National Repository of Grey Literature 32 records found  previous11 - 20nextend  jump to record: Search took 0.01 seconds. 
Synthesis of Neuraminidase binders suitable for theranostics
Berenguer Albiñana, Carlos ; Machara, Aleš (advisor) ; Cibulka, Radek (referee) ; Soural, Miroslav (referee)
Influenza viruses cause respiratory illnesses which can vary in severity depending on the strain of the virus, as well as the age and health condition of the host. Influenza remains a major threat to public health due to its nature prone to suffer mutations. As a result, vaccines have to be reformulated annually and new strains may cause sporadic global pandemics. Furthermore, the recent emergence of resistant strains of the virus against the current standard of care (oseltamivir and zanamivir) underlines the need of novel anti-influenza therapeutics. The aim of this dissertation work is to contribute to the discovery of new anti-influenza inhibitors either by rational drug-design and optimization of oseltamivir structure, or by developing screening assays suitable for the discovery of novel inhibitors of the enzymes neuraminidase or RNA-polymerase. Scheme 1. Overview of the strategy used for the development of new anti-influenza therapeutics. The dashed arrows indicate the inhibitors that were converted into probes and their corresponding target enzymes Two main modification points were explored for the improvement of oseltamivir properties (Scheme 1); modifications at carbon C-3 aimed to overcome oseltamivir resistance caused by common mutations like H274Y, meanwhile modifications at carbon C-5...
Carborane structural blocks in medicinal chemistry
Nekvinda, Jan ; Grüner, Bohumír (advisor) ; Machara, Aleš (referee) ; Janoušek, Zbyněk (referee)
This work deals with carborane and metallacarborane clusters, in terms of their fundamental chemistry and complexation with cyclodextrins, and in the context of emerging pharmacophores applicable in medicinal chemistry. Arguably, the most important part of this work is the preparation of cobalt bis(dicarbollide) sulfamide derivatives. The sulfamido group is attached to the metallacarborane carbon vertex by an alkyl chain that may be modified in its length. This was accomplished by, firstly, the abstraction of the acidic hydrogen, located on the {CH}-vertex from the metallacarborane, by reaction with lithium base, followed by, secondly, reaction with electrophilic agents (PFA, oxirane and oxetane), which leads to a cascade of reactions to give the desired sulfamide derivatives. These compounds were then tested by collaborators in other institutes for in vitro and in vivo activity towards Carbonic Anhydrase IX (CA IX), which is an enzyme associated with tumour growth. In vivo tests on mice have shown that these types of substances are able to effectively reduce tumour size by 30%. The synthetic research continued with the preparation of sulfonamide compounds of the isomers of the carborane series. The reactions began exclusively with propylhydroxy carborane starting materials, which provide optimum...
Preparation of Influenza Neuraminidase and Polymerase Inhibitors
Zima, Václav ; Machara, Aleš (advisor) ; Cibulka, Radek (referee) ; Soural, Miroslav (referee)
Influenza is an infectious disease caused by the influenza virus. This virus causes a severe viral infection that spreads easily from person to person in yearly pandemics. Vaccination is the most effective way to prevent the infection, however, due to the high rate in mutations of the virus, the vaccine needs to be often reformulated. Another option to combat influenza is based on administration of antiviral drugs. Clinical studies of isolated influenza strains ("avian flu" H5N1, 2004; "swine flu" H1N1, 2009) revealed resistance towards known influenza neuraminidase inhibitors (zanamivir, oseltamivir). The resistance is caused by structural changes close to the enzymatic site. This calls for the development of new neuraminidase inhibitors as well for development of inhibitors targeting different influenza enzymes. This Thesis is focused on design and synthesis of new inhibitors of influenza neuraminidase and RNA-dependent RNA polymerase, namely PA subunit and the assembly of PA-PB1 heterodimer enzymes (Scheme 1). Influenza neuraminidase inhibitors were prepared by C-5 derivatization of oseltamivir followed by subsequent extension of its structure with binders of 150-cavity. Binding potencies of new oseltamivir derivatives against two influenza strains were determined. The next part contributed to...
Synthesis of prodrugs of glutamine antimetabolite 6-diazo-5-oxo-L-norleucine
Novotná, Kateřina ; Majer, Pavel (advisor) ; Machara, Aleš (referee)
The 6-diazo-5-oxo-L-norleucine (DON) is a glutamine antimetabolite, which has shown promissing antitumor activity in preclinical and several clinical studies. However, its high toxicity leading to gastrointestinal side effects prevented its further development. The aim of this Bachelor thesis was to prepare DON prodrugs with similar anticancer activity but less side effects. Biochemical and biological tests of synthesized prodrugs were performed at Johns Hopkins University in Baltimore (USA). Key words: 6-diazo-5-oxo-L-norleucine (DON), prodrugs, antimetabolite, ProTide
Carborane structural blocks in medicinal chemistry
Nekvinda, Jan ; Grüner, Bohumír (advisor) ; Machara, Aleš (referee) ; Janoušek, Zbyněk (referee)
This work deals with carborane and metallacarborane clusters, in terms of their fundamental chemistry and complexation with cyclodextrins, and in the context of emerging pharmacophores applicable in medicinal chemistry. Arguably, the most important part of this work is the preparation of cobalt bis(dicarbollide) sulfamide derivatives. The sulfamido group is attached to the metallacarborane carbon vertex by an alkyl chain that may be modified in its length. This was accomplished by, firstly, the abstraction of the acidic hydrogen, located on the {CH}-vertex from the metallacarborane, by reaction with lithium base, followed by, secondly, reaction with electrophilic agents (PFA, oxirane and oxetane), which leads to a cascade of reactions to give the desired sulfamide derivatives. These compounds were then tested by collaborators in other institutes for in vitro and in vivo activity towards Carbonic Anhydrase IX (CA IX), which is an enzyme associated with tumour growth. In vivo tests on mice have shown that these types of substances are able to effectively reduce tumour size by 30%. The synthetic research continued with the preparation of sulfonamide compounds of the isomers of the carborane series. The reactions began exclusively with propylhydroxy carborane starting materials, which provide optimum...
Synthesis of Neuraminidase binders suitable for theranostics
Berenguer Albiñana, Carlos ; Machara, Aleš (advisor) ; Cibulka, Radek (referee) ; Soural, Miroslav (referee)
Influenza viruses cause respiratory illnesses which can vary in severity depending on the strain of the virus, as well as the age and health condition of the host. Influenza remains a major threat to public health due to its nature prone to suffer mutations. As a result, vaccines have to be reformulated annually and new strains may cause sporadic global pandemics. Furthermore, the recent emergence of resistant strains of the virus against the current standard of care (oseltamivir and zanamivir) underlines the need of novel anti-influenza therapeutics. The aim of this dissertation work is to contribute to the discovery of new anti-influenza inhibitors either by rational drug-design and optimization of oseltamivir structure, or by developing screening assays suitable for the discovery of novel inhibitors of the enzymes neuraminidase or RNA-polymerase. Scheme 1. Overview of the strategy used for the development of new anti-influenza therapeutics. The dashed arrows indicate the inhibitors that were converted into probes and their corresponding target enzymes Two main modification points were explored for the improvement of oseltamivir properties (Scheme 1); modifications at carbon C-3 aimed to overcome oseltamivir resistance caused by common mutations like H274Y, meanwhile modifications at carbon C-5...
Synthesis of peptidic inhibitors targeting PA-PB1 interface of influenza RNA polymerase
Palacková, Miroslava ; Machara, Aleš (advisor) ; Veselý, Jan (referee)
The submitted Thesis deals with preparation of a hexapeptides inhibiting protein-protein interaction of PA-PB1 subunits of influenza RNA polymerase. Crucial part of the Thesis represent modifications of particular small hexapeptide at its two "hot spots". It means at positions that significantly contribute to the binding of both subunits. These modifications resulted in preparation of two series of distinct hexapeptides. With regards to the fact that one designed hexapeptide contains unnatural and commercially unavailable amino acids this amino acid had to be prepared from simple building blocks. Apart from aforementioned work the Thesis also covers effort to prepared bicyclic peptide that contains sequences of peptidic inhibitor of protein-protein interactions and also cell-penetration peptide. Key words: synthesis, peptides, inhibitors, influenza, polymerase
Enantioselective synthesis of an actinofuranone fragment
Morávková, Terézia ; Kotora, Martin (advisor) ; Machara, Aleš (referee)
This bachelor thesis is focused on the new preparation procedure of the unsaturated actinofuranone fragment JBIR-108 which was isolated from actinobacteria Streptomyces gramineu. This exotoxin appears to be cytotoxic to some types of cancer cells. Although the synthesis of this actinofuranone has already been published by the group of T. Doi,1 this work brings a new method for the preparation of fragment C7-C18. The key steps for this synthesis are crotylation reaction, cross metathesis and Suzuki cross-coupling. Key words: crotylation, natural compound, actinofuranone fragment, Suzuki cross-coupling, asymmetric synthesis
Preparation of modified ligands of mu-opioid receptors
Hadzima, Martin ; Machara, Aleš (advisor) ; Veselý, Jan (referee)
This diploma thesis deals with preparation of modified ligands of mu, delta and kappa opioid receptors, following up on the author's bachelor's thesis.1 The main goal of the submitted thesis is ligand tethering at an appropriate position using oligoethylene glycol linkers, to enable their use in the innovative iBodies concept.2 Ligands chosen for modifications were: naltrexone (μ-opioid receptor), naltrindole (δ-opioid receptor) and nalfurafine (κ-opioid receptor). Naltrexone was modified, according to the bachelor's thesis results, at the C-6 position with linker attachment via ether and amide. At the same time, the influence of the configuration at the newly formed C-6 stereogenic center on biological activity was studied. In case of naltrindole, access through indole nitrogen was chosen based on the information in literature.3-5 Nalfurafine was modified on the furane fragment. Series of fluorescently labeled ligands were prepared. Attachment of the fluorescent tag allowed us to study the affinity and selectivity of these modified ligands. Based on the results, ligands for development of DIANA method and for preparation of synthetic iBodies were synthesised.6 Key words: naltrexone, receptor, conjugate, opioid receptor 1 M. Hadzima. Fluorescenčně značené ligandy μ-opioidních receptorů, 2016. 2 P....

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