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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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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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Gold-Catalyzed Cyclizations of 1,5-Enynes
Matouš, Petr ; Pour, Milan (advisor) ; Hlaváč, Jan (referee) ; Veselý, Jan (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department Department of Organic and Bioorganic Chemistry Candidate Mgr. Petr Matouš Supervisor prof. RNDr. Milan Pour, Ph.D. Titel of Doctoral Thesis Gold-Catalyzed Cyclizations of 1,5-Enynes This Ph.D. thesis deals with the development of gold(I)-catalyzed cyclizations of propargylamino acrylates (3-aza-1,5-enynes) in the presence of an external nucleophile. A library of tetrahydropyridines with an unusual hemiaminal ether functional group was thus prepared via the cyclization of a series of substituted enynes. The influence of the protective group as well as the substitution on the chemoselectivity of the reaction was demonstrated. The tetrahydropyridines were further utilized as precursors for the preparation of pharmaceutically important nitrogen heterocycles. The reduction of selected compounds furnished substituted piperidines, while Diels-Alder cycloaddition of alkenylated tetrahydropyridines gave rise to isoquinoline derivatives. Additional ortho-fused heterocycles (furopyridine, pyrrolopyridine and chromenopyridine) were prepared by the intramolecular version of the cyclizations of enynes with pending internal nucleophiles.
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Enzymatic synthesis of DNA modified in the minor groove
Matyašovský, Ján ; Hocek, Michal (advisor) ; Hlaváč, Jan (referee) ; Urban, Milan (referee)
In the first part of the thesis, a series of six modified 2'-deoxyadenosine triphosphates, bearing small functional groups (chloro, amino, methyl, vinyl, ethynyl and phenyl) at position 2 of adenine, was designed and synthesised. They were then tested as substrates for DNA polymerases in enzymatic synthesis of minor-groove modified DNA. The 2-phenyl modified dATP was the only triphosphate unable to be incorporated, meaning that the phenyl group is already too big for minor-groove incorporations. All of the other tested nucleotides were good substrates for tested DNA polymerases [KOD XL, Vent(exo-) and Bst LF] affording minor- groove modified DNA bearing one or four modifications. The vinyl- and ethynyl-modified DNAs were then used for post-synthetic modification of DNA minor groove with fluorescent labels utilising click reactions. Ethynyl group reacted in copper-catalysed alkyne-azide cycloaddition (CuAAC), whereas the vinyl group participated in thiol-ene reaction. This procedure allowed for the attachment of big functional groups otherwise unable to be installed into the DNA minor groove using direct enzymatic incorporation. The second part of the thesis was devoted to the study of 2-alkylamino-2'- deoxyadenosine triphosphates and their use in enzymatic synthesis of base-modified ONs and DNA....
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Gold-Catalyzed Cyclizations of 1,5-Enynes
Matouš, Petr ; Pour, Milan (advisor) ; Hlaváč, Jan (referee) ; Veselý, Jan (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department Department of Organic and Bioorganic Chemistry Candidate Mgr. Petr Matouš Supervisor prof. RNDr. Milan Pour, Ph.D. Titel of Doctoral Thesis Gold-Catalyzed Cyclizations of 1,5-Enynes This Ph.D. thesis deals with the development of gold(I)-catalyzed cyclizations of propargylamino acrylates (3-aza-1,5-enynes) in the presence of an external nucleophile. A library of tetrahydropyridines with an unusual hemiaminal ether functional group was thus prepared via the cyclization of a series of substituted enynes. The influence of the protective group as well as the substitution on the chemoselectivity of the reaction was demonstrated. The tetrahydropyridines were further utilized as precursors for the preparation of pharmaceutically important nitrogen heterocycles. The reduction of selected compounds furnished substituted piperidines, while Diels-Alder cycloaddition of alkenylated tetrahydropyridines gave rise to isoquinoline derivatives. Additional ortho-fused heterocycles (furopyridine, pyrrolopyridine and chromenopyridine) were prepared by the intramolecular version of the cyclizations of enynes with pending internal nucleophiles.
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Design of presentation electric switchboard for LV
Hlaváč, Jan ; Štefanov, Marek (referee) ; Bátora, Branislav (advisor)
This master’s thesis deals with the design of electric switchgear for low voltage, which will serve for presentation purposes. The switchgear is analogy of the modular system MNS 3.0, which includes the latest equipment of ABB Ltd. that is currently available on the market. Switchgears of this type are widely used in industry primarily for controlling motor units. For this reason, in the switchgear there are located motor starters in various performances, as well as distribution modules. In addition, the switchgear has an automatic transfer switch function in case of failure of one of the power supplies. The complete documentation of the switchgear is processed in the professional software EPLAN Electric P8 with use of the 3D software EPLAN Pro Panel for modelling device compartments. The final part of the thesis is the calculation of the maximum cable lengths that a potential customer can connect to the switchgear. In addition, an analysis of the power and control circuits was carried out for voltage drop calculations, as well as the effect of these voltage drops and capacitance of long control cables on the actuation of contactors.
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New C-H activations and cross-coupling reactions for modification of deazapurine nucleobases
Sabat, Nazarii ; Hocek, Michal (advisor) ; Tobrman, Tomáš (referee) ; Hlaváč, Jan (referee)
This PhD thesis reports the development of novel C-H activation strategies and aqueous-phase Suzuki-Miyaura cross-coupling reactions for the synthesis of modified deazapurine nucleobases. The methodologies of chemo- and regioselective synthesis of highly functionalized deazapurines have been developed by using modern C-H activation chemistry. Various functional groups such as amino-, imido-, silyl- and phosphonyl- were introduced by C-H activation reactions. Amino deazapurine derivatives were synthesized by developed Pd/Cu-catalyzed direct C-H amination and C-H chloroamination of 6-substituted 7-deazapurines with N-chloro-N- alkyl-arylsulfonamides. C-H imidation reactions of pyrrolopirimidines were performed under ferrocene catalysis with N-succinimido- or N-phtalimidoperesters. In order to obtain silylated derivatives, Ir-catalyzed C-H silylations of phenyldeazapurines with alkyl silanes were designed. Highly interesting deazapurine phosphonates were prepared by using Mn-promoted C-H phosphonation method and were further transformed into the corresponding phosphonic acids. All of the developed direct C-H functionalization reactions proceeded regioselectively at position 8 in deazapurine core, except for C-H silylation where reaction undergoes mainly as directed ortho C-H silylation on phenyl ring,...
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