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Transition metal complexes catalyzed synthesis of biologically active estrone derivatives
Prchalová, Eva ; Kotora, Martin (advisor) ; Moravcová, Jitka (referee) ; Hlaváč, Jan (referee)
This thesis relates to the preparation and use of new non-estrogenic ligands selective for certain types of the 17β-hydroxysteroid dehydrogenase superfamily (17βHSD). Such nonestrogenic compounds, which selectively regulate the activity of 17βHSD are believed to offer new solutions in endocrine therapy, diagnosis and treatment of estrogen-dependent types of diseases. In recent years in the laboratories of my supervisor prof. Kotora differently substituted steroid derivatives with interesting biological properties were prepared. Based on the gained experiences, it was decided to prepare C-15 estrone derivatives. Such compounds are mostly unexplored, and therefore they might be a new class of interesting biologically active compounds. A method was developed for the preparation of C-15 estrone derivatives. Estrone, the starting material for the synthesis, was first converted to the appropriate intermediate, protected estra-1,3,5(10),15-tetraene-17-one. Conjugate addition of vinylmagnesium bromide to this enone yielded the starting material for further reactions, 15β-vinylestrone. Cross metathesis of 15β-vinylestrone with suitable terminal olefins provided large series of C-15 estrone derivatives with perfluoroalkylated, aliphatic and aromatic side chains. Selected unsaturated derivatives were tested...
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C-H activations of deazapurine heterocycles
Klečka, Martin ; Hocek, Michal (advisor) ; Hlaváč, Jan (referee) ; Rádl, Stanislav (referee)
Direct C-H borylations of 7-deazapurines (7H-pyrrolo[2,3-d]pyrimidine) were developed at position 8 using B2pin2 and Ir catalysis. The obtained boronates were efficiently applied in the Suzuki cross-couplings with aryl halides and other functional group transformations to give diverse 6-substituted 8-aryl-7-deazapurine derivatives. Furthermore, I was also interested in the synthesis of biologically relevant 8-aryl-7- deazaadenines and -7-deazahypoxanthines. As the direct C-H borylation of 7- deazaadenines was unsuccessful and the borylation/Suzuki reaction of 6-chloro-7- deazapurine gave only low yield (20%) of the desired 8-aryl derivative, I focused on the one-pot borylation/arylation of SEM-protected 6-methylsulfanyl- or 6-methoxy-7- deazapurines. The one-pot borylation/Suzuki coupling reactions were followed either by demethylation and deprotection to yield deazahypoxanthine base, or by oxidation of sulfide to sulfone, amination and deprotection to give deazaadenines. In addition, the boronate intermediates were successfully converted to 8-halo- or 8-trifluoromethyl-7- deazapurine derivatives. While the 7-deazahypoxantine analogues were almost entirely inactive, most of the 8-subtituted 6-methoxy-7-deazapurine and 7-deazaadenines bases showed significant cytostatic activities. Also a general...
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Synthesis of novel types of annulated deazapurine nucleosides with potential biological activity
Tichý, Michal ; Hocek, Michal (advisor) ; Dvořák, Dalimil (referee) ; Hlaváč, Jan (referee)
This thesis reports the syntheses and biological activities of benzo- and thieno-fused 7-deazapurine ribonucleosides, which were designed as extended analogues of potent cytostatic 6-hetaryl-7-deazapurine or 6-amino-7-hetaryl-7-deazapurine ribonucleosides. First of all, multigram syntheses of (di)chloro-9H-pyrimido[4,5-b]indoles from simple chloro- nitrobenzenes were developed. Pyrimidoindoles were successfully glycosylated and used for the synthesis of 4-hetaryl-6-chloro-, 4,6-bis(hetaryl)-, 4-amino-6-hetaryl-, 4-amino-5-hetaryl- and 4-susbtituted pyrimido[4,5-b]indole ribonucleosides. Hetaryl groups were introduced by Suzuki or Stille cross-coupling reaction. Standard catalysts and conditions were used for reaction in position 4. To observe some reactivity of unreactive chlorine in position 6, modification of standard protocol was necessary. Screening of several ligands had been done and Buchwald ligand X-Phos was found to be optimal. As chlorine in position 4 is activated for nucleophilic substitution, amino and dimethylamino derivatives were prepared by reaction with aqueous ammonia and dimethylamine, respectively. 4-Alkyl derivatives were synthesized by palladium-catalyzed alkylation with trialkylaluminium or by Negishi coupling in case of cyclopropyl derivative. Desired free nucleosides were...
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The performance of the Czech Private Pension scheme: Current design and its position within CEE countries
Hlaváč, Jan ; Schneider, Ondřej (advisor) ; Benáček, Vladimír (referee)
This thesis focuses on the comparison of financial performance of the Czech voluntary private pension scheme with five other reformed private pension schemes in the region of Central Eastern Europe (Bulgaria, Croatia, Hungary, Poland and Slovak Republic). The current state and the recent development of the Czech private pension scheme are analyzed in the first part of the thesis. In the main part of this work we construct the dataset of periodic scheme returns covering the last decade, and estimate the schemes Sharpe ratios (SR) for four reference benchmarks. To complement the analysis we also employ the Sharpe style analysis to evaluate the impact of managerial decisions of market selection/timing on the scheme returns. The findings suggest that except for Poland none of the schemes managed to beat its long- term domestic benchmark (10- year government bonds) as the SRs estimates turn out to be negative. The highest underperformance was found in the case of Czech Republic. The results of style analysis suggest a modest positive influence of the active managerial decisions on the scheme returns with respect to the passive investment strategies. JEL Classification G23, G28, O57, H55 Keywords: Private pension schemes, Czech voluntary pension scheme, financial performance, Sharpe ratio, Sharpe Style...
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Synthesis of novel cytostatic deazapurine nucleosides and pronucleotides
Perlíková, Pavla ; Hocek, Michal (advisor) ; Jindřich, Jindřich (referee) ; Hlaváč, Jan (referee)
The synthetic routes to three types of phosphate prodrugs of 6-hetaryl-7-deazapurine ribonucleosides based on palladium-catalyzed cross-coupling reactions have been developed. CycloSal- and phosphoramidate pronucleotides and octadecyl phosphates derived from 6- hetaryl-7-deazapurine ribonucleosides were screened for their in vitro cytostatic activity. It was shown that cytostatic activity of cycloSal phosphates was similar or slightly lower compared to the parent nucleosides. Significant drop of cytostatic activity was observed in phosphoramidate pronucleotides. Octadecyl phosphates were devoid of any cytostatic activity. 6-Hetaryl-7-deazapurine ribonucleosides with bulky groups in position 6 showed very strong and selective inhibition of adenosine kinase from Mycobacterium tuberculosis. 2'-Modified 6-hetaryl-7-deazapurine nucleosides: 2'-O-methylribonucleosides, arabinonucleosides and 2'- deoxy-2'-fluororibonucleosides, were prepared by multistep functional group transformations from a ribonucleoside. The synthesis of 2'-deoxy-2',2'-difluoro-erythro-pentofuranosyl nucleosides was based on a glycosylation of 6-chloro-7-deazapurine with a sugar synthon followed by palladium-catalyzed cross-coupling reaction and deprotection. Despite the low yields and laborious separation of the anomers,...
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The performance of the Czech Private Pension scheme: Current Design and its position within CEE countries
Hlaváč, Jan ; Schneider, Ondřej (advisor) ; Benáček, Vladimír (referee)
This thesis focuses on the comparison of financial performance of the Czech voluntary private pension scheme with five other reformed private pension schemes in the region of Central Eastern Europe (Bulgaria, Croatia, Hungary, Poland and Slovak Republic). The current state and the recent development of the Czech private pension scheme are analyzed in the first part of the thesis. In the main part of this work we construct the dataset of periodic scheme returns covering the last decade, and estimate the schemes Sharpe ratios (SR) for four reference benchmarks. To complement the analysis we also employ the Sharpe style analysis to evaluate the impact of managerial decisions of market selection/timing on the scheme returns. The findings suggest that except for Poland none of the schemes managed to beat its long-term domestic benchmark (10-year government bonds) as the SRs estimates turn out to be negative. The highest underperformance was found in the case of Czech Republic. The results of style analysis suggest a modest positive influence of the active managerial decisions on the scheme returns with respect to the passive investment strategies.
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Verification and testing of the experimental model of 22 kV distribution system
Hlaváč, Jan ; Novotný, Jan (referee) ; Topolánek, David (advisor)
This bachelor’s thesis deals with the practical verification of the various elements of the model of 22 kV distribution system. This model was designed within the laboratory space to remind of the most realistic distribution system. User of the model can (besides the normal operating conditions) perform a simulation of a fault condition. The aim of the work is to create guidelines for measuring key parameters of the system components (transformers, power lines), to compare the designed a measured values and to create the complete assembly documentation. This documentation serves as a guide with the detailed description of each component. The final part of the work is to create a complete schematic diagram of the power substation and the selection of the suitable protective devices.
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Instore communication in the Czech Republic
Hlaváč, Ján ; Filipová, Alena (advisor) ; Zeman, Jiří (referee)
This thesis deals with communication at the point of sale and instore advertising in particular. The aim is to analyze instore communication as such, with focus on selected POS materials and instore media, to assess the effectiveness of different formats and introduce trends in the area and demonstrate the use on a specific brand, emphasizing the most used tools.
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The evolution of euro exchange rate from its introduction to present
Hlaváč, Ján ; Taušer, Josef (advisor) ; Karlíček, Miroslav (referee)
Práce ve své první části popisuje evropskou spolupráci a konvergenci v hospodářské a měnové oblasti. Druhá část je zaměřena na převážně deskriptivní hodnocení směnného kurzu eura s americkým dolarem. Vývoj kurzu je komentován na základě různých studií, odborných publikací a agenturních zpráv a pozoruje vliv očekávaného růstu ekonomik USA a Eurozóny a pohyby úrokových sazeb v těchto oblastech na vývoj směnného kurzu.
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