inactive towards chosen enzymes (values IC50 > 100 µM). Key words: Papaver rhoeas, Papaveraceae, Alzheimerʼs disease, acetylcholinesterase, butyrylcholinesterase, prolyl...
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Design and Synthesis of Hybrid Compounds Based on Tacrin/Resveratrol Derivatives
Jeřábek, Jakub ; Doležal, Martin (advisor) ; Miletín, Miroslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Jakub Jeřábek Supervisors: Prof. PharmDr. Martin Doležal, Ph.D. Prof. Maria Laura Bolognesi Title of Thesis: Design and Synthesis of Hybrid Compounds Based on Tacrine/Resveratrol Derivatives Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder, in which a progressive dementia appears. The cause of AD is currently unknown, however, scientific research has revealed several pathological hallmarks - β-amyloid plaques and neurofibrillary tangles. These changes cause gradual disintegration of nerve cells and they change the metabolism in the brain. The current drugs are not able to treat the cause of the disease, being able only to delay the onset of severe symptoms. The basic drugs for AD treatment are acetylcholinesterase (AChE, E.C. 3.1.1.7) inhibitors and, more recently approved, N-methyl- D-aspartate (NMDA) receptor antagonist memantine. These drugs are able to increase cholinergic activity or preventing glutamate excitotoxicity in the patient's brain, thus improving cognitive functions and delaying severe stages of the disease. One of the emerging approaches in drug synthesis represents multi-target-directed ligands (MTDLs). Apart from the ability...
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Design and Synthesis of Hybrid Compounds Based on Tacrin/Resveratrol Derivatives
Jeřábek, Jakub ; Doležal, Martin (advisor) ; Miletín, Miroslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Drug Control Student: Jakub Jeřábek Supervisors: Prof. PharmDr. Martin Doležal, Ph.D. Prof. Maria Laura Bolognesi Title of Thesis: Design and Synthesis of Hybrid Compounds Based on Tacrine/Resveratrol Derivatives Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder, in which a progressive dementia appears. The cause of AD is currently unknown, however, scientific research has revealed several pathological hallmarks - β-amyloid plaques and neurofibrillary tangles. These changes cause gradual disintegration of nerve cells and they change the metabolism in the brain. The current drugs are not able to treat the cause of the disease, being able only to delay the onset of severe symptoms. The basic drugs for AD treatment are acetylcholinesterase (AChE, E.C. 3.1.1.7) inhibitors and, more recently approved, N-methyl- D-aspartate (NMDA) receptor antagonist memantine. These drugs are able to increase cholinergic activity or preventing glutamate excitotoxicity in the patient's brain, thus improving cognitive functions and delaying severe stages of the disease. One of the emerging approaches in drug synthesis represents multi-target-directed ligands (MTDLs). Apart from the ability...
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Alkaloids of Narcissus 'Dutch Master' (Amaryllidaceae) and their biological activity III.
Rýdlová, Kateřina ; Chlebek, Jakub (advisor) ; Cahlíková, Lucie (referee)
Rýdlová Kateřina: Alkaloids Narcissus 'Dutch Master' (Amaryllidaceae) and their biological activity III. Diploma thesis 2017. Charles university in Prague, Faculty of Pharmacy in Hradec Králové, Department of Pharmaceutical Botany and Ecology. The aim of this work was isolation of compounds from the selected fraction ND 3 - 5 obtained by column chromatography of a Narcissus 'Dutch Master' alkaloid extract. Preparation of the extract and its column chromatography was performed by Mgr. Daniela Hulcová as a part of her doctoral study. Two substances NDM-1 and NDM-2 were isolated from fraction ND 3 - 5 by column chromatography and preparative TLC. The structures were determined as (+)-masonine and (+)-homolycorine on the basis of NMR, GC-MS analysis, optical rotation and their comparison with literature data. Isolated alkaloids were tested on inhibitory activity against human erythrocyte acetylcholinesterase, plasma butyrylcholinesterase and prolyloligopeptidase. Activity of alkaloids was expressed as IC50 values: (+)-masonine (IC50 AChE = 305 ± 34 μM, IC50 BuChE = 229 ± 24 μM, IC50 POP = 314 ± 34 μM), (+)-homolycorine (IC50 AChE = 63.7 ± 4.3 μM, IC50 BuChE = 151 ± 20 μM, IC50 POP = 173 ± 41 μM). In comparison with standards of galanthamine (IC50 AChE = 1.710 ± 0.1 μM, IC50 BuChE = 42.3 ± 1.3 μM),...
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Study of biological activity of alkaloids isolated from Fumaria officinalis L. (Fumariaceae) I.
Kostelník, Jan ; Chlebek, Jakub (advisor) ; Cahlíková, Lucie (referee)
Kostelník, J.: Study of biological activity of alkaloids isolated from Fumaria officinalis L. (Fumariaceae) I. Diploma thesis, Charles University in Prague,Faculty of Pharmacy in Hradec Králové, Department of Pharmaceutical Botany and Ecology, Hradec Králové 2014, 63 p. The aim of this study was to isolate alkaloids from joined fraction no. 55-67 (A2) obtained from the total alkaloid fraction of extract of Fumaria officinalis L. (Fumariaceae) plant. Using chromatography methods three alkaloids were isolated and then identified by structural analysis (GC-MS, NMR). Three alkaloids were isolated by using common chromagografic methods and then identified by structural analyses optical rotation and melting point as (-)-O- methylfumarophycine, (-)-sinactine a (-)-stylopine. Inhibitory activity of isolated alkaloids was assessed against human erythrocyte acetylcholinesterase, human butyrylcholineesterase and prolyl oligopeptidase. The results were expressed as IC50 values ((-)-stylopine: IC50 AChE and IC50 BuChE > 1000 μM, IC50 POP > 1000 mM; (-)-O-methylfumarophycine: IC50 AChE = 963.10 ± 135.98 µM, IC50 BuChE = 1771.0 ± 380.94 µM, IC50 POP - unmeasured; (-)-sinactine IC50 AChE = 632.0 ± 68.12 µM, IC50 BuChE = 8154.3 ± 981.42 µM, IC50 POP = IC50 POP = 52.9 ± 1.8 µM). None of alkaloids isolated showed...
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Alkaloids from Narcissus pseudonarcissus L. cv. Dutch Master and their cholinesterase and prolyl oligopeptidase inhibitory activity.
Farkašovský, Marek ; Chlebek, Jakub (advisor) ; Siatka, Tomáš (referee)
Farkašovský Marek: Alkaloids from Narcissus pseudonarcissus L. cv. Dutch Master and their cholinesterase and prolyl oligopeptidase inhibition activity. Rigorous thesis 2017, Charles university, Faculty of Pharmacy in Hradec Králové, Department of Pharmaceutical Botany and Ecology. The content of this work was isolation of minimum two compound from alkaloid fraction ND 3 - 5/2, obtained by column chromatography of Narcissus pseudonarcissus L. cv. Dutch Master alkaloid extract. Preparation of extract and its column chromatography was performed by Mgr. Daniela Hulcová as a part of her doctoral studies. Two different alkaloids were isolated with preparative TLC method. Their structure was determined with optical rotation, MS (EI, ESI), 1H NMR and 13C NMR analysis. Obtained data were compared with facts with those in literature. The first isolated compound was lycorine type alkaloid O-acetylpluvine. Its inhibition activity compared to positive standards (galanthamine, huperzine A, physostigmine, berberine and Z-pro-prolinal) was mild - IC50 AChE: 684 ± 54 µM, IC50 BuChE: 603 ± 49 µM, IC50 POP ˃1000 µM. From the point of its cholinesterase and POP inhibition, this results make O-acetylpluvine unusable compound in treatment of AD. The second isolated compound was a new alkaloid, which has not been...
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Biological aktivity of secondary plants metabolites I. Alkaloids of Narcissus jonquilla L.
Nováková, Dana ; Ločárek, Miroslav (advisor) ; Chlebek, Jakub (referee)
Nováková D.: Biological activity of secondary plants metabolites I. Alkaloids of Narcissus jonquilla L. Charles University in Prague, Faculty of Pharmacy in Hradec Králové, Department of Pharmaceutical Botany and Ecology, Hradec Králové 2015, pp. 70. The aim of the diploma thesis was a preparation of alkaloid extracts to identification of alkaloid patterns and measure cholinesterase inhibitory activity. This activity is useful for treating Alzheimer's disease. Alkaloid extracts of seven Narcissus jonquilla L. (Amaryllidaceae) varieties (Sundial, Sundisc, Sweetness, Waterperry, Simplex, Twinkling Yellow, Yazz) were studied with respect to their acetylcholinesterase (HuAChE) and butyrylcholinesterase (HuBuChE) inhibitory activity and alkaloid patterns. Twenty-three alkaloids were determined by GC/MS, and ten of them identified from their mass spectra and retention times. All samples exhibited content of galanthamine, most samples contained lycorine and tazettine. Promising HuAChE inhibition activity was demonstrated by Narcissus jonquilla L. cv. Waterperry with IC50 values of 6.53 ± 0.88 μg/mL. The strongest inhibitory activity against HuBuChE was detected in extract from Narcissus jonquilla L. cv. Sundisc with IC50 value of 5.09 ± 0.64 μg/mL. Keywords: Alzheimer's disease, Amaryllidaceae, Narcissus,...
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