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Synthesis of deuterium labelled neuroactive steroids.
Slavíčková, Alena ; Chodounská, Hana (advisor) ; Pouzar, Vladimir (referee)
The work si focused on the synthesis of deuterium-labelled neuroactive steroids useful as inner standards for determination of their farmaco-kinetics and bioavailibility. The starting material for the syntheses was comercial 11α-hydroxyprogesterone 16. The target compound, 20-Oxo-[9,12,12-2 H3]5β-pregnan-3α-yl L-glutamyl 1-ester (47), contains 3 deuterium atoms in positions 9α, 12α, 12β. Alternative target with a 18-functionalized group (34) was also studied. It will be used for an analogue with deuterium atoms on carbon C-18.
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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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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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Synthesis of deuterium labelled neuroactive steroids.
Slavíčková, Alena ; Pouzar, Vladimir (referee) ; Chodounská, Hana (advisor)
The work si focused on the synthesis of deuterium-labelled neuroactive steroids useful as inner standards for determination of their farmaco-kinetics and bioavailibility. The starting material for the syntheses was comercial 11α-hydroxyprogesterone 16. The target compound, 20-Oxo-[9,12,12-2 H3]5β-pregnan-3α-yl L-glutamyl 1-ester (47), contains 3 deuterium atoms in positions 9α, 12α, 12β. Alternative target with a 18-functionalized group (34) was also studied. It will be used for an analogue with deuterium atoms on carbon C-18.
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