National Repository of Grey Literature 29 records found  1 - 10nextend  jump to record: Search took 0.00 seconds. 
Syntéza pyrimido[4,5-b]indolových nukleosidů s modifikovaným cukrem
Konč, Juraj ; Hocek, Michal (advisor) ; Janeba, Zlatko (referee)
Study of glycosylation reactions of base- and sugar-modified nucleosides was performed and some of the procedures were applied for the synthesis of pyrimido[4,5-b]indole nucleosides. Only 2′-deoxy-2′-fluoro-arabinonucleoside was successfully synthesized with nucleobase anion glycosylation. Series of 4-substituted derivatives of this nucleoside was prepared for biological activity testing.
Design and synthesis of novel type of prodrugs of acyclic nucleoside phosphonates based on ProTides
Markušová, Katarína ; Janeba, Zlatko (advisor) ; Kundrát, Ondřej (referee)
This diploma thesis focuses on the synthesis of novel prodrugs of tenofovir, one of the main components of medications against human immunodeficiency virus (HIV) infection. The design of the compounds is based on the concept of ProTides and takes inspiration from the previous work of Filip Kalčic. In this work, the aromatic ester on the phosphonate moiety, typical for the ProTides, is replaced by an aliphatic ester. This aliphatic moiety is represented by a derivative of the amino acid L-serine. All of the target compounds were synthesized in a one-pot manner from three key components (L-serine, L-alanine, and tenofovir), except for one, the synthesis of which remains unsuccessful. The prepared compounds exhibit single-digit micromolar to low nanomolar potency against HIV-1. The most active compound (as a mixture of epimers) exhibited similar anti-HIV-1 activity to the reference ProTide prodrug, tenofovir alafenamide. Most importantly, none of the synthesized ProTides showed cytotoxicity. This was one of the key properties of the compounds from Kalčic's project that we wanted to improve. The results of this thesis represent a stepping stone to a new category of ProTide prodrugs of phosphonates. Key words: prodrugs, acyclic nucleoside phosphonates, ProTides, tenofovir, serine, TAF
Approaches to the enzymatic synthesis of hypermodified DNA polymers
Ondruš, Marek ; Hocek, Michal (advisor) ; Janeba, Zlatko (referee) ; Zimčík, Petr (referee)
The aim of this thesis was to synthesize new series of modified 2'-deoxynucleoside triphosphates (dNTPs) bearing hydrophobic modifications, use them in enzymatic synthesis of fully-modified DNA and study its bio-physical properties. In the first part of the thesis, a set of four 2'-deoxynucleosides bearing a linear or branched alkane, indole or phenyl group were synthesized by Sonogashira cross-coupling reactions using alkynes and iodinated nucleosides. Ethynyl linkers of corresponding nucleosides were reduced by catalytic hydrogenation to obtain another four nucleosides bearing the modifications through alkyl linker. All eight nucleosides were then transformed into 2'-deoxynucleoside triphosphates (dNTPs) by Yoshikawa phosphorylation and individually tested as substrates for polymerase synthesis by primer extension (PEX). Their combinations were systematically tested to generate DNA containing one or even four modified nucleotides. It was possible to replace all four canonical nucleotides with hydrophobically-modified counterparts and thus synthesize DNA with high density of modifications. Nevertheless, only nucleotides bearing modifications through rigid ethynyl linker were suitable for synthesis of longer hypermodified DNA. Nucleotides with more flexible alkyl linker destabilized duplex during...
Synthesis of new nucleosides as potential inhibitors of flaviviral replication
Horkelová, Simona ; Nencka, Radim (advisor) ; Janeba, Zlatko (referee)
Viruses of the Flaviviridae family are the causative agents of many dangerous diseases for which we currently have no known cure, and research into new drugs against them therefore represents one of the major challenges for modern medicinal chemistry. Targeting the proteins encoded by viruses is the most common approach to combat them. For flaviviruses, the non- structural protein NS5 exhibiting methyltransferase (MTase) and RNA-dependent-RNA polymerase (RdRp) enzyme activity appears to be one of the most suitable molecular targets. This bachelor thesis deals with the synthesis of new potential drugs capable of inhibition skill of flaviviral RdRp. C-nucleoside analogues were prepared, containing 2 types of heterocyclical base: 3-fluoropicolamide modified in positions 5 or 6 and pyrido[3,2-d]pyrimidine-4-amine modified in positions 6 or 7 using aryl or heteroaromatic substituent Key words: C-nucleosides, polymerase, flaviviruses, Tick-borne encephalitis virus, Suzuki reaction, Grignard reaction
Synthesis of novel types of acyclic nucleoside phosphonates and preparation of prodrugs and drug delivery systems
Kalčic, Filip ; Janeba, Zlatko (advisor) ; Míšek, Jiří (referee) ; Krečmerová, Marcela (referee)
First part of this thesis was focused on the previously overlooked field of C1'-branched acyclic nucleoside phosphonates (ANPs). Five diverse synthetic approaches were developed/optimized affording key 6-chloropurine intermediates bearing N9 -phosphonomethoxyethyl (PME) branched at C1' position in 2-4 steps. It was demonstrated that these intermediates can be further vastly diversified into ANPs bearing both natural and unnatural nucleobases. Single enantiomers as well as racemates of final C1'-branched ANPs (overall 48 final compounds) were prepared and selected compounds were evaluated with respect to their biological properties. The aforementioned ANPs showed no antiviral potency against studied viruses and only weak to moderate cytostatic activity. Adenine C1'-branched ANPs proved to be the most potent currently known inhibitors of Trypanosoma brucei adenine phosphoribosyl transferase (TbrAPRT), an enzyme involved in purine salvage pathway (PSP) of T. brucei. Further biological evaluation of prepared compounds is in progress. Second part of this thesis was focused on development of novel prodrug moieties with higher selectivity index (i.e. toxicity/potency ratio - SI) based on so-called ProTide prodrugs where phenol (present in ProTides) was replaced by tyrosine derivatives. Tenofovir was...
Separation of rotamers of 5-nitrosopyrimidines by capillary electrophoresis
Štěpánová, Sille ; Procházková, Eliška ; Čechová, Lucie ; Žurek, Jiří ; Janeba, Zlatko ; Dračínský, Martin ; Kašička, Václav
A new capillary electrophoresis (CE) method was developed for the separation of a new type of stereoisomers - rotamers of polysubstituted 5-nitrosopyrimidine derivatives. Partial separation of some rotamers was obtained in sodium borate, pH 9.3, or in Tris-phosphate, pH 2.2, background electrolytes (BGEs) free of cyclodextrins (CDs). However, the best, baseline separations of the rotamers of 5-nitrosopyrimidines were achieved in sodium borate BGE, pH 9.3, containing 20 mg/mL beta-CD as stereoselector, or in Tris-phosphate BGE, pH 2.2, with carboxymethyl-beta-CD as stereoselector.
Synthesis of polysubstituted pyrimidines with potential anti-inflammatory properties
Kalčic, Filip ; Janeba, Zlatko (advisor) ; Dvořák, Dalimil (referee)
This thesis is engaged in the synthesis of polysubstituted pyrimidines with anti- inflammatory properties. Such molecules can inhibit production of prostaglandin E2 (PGE2). The aim of this study was to enhance water-solubility and anti-inflammatory efficacy of such derivatives via structural modifications of the lead scaffold. Among applied synthetic tools, the Suzuki-Miyaura cross-coupling was the prevalent reaction, however, many other synthetic procedures (Heck reaction, condensation, borylation, ozonolysis, nucleophilic substitution, etc.) were utilized as well. Overall, 43 final products were prepared. The anti-inflammatory efficacy (inhibition of PGE2 production) was successfully increased as the most potent compound achieved three orders of magnitude higher activity compared to the current lead structure WQE-134. Furthermore, no general influence of the length of the substituent in the C5 position of pyrimidine (C5pyr) on the anti-inflammatory efficacy of synthesized compounds was observed. Significant bioavailability obstacle in future development of the current lead WQE-134 is its poor solubility which was successfully enhanced by introduction of heteroatom bearing moieties to C5pyr. The most water-soluble compound achieved two orders of magnitude higher solubility than WQE-134 while...
Synthesis of novel prodrugs for antiviral therapy
Štefek, Milan ; Nencka, Radim (advisor) ; Janeba, Zlatko (referee)
This bachelor thesis is dedicated to preparation of prodrugs derived from 2'-C- methyladenosine, which is a potent inhibitor of the RNA dependent RNA polymerase of flaviviruses. Prodrugs modifying 3' and 5' hydroxy groups able to deliver the drug to brain and were prepared. As targeting moieties tropine and the redox system trigonelline/1,4- dihydrotrigonelline were used. In the case of tropine a suitable method for the preparation of prodrugs was developed. Reliable procedure for performing the last step of synthesis of compounds utilizing the trigonelline redox system is yet to be discovered.

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