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Synthesis of ligands for farnesoid X receptor
Kašpar, Miroslav ; Chodounská, Hana (advisor) ; Kasal, Alexander (referee)
Farnesoid X receptor is mostly expressed in liver cells and its activation may be used for the treatment of cirrhosis causing diseases, especially biliary cirrhosis and nonalcoholic steatosis. These two latter diseases are most common in developed countries and, as of date, no effective treatments are available. Therefore, the aim of this project is the design and synthesis of novel bile acid analogues with subsequent biological evaluation towards farnesoid X receptor. Thus, a series of new compounds were designed using computational modeling studies and chemical synthesis was done to develop structure-activity relationships. Chemical structure analysis and purity was confirmed by conventional analytical methods. Finally, synthetic compounds were profiled against farnesoid X receptor in collaboration with the Pharmaceutical faculty of Charles University in Hradec Králové. Keywords: farnesoid X receptor, FXR, bile acids
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Synthesis of steroid phosphoramidates and studies of their properties
Kouřilová, Kateřina ; Chodounská, Hana (advisor) ; Kasal, Alexander (referee)
Signaling pathway of most important excitatory neurotransmitter - glutamic acid consists of several controllable processes. One of these is modulation of N-methyl-D-aspartate receptor (NMDAR), by endogenous ligands leads to temporary improvement of memory skills and cognitive functions. Positive effects of endogenous or exogenous ligands were also demonstrated on membrane protein Glutamate Carboxypeptidasa II (GCPII). The aim of this work was to prepare steroid derivatives suitable for inhibiting of NMDAR and also GCPII. Steroidal skeleton without substituent at C17 was chosen as a scaffold. The influence of compounds on NMDA receptor will be tested on cultures of human embryonic kidney cells (HEK293) transfected by NR1-1a/NR2B/GFP plasmids of subunits NMDAR. Inhibitory activity on GCPII will be tested on human GCPII with folyl-n-γ-L- glutamic acid as a substrate.
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Modification of Isoprenoids.
Eignerová, Barbara ; Kotora, Martin (advisor) ; Kvíčala, Jan (referee) ; Kasal, Alexander (referee)
CHARLES UNIVERSITY IN PRAGUE Faculty of Science Department of Organic and Nuclear Chemistry MODIFICATION OF ISOPRENOIDS Synopsis of PhD Thesis Mgr. Barbara Eignerová Prague 2010 Supervisor: Prof. Martin Kotora Introduction This PhD work is focused on the development of a new methodology aiming at the introduction of the perfluoroalkylated side-chains into various types of molecules. Synthesis of perfluoroalkylated compounds, owing to their biological properties, is a frequent target of organic chemistry.1 During the last couple of decades a number of different methods enabling the perfluoroalkylation have been developed. Among the classical methods belong procedures based on nucleophilic, electrophilic, or radical reactions.2 Interestingly, only a few examples of a transition metal catalyzed perfluoroalkylation reactions have been reported.3 Despite the fact that many of these methods have wide synthetic applicability, they are not general and search for new procedures is a desirable target. One of the possible and hitherto unexplored methods for the synthesis of perfluoroalkylated compounds is a ruthenium-complex catalyzed alkene cross-metathesis. Potentially, a reaction of a suitable terminal alkene reactant bearing a perfluoroalkylated moiety with the second terminal alkene could give rise to a new and...
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Panels of steroid receptor reporter cell lines for compound profiling and development of selective ligands for estrogen receptor alpha and beta
Sedlák, David ; Bartůněk, Petr (advisor) ; Anzenbacher, Pavel (referee) ; Kasal, Alexander (referee)
of the Ph.D. thesis Steroid hormone receptors represent a major target in the drug discovery. As ligand inducible transcription factors, their activity can be modulated by small lipophilic molecules. The first part of this work describes a preparation of two panels of potent, selective and robust luciferase reporter cell lines on the unified cellular background in U2OS osteosarcoma cell line. This system consists of two panels of stable luciferase reporter cell lines for estrogen receptor α (ERα), estrogen receptor β (ERβ), androgen receptor (AR), glucocorticoid receptor (GR), mineralocorticoid receptor (MR) and progesterone receptor (PR). The first panel of reporter cell lines relies on the expression of the chimeric steroid receptors created by the replacement of the N-terminal part of the steroid receptor molecule by Gal4 DNA binding domain (Gal4 DBD) binding to 9 copies of Gal4 upstream activation sequences (Gal4 UAS) in the promoter of the pGL4 luciferase reporter vector. In the second panel of reporter cell lines the activation of either synthetic promoter containing multiple hormone response elements or viral promoter derived from MMTV LTR is mediated by full- length exogenously expressed steroid receptors. We have extensively validated both panels using 28 well established ligands, carefully...
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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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