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Synthesis and Properties of Neuroactive Steroids
Kapras, Vojtěch ; Chodounská, Hana (advisor) ; Pour, Milan (referee) ; Drašar, Pavel (referee)
Herein is reported the synthesis of molecular probes for action of neuroactive steroids in vitro and in living organisms. In the first part, preparation of enantiomeric pregnane steroids is investigated, ultimately resulting into the total synthesis of ent-progesterone. The chirality of the target molecule is introduced by a highly effective organocatalytic asymmetric Robinson annulation. A new method for the sequential construction of five-membered carbocyclic ring is introduced as the key step. This is composed of substrate-controlled copper-catalyzed conjugate addition followed by radical oxygenation and subsequent thermal cyclization employing the persistent radical effect. The synthesis of truncated neurosteroid analogs is described and their biological activity at the NMDA receptor is compared with the native hormone. In the second part, methodology for specific deuterium labeling of both angular methyls of the 5β-pregnane steroid core is explored. Special attention was paid to the Barton-McCombie deoxygenation as the tool for introduction of the last deuterium atom into the methyl group. Both positions were labelled with total of three deuterium atoms in high isotopic purity.
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Study of Chemical Constituents of Taxons from Order Laurales and Ranunculales with Potential Neuroprotective Activity
Hošťálková, Anna ; Opletal, Lubomír (advisor) ; Kokoška, Ladislav (referee) ; Drašar, Pavel (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Botany and Ecology Candidate: Mgr. Anna Hošťálková Supervisor: Prof. RNDr. Lubomír Opletal, CSc. Title of Doctoral Thesis: Study of chemical constituents of taxons from order Laurales and Ranunculales with potential neuroprotective activity. Key words: Berberis vulgaris, Peumus boldus, Hydrastis canadensis, isoquinoline alkaloids, acetylcholinesterase, butyrylcholinesterase, prolyl oligopeptidase. Commercial goldenseal extrakt, boldo leaves and barberry root bark were selected as sources of isoquinoline alkaloids for study of their biological activity. Mixtures of summary tertiary alkaloids were prepared by standard extraction and subsequently fractionated in aluminium oxide chromatography column using the step gradient elution with petrol, chloroform and ethanol. Repeated column chromatographies, preparative TLC and crystallizations led to the isolation of 28 isoquinoline alkaloids, 6 of them were identificated as new structures (some of them were propably artifacts). The chemical structures of isolated compounds were determined on the basis of spectrometric techniques (NMR, MS) and by comparison with literature. Isolated alkaloids in sufficient amount were tested on ability to inhibit human...
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Study of biological activity of isolated alkaloids from Corydalis cava (Fumariaceae)
Chlebek, Jakub ; Opletal, Lubomír (advisor) ; Drašar, Pavel (referee) ; Kuča, Kamil (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Botany and Ecology Candidate: Mgr. Jakub Chlebek Supervisor: Doc. RNDr. Lubomír Opletal, CSc. Title of Doctoral Thesis: Study of biological activity of isolated alkaloids from Corydalis cava (Fumariaceae). Key words: Corydalis cava, isoquinoline alkaloids, DPPH, AChE, BuChE, BACE1, IMER. Tubers of Corydalis cava were selected on the basis of bio-guided spectrophotometric Ellman's method as a source of isoquinoline alkaloids for study of their selected biological activities. The tubers of Corydalis cava were extracted with ethanol and the mixture of summary tertiary alkaloids (fraction A) was fractionated in silica gel chromatography column using step gradient elution with hexane, chloroform and ethanol. Repeated column chromatography, preparative TLC and crystallization led to the isolation of fifteen isoquinoline alkaloids. The chemical structures of isolated compounds were determined on the basis of spectroscopic techniques and by comparison with literature data. Isolated alkaloids were tested on ability to inhibit AChE, serum BuChE (IC50), BACE1 and for its free-radical scavenging activity (EC50). The cholinesterase inhibitory activity was determined in vitro by modified spectrophotometric Ellman's...
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Synthesis of Neurosteroids: Modulators of NMDA Receptor
Šťastná, Eva ; Chodounská, Hana (advisor) ; Klinotová, Eva (referee) ; Drašar, Pavel (referee) ; Hampl, Richard (referee)
Charles University in Prague Faculty of Science Department of Organic and Nuclear Chemistry Karlova Universita v Praze Přírodovědecká fakulta Katedra organické chemie a jaderné chemie Mgr. Eva Šťastná Synthesis of Neurosteroids: Modulators of NMDA receptor Syntéza neurosteroidů: modulátorů NMDA receptoru PhD. Thesis Abstract Autoreferát disetační práce Praha 2009 Prague, 2009 Scientific Presentations and Posters Papers Šťastná E.: Diazomethane (CH2N2). Synlett, 2007,15,2454. Stastna E., Chodounska H., Pouzar V., Kapras V., Borovska J, Cais O., L Vyklicky L.: Synthesis of C3, C5, and C7 pregnane derivatives and their effect on NMDA receptor responses in cultured rat hippocampal neurons. Steroids 2009, 74, 256-263. Kapras V., Šťastná E., Chodounská H., Pouzar V., Krištofíková Z.: Preparation of steroid sulfamates and their interaction with GABAA receptor. Coll. Czech. Chem. Comm., submitted, manuscript number CCCC/2008/000187. Eignerová B., Slavíková B., Buděšínský M., Stastna E., Kotora M.: Synthesis of Fluorinated Brassinosteroids Based on Alkane Cross-Metathesis and Preliminary Biological Assessment. J. Org. Chem., under revision, manuscript number jo-2009- 002079. Patents Stastna E., Chodounska H., Cais O., Vyklicky L., Kapras V., Pouzar V., Kohout L.: Steroidní anionické sloučeniny, způsob...
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Preparation of Quaternary ammonium salts of triterpenoids
Biedermann, David ; Šarek, Jan (advisor) ; Klinot, Jiří (referee) ; Drašar, Pavel (referee) ; Kasal, Alexander (referee)
) Conclusion CONCLUSIONS This doctoral thesis was focused onto the synthesis if new quaternary ammonium salts oÍ. triterpenoids Ířom lupane, oleanane and ursane family for in vilro assessment of ťollowing biological activities: anti-HIV, antimicrobial, antiinflammatory and cýotoxic. Results are summed up in Íbllowing points: 1' Author co-operated pilot project of industrial isolation of betulin (1a) from approximately 400 kg of birch bark. Futhermore, research of side products and optimisation of preparation of bromoethyl-esters triterpenic acids was concluded. 2' Precursors for preparation of quaternary ammonium esters, bromoethyl-esters 2a, 3f, 3i, l1b, I2b, 14a,15a, and chloroethyl-ester 39, were slmthesised. 3' Six series of compounds, each consisting of three quaternary salts and one tertiary amine, were synthesised from betulinic acid (1b), oleanolic acid (1c), ursolic acid (1c), oxoac id, 3e, platanic acid (11a) a dihydrobetulinic acid (12a). Experimetal procedures are suitable for bulk syntheses. other quaternary salts of triterpenoids were also prepared. 4. oxoacid 3e was derivatised to yield group of heterocyclic hydrochlorides 6a, 6b,ód' 6f and group of heterocyclic salts 6c,6e,69. 5. All new cornpound s were assesed in vitro for cýotoxic activity against T-lymfoblatic leukemia CEM in research...
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