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Synthesis of new antimitotic agents
Hoppová, Martina ; Kučerová, Marta (advisor) ; Miletín, Miroslav (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Student: Martina Hoppová Supervisors: PharmDr. Marta Kučerová, Ph.D.; Dr. Rafael Peláez Lamamie de Clairac Arroyo Title of diploma thesis: Synthesis of new antimitotic agents Cancer is one of the main causes of death all around the world and therefore the development of new chemotherapeutic drugs is one of the major areas of pharmaceutical research. The effort is to obtain an agent that would be highly effective, target the neoplastic tissue, and have advantageous pharmacological properties and minimum side effects. Rapid proliferation is one of the main features of cancerous growth, thus influencing mitosis as the phase of cell division may be a convenient way for cancer treatment. Tubulin is a protein, which rapidly polymerizes into microtubules and again depolymerizes and beside others it forms mitotic spindle during mitosis, and according to its important role, tubulin is an attractive target for antitumoral agents. Many drugs inhibiting polymerization or stabilizing already formed microtubules are actually in clinical practice, and research regarding new antimitotics interacting with tubulin is going on at the same time. Such an example is natural combretastatin A-4...
Preparation of fluorescent phthalocyanines for labeling of oligonucleotide probes IV.
Mikula, Daniel ; Miletín, Miroslav (advisor) ; Zitko, Jan (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate Daniel Mikula Supervisor doc. PharmDr. Miroslav Miletín, Ph.D. Consultant Mgr. Michaela Kolářová Title of thesis Preparation of fluorescent phthalocyanines for labeling of oligonucleotide probes IV. Phthalocyanines (Pcs) are macrocyclic compounds with a conjugated system of double bonds. Thanks to this, they have interesting photophysical and photochemical properties that enable their practical use in pharmacy and medicine in the field of diagnostics or treatment of cancer diseases. This work deals with the preparation of axially disubstituted silicon complexes of phthalocyanines (SiPcs), which would have suitable properties for subsequent use in the labeling of oligonucleotide probes. The theoretical part is primarily devoted to the methods of Pcs preparation, from the choice of precursors, through the formation of the macrocycle and insertion of the central atom, to the modifications of the resulting molecule, including the specifics related to SiPcs. The basic properties of Pcs and the degree of influence of different changes of the molecule on these properties are also described. The basic areas of use of Pcs are also mentioned. The experimental part...
Novel quinazoline derivatives with biological activity
Brožová, Zuzana Rania ; Pour, Milan (advisor) ; Miletín, Miroslav (referee) ; Soural, Miroslav (referee)
Faculty of Pharmacy in Hradec Králové, Charles University Department of Organic and Bioorganic Chemistry Candidate: Mgr. Zuzana Rania Brožová Supervisor: prof. RNDr. Milan Pour, Ph.D. Title of Doctoral Thesis: Novel quinazoline derivatives with biological activity This thesis is divided into two parts, both dealing with the synthesis of novel quinazoline derivatives and evaluation of their biological activity. The first part is focused on the synthesis of bronchodilatory active derivatives derived from vasicinone as a lead compound and 3-[3-(piperidin-1-yl)-propyl]-3,4- dihydroquinazoline-4-one and 4-[3-(piperidin-1-yl)-propylsulfanyl]-3,4-dihydroquinazoline-4- one, the most active derivatives from our previous work. The derivatives were subsequently tested on isolated rat trachea and their bronchodilatory activity was evaluated. Their toxicity, in vivo activity, mechanism of action and the relationships between structure and activity (SAR) were also investigated. The second part deals with the synthesis of novel derivatives of 2,4-disubstituted quinazoline and their testing for affinity to nuclear constitutive androstane receptor (CAR). This work follows up on the previous random discovery that 2-(3-methoxyphenyl)quinazoline- 4-ol is a promising CAR agonist which own activity comparable to that of...
Preparation of conjugates oligonucleotide probes with functional molecules.
Grossová, Petra ; Miletín, Miroslav (advisor) ; Demuth, Jiří (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Supervisor: doc. PharmDr. Miroslav Miletín, Ph.D. Consultant: Mgr. Michaela Beranová Student: Petra Grossová Title of Thesis: Preparation of conjugates oligonucleotide probes with functional molecules The aim of this thesis was to find the optimal conditions for conjugation of an oligonucleotide to a fluorescent dye by solid-phase click chemistry. The traditional fluorescent dye Cyanine5 was chosen as the labelling molecule. The effect of the concentration of fluorescent dye, the position of the labelling, the type of solid phase and the reaction time were examined. The deprotection conditions were optimized. Two series of reactions followed by deprotection and purification were performed. The efficiency of the reaction was evaluated by comparing the peak areas under the curve of conjugated and unconjugated molecules in the chromatograms of the samples after analysis by HCPL with UV detection. Peak integration was performed in LabSolutions software. The reactions running on the polystyrene solid phase gave the highest yields, with labelling at any position of the chain. For labelling at the 5'-end of the chain, more than 90% efficiency was achieved using all tested solid...
Design, synthesis and evaluation of heterocyclic compounds with potential antimicrobial activity IV
Fekri, Amir Hossein ; Zitko, Jan (advisor) ; Miletín, Miroslav (referee)
(English) Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Thesis title: Design, synthesis and evaluation of heterocyclic compounds with potential antimicrobial activity IV Candidate: Amirhossein Fekri Supervisor: doc. PharmDr. Jan Zitko, Ph.D. Consultant: Mgr. Vinod S. K. Pallabothula Tuberculosis has remained one of the deadliest infectious diseases worldwide caused by a single infectious agent, the rapid growth of resistance to anti-tubercular drugs hinders the successful control and treatment of TB worldwide, which challenges the scientific community to develop new drugs to improve currently available treatment. This diploma thesis represents the design, synthesis, and biological evaluation of two series of compounds including cyclized (pyrazine- oxazinone) and carboxamide derivatives as potentially active antimycobacterial agents sharing a pyrazine core as common structural features that could potentially target mycobacterial aspartate decarboxylase (PanD) and prolyl-tRNA synthetase (mtProRS), respectively. Synthesis of final compounds was achieved through individual reaction steps involving acylation of methyl 3-aminopyrazine-2-carboxylate for preparation of a common intermediate which in turn was used for the...
Preparation of fluorescent phthalocyanines for labeling of oligonucleotide probes IV.
Mikula, Daniel ; Miletín, Miroslav (advisor) ; Zitko, Jan (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate Daniel Mikula Supervisor doc. PharmDr. Miroslav Miletín, Ph.D. Consultant Mgr. Michaela Kolářová Title of thesis Preparation of fluorescent phthalocyanines for labeling of oligonucleotide probes IV. Phthalocyanines (Pcs) are macrocyclic compounds with a conjugated system of double bonds. Thanks to this, they have interesting photophysical and photochemical properties that enable their practical use in pharmacy and medicine in the field of diagnostics or treatment of cancer diseases. This work deals with the preparation of axially disubstituted silicon complexes of phthalocyanines (SiPcs), which would have suitable properties for subsequent use in the labeling of oligonucleotide probes. The theoretical part is primarily devoted to the methods of Pcs preparation, from the choice of precursors, through the formation of the macrocycle and insertion of the central atom, to the modifications of the resulting molecule, including the specifics related to SiPcs. The basic properties of Pcs and the degree of influence of different changes of the molecule on these properties are also described. The basic areas of use of Pcs are also mentioned. The experimental part...
Study of the effect of macrocycle on intramolecular charge transfer at phthalocyanines
Bednárik, Štefan ; Nováková, Veronika (advisor) ; Miletín, Miroslav (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Štefan Bednárik Supervisor: doc. PharmDr. Veronika Nováková, Ph.D. Consultant: PharmDr. Jiří Demuth, Ph.D. Diploma thesis: Study of the effect of macrocycle on intramolecular charge transfer at phthalocyanines Porphyrazine derivates phthalocyanines (Pcs) and their aza-analogues (AzaPcs) have been largely investigated in number of applications due to their unique photophysical and photochemical properties. One of the investigated research areas involves intramolecular charge transfer (ICT) - deactivation of excited states. This phenomenon is a competitive pathway to fluorescence emission and requires electron donors as peripheral substituents while the macrocyclic core serves as electron acceptor. The aim of this work was to study how modifications to the Pc macrocycle will affect its electron acceptor properties and subsequently the strength of ICT. The synthesis involved preparation of suitable precursors, i.e. 4,5-disubstituted phthalonitriles or 5,6-disubstituted pyrazine-2,3-dicarbonitriles. It was followed by their cyclotetramerization leading to the mixture of six different congeners, from which the desired asymmetrical ABBB type macrocycle was...
Synthesis of new antimitotic agents
Hoppová, Martina ; Kučerová, Marta (advisor) ; Miletín, Miroslav (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Student: Martina Hoppová Supervisors: PharmDr. Marta Kučerová, Ph.D.; Dr. Rafael Peláez Lamamie de Clairac Arroyo Title of diploma thesis: Synthesis of new antimitotic agents Cancer is one of the main causes of death all around the world and therefore the development of new chemotherapeutic drugs is one of the major areas of pharmaceutical research. The effort is to obtain an agent that would be highly effective, target the neoplastic tissue, and have advantageous pharmacological properties and minimum side effects. Rapid proliferation is one of the main features of cancerous growth, thus influencing mitosis as the phase of cell division may be a convenient way for cancer treatment. Tubulin is a protein, which rapidly polymerizes into microtubules and again depolymerizes and beside others it forms mitotic spindle during mitosis, and according to its important role, tubulin is an attractive target for antitumoral agents. Many drugs inhibiting polymerization or stabilizing already formed microtubules are actually in clinical practice, and research regarding new antimitotics interacting with tubulin is going on at the same time. Such an example is natural combretastatin A-4...
Synthesis of substituted acridines
Voštová, Kateřina ; Zimčík, Petr (advisor) ; Miletín, Miroslav (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate Kateřina Voštová Supervisor prof. PharmDr. Petr Zimčík, Ph.D. Consultant Mgr. Filip Kostelanský Title of Thesis Synthesis of substituted acridines Real-time PCR is a widely used method in many laboratories for diagnostic purposes. This method combines PCR with the use of fluorescent signaling agents, probes, to monitor the number of amplicons during each PCR cycle. There are several types of probes used for DNA analysis. Short probes do not form sufficiently stable duplexes with the target DNA sequence to be able to detect single base mismatching. This work provides an overview of the oligodeoxynucleotides (ODN) probes in use and in what way is their thermostability is affected. In the practical part, two structurally distinct acridine derivatives were prepared because they may increase duplex thermostability due to their ability to intercalate between DNA bases. By increasing the thermostability, the melting temperature of the duplex between probe and the target sequence is also increased. For this reason, acridine derivatives form promising compounds suitable for short ODN probes that are characterized by low thermal stability. The described reactions...
Synthesis of unsymmetrical derivatives of azaphthalocyanines V.
Nejedlá, Marcela ; Zimčík, Petr (advisor) ; Miletín, Miroslav (referee)
Title of diploma thesis: Synthesis of usymmetrical derivates of azaphthalocyanines V. Author: Marcela Nejedlá The aim of diploma thesis was synthesis of unsymmetrical derivates of azaphthalocyanines (Aza- Pc) with carboxy or hydroxy group, and the preparation of suitable precursors of Aza-Pc. Required zinc and magnesium complexes were synthesized using statistical condensation of two different precursors. The desired complex was isolated from the mixture, purified and characterized. The preparation of the precursor 6-(3-tert-butylsulfanyl-5,6-dicyanopyrazine-2- ylamino)hexanoic acid was successful. The cyclization of two precursors yielded the following Aza-Pc: 3-carboxy[2',3'-b]quinoxalino-11,12,18,19,25,26-hexakis(tert- butylsulfanyl)tripyrazino[g,l,q]porphyrazinato zinc (II); 3-carboxy[2',3'-b]quinoxalino- 11,12,18,19,25,26-hexakis(tert-butylsulfanyl)tripyrazino[g,l,q]porphyrazinato magnesium (II). The modification of the preparation of precursor 5,6-dioxo-1,4,5,6-tetrahydropyrazine-2,3- dicarbonitrile by decreasing the reaction temperature has shown to be unsuitable

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