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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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Novel modified nucleosides with antiviral or cytostatic activity
Tokarenko, Anna ; Hocek, Michal (advisor) ; Rádl, Stanislav (referee) ; Dvořák, Dalimil (referee)
A general and modular synthetic approach to 4-substituted phenyl, 2-substituted pyridin- 5-yl and 5-substituted pyridin-2-yl 2′-C-methyl-C-ribonucleosides as potential anti-HCV agents was developed. Addition of halo(het)aryllithium reagents to benzylated 2-C-methyl-D- ribonolactone gave the corresponding hemiketals, which were subsequently converted to the β-anomeric benzyl-protected bromo(het)aryl-C-nucleosides via either direct reduction (in the case of phenyl derivative) or acetylation followed by reduction of the resulting hemiketal acetates (in the case of pyridyl derivatives). The key halogenated (het)aryl-C-nucleoside intermediates were further transformed by Pd-catalyzed cross-coupling, hydroxylation and amination reactions affording series of protected C-nucleosides with small hydrophilic and hydrophobic substituents. The final protecting group removal was rather problematic, and different debenzylation methods, such as hydrogenation on Pd/C or treatment with BCl3, had to be optimized for each derivative to minimize the formation of side-products. The final C- nucleosides were also converted into their 5′-O-triphosphates, and biological activity screenings revealed that none of the free C-nucleosides possesses any antiviral activity in the HCV replicon assay, and none of their NTPs...
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Functionalization of pyrimidine nucleobases by direct C-H arylations.
Čerňová, Miroslava ; Hocek, Michal (advisor) ; Dvořák, Dalimil (referee) ; Rádl, Stanislav (referee)
Within presented dissertation thesis Pd-catalyzed direct C-H arylation of 1,3-dimethyluracil to position 5 or 6 was developed. An interesting dichotomy in the regioselectivity and mechanism of reactions were observed. A reaction of 1,3-dimethyluracil with diverse aryl halides performed in the absence of CuI led preferentially to 5-aryl-1,3-dimethyluracils, while with the addition of CuI 6-aryl-1,3-dimethyluracils were formed as the major products. Reactions mediated only in the presence of copper(I) iodide (in the absence of a Pd-catalyst) proceeded with lower yields but led exclusively to 6-arylated derivatives. In order to prepare free 5- and 6 arylated uracils for biological activity screening, the developed methodologies for the direct C-H arylations were applied to various 1,3-protected uracils. Benzyl-protected uracil was selected as the best candidate both in terms of stability during the arylations, as well as facile cleavage of the benzyl groups during deprotection of arylated uracils. Synthesis of various substituted 5- and 6-aryl-1,3-dibenzyluracils proceeded with the same regioselectivity as with the model compound 1,3-dimethyluracil. For deprotection of synthesized derivatives either transfer hydrogenolysis over Pd/C or treatment with BBr3 in case of uracils bearing bulky aromatic...
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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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Design and Synthesis of New Compounds Active Especially Against Multidrug-Resistant Mycobacterial Strains
Krátký, Martin ; Vinšová, Jarmila (advisor) ; Doležal, Martin (referee) ; Rádl, Stanislav (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Inorganic and Organic Chemistry Candidate Martin Krátký Supervisor Prof. Dr. Jarmila Vinšová, Ph.D. Title of Doctoral Thesis Design and Synthesis of New Compounds Active Especially against Multidrug-Resistant Mycobacterial Strains This work is focused mainly on the field of searching of new potential antimicrobial agents, particularly against multidrug-resistant Mycobacterium tuberculosis strains, based on the modification of the salicylanilide (2-hydroxy-(N-phenyl)benzamide) group. The second research topic is a study of the rearrangement in the series of salicylanilide amino acids esters to form 2-hydroxy-N-[2-oxo-2-(phenylamino)-alkan-2-yl]benzamides called "diamides". At the beginning, the thesis summarizes some basic facts about tuberculosis, a very important and serious bacterial infectious disease caused by Mycobacterium tuberculosis complex, about its treatment and related troubles and limitations. Proper attention is given for the problematic of drug-resistant tuberculosis, especially multidrug-resistant and extensively drug-resistant forms, their epidemiology and therapy. The development of new drugs against multidrug-resistant tuberculosis is largely discussed, including requirements for them, recent...
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