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Synthesis of anionic phthalocyanines
Lozano Canadilla, Jorge ; Zimčík, Petr (advisor) ; Miletín, Miroslav (referee)
Univerzita Karlova, Farmaceutická fakulta v Hradci Králové Katedra farmaceutické chemie a farmaceutické analýzy Kandidát: Jorge Lozano Cañadilla Školitel: prof. PharmDr. Petr Zimčík, Ph.D. Název: Syntéza anionických ftalocyaninů Tato diplomová práce je zaměřena na syntézu anionických ftalocyaninů s karboxylovými skupinami pro potenciální využití ve fotodynamické terapii (PDT). Studie nastiňuje význam rozpustnosti ve vodě při návrhu fotosenzitizérů pro účinnou PDT. Syntetické postupy zahrnovaly různé reakce, včetně esterifikace, Suzuki-Miyaura cross couplingu a cyklotetramerizace, za účelem vytvoření ve vodě rozpustných sloučenin. V experimentální části jsou podrobně popsány kroky, které byly podniknuty k získání konečných produktů, přičemž jsou zdůrazněny problémy, kterým bylo třeba čelit, jako jsou experimentální chyby a obtíže při separaci. Sekce Výsledky a diskuse analyzuje výsledky a zdůrazňuje význam specifických reakčních podmínek a purifikačních technik. Celkově tato práce přispívá k vývoji anionických ftalocyaninů s lepšími vlastnostmi pro PDT s cílem zvýšit jejich účinnost.
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Design, synthesis and evaluation of heterocyclic compounds with potential antimicrobial activity V
Askari, Asal ; Zitko, Jan (advisor) ; Zimčík, Petr (referee)
(CZECH) Univerzita Karlova, Farmaceutická fakulta v Hradci Králové, Katedra farmaceutické chemie a farmaceutické analýzy Řešitel: Asal Askari Vedoucí diplomové práce: doc. PharmDr. Jan Zitko, Ph.D. Konzultant: Ghada Bouz, Ph.D. Název diplomové práce: Návrh, syntéza a hodnocení heterocyklických sloučenin s potenciální antimikrobní aktivitou V Staphylococcus aureus (SA) je jednou z nejčastějších příčin život ohrožujících infekcí. Jedním ze způsobů, jak kontrolovat infekčnost SA, je vývoj inovativních látek, nejlépe s novým mechanismem účinku, které jsou účinné jak proti kmenům citlivým na léky, tak proti kmenům lékově rezistentním. Chinazolon slouží jako základní kostra pro mnoho různých biologicky aktivních sloučenin. Antistafylokokové chinazolony (AQs) mají v literatuře popsané vztahy mezi strukturou a aktivitou. Penicilin vázající protein (PBP), DNA topoizomeráza a laktátdehydrogenáza jsou některé z molekulárních cílů pro AQs. S využitím in silico molekulového dokování jsme spojili naše rozsáhlé znalosti antibakteriálních léčiv s tím, co bylo popsáno v literatuře, abychom vytvořili nové, potenciálně aktivní AQs zaměřené na PBP. Výsledkem bylo, že jsme připravili 11 finálních sloučenin s lipofilitou v rozmezí 2,69 až 4,06 reakcí laktonového meziproduktu, benzoxazinonu, s různými benzylaminy....
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Synthesis of photoactive derivatives of phthalocyanines and study of their biological activity
Rychvalská, Lucia ; Zimčík, Petr (advisor) ; Vícha, Robert (referee) ; Zitko, Jan (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Mgr. Lucia Rychvalská Supervisor: prof. PharmDr. Petr Zimčík, PhD. Doctoral Thesis: Synthesis of photoactive derivatives of phthalocyanines and study of their biological activity Phthalocyanines (Pc) are macrocyclic compounds with conjugated system of double bonds with absorption maximum around 650 - 750 nm. They are characterized by high singlet oxygen production which makes them suitable candidates for photosensitizers in photodynamic therapy. However, they form inactive aggregates in water environment because of their planar hydrophobic aromatic core. There are many strategies to solve this problem, and this thesis is focused on fighting aggregation of Pc by their supramolecular interactions with cucurbiturils (CB). Subphthalocyanines (SubPc) are similar macrocyclic compounds composed of only three (instead of four) isoindol units with boron as a central atom, which has also axial substituent. Because of their cone-shape and axial substituent they are less aggregated in water but usually not very soluble, which could also be solved by interaction with CB. First part of this thesis was focused on synthesis of Pc with aminoadamantyl substituents on...
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Synthesis and delivery of novel fluorescently-labelled nucleotides and their nucleic acids for bio-analytical applications
Güixens Gallardo, Pedro ; Hocek, Michal (advisor) ; Zimčík, Petr (referee) ; Klán, Petr (referee)
1 Abstract The goals of the thesis were to synthesise novel fluorescently labelled nucleotides and the corresponding nucleic acids for bio-analytical applications as well as their delivery into cells. The thesis also aimed at the development of an effective method to inhibit non-templated incorporation of nucleotides. The problematic non-templated enzymatic incorporation of nucleotides is addressed by using several commercially available 5'-modified-oligonucleotides. The oligonucleotides (ONs) that we tested bore ortho twisted intercalating nucleic acid (oTINA), a trityl group, or biotin at the 5'-end. The modified ONs were used as templates in the enzymatic primer extension (PEX) experiments in the presence of either modified nucleotides or only natural deoxynucleoside triphosphates (dNTPs). The oTINA templates underwent PEX reaction using natural dNTPs and different DNA polymerases of the A or B family. In parallel, two types of fluorescent nucleoside derivatives were independently designed and synthesised. Firstly, we envisaged new fluorescent nucleotide tags containing the hexamethylated BODIPY moiety as a bright fluorescent label. Conversely, we focused on the improvement of fluorescent nucleotide probes sensitive to the viscosity or polarity. The fluorescently labelled methylated BODIPY nucleotides...
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Synthesis of neutral amphiphilic phthalocyanines
Sidorová, Barbora ; Zimčík, Petr (advisor) ; Nováková, Veronika (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Barbora Sidorová Supervisor: prof. PharmDr. Petr Zimčík, Ph.D. Consultant: PharmDr. Jan Kollár, Ph.D. Diploma thesis: Preparation of neutral amphiphilic phthalocyanines Phthalocyanines are synthetic planar macrocycles, with structure similar to porphyrins. They contain 18 delocalized π electrons, which give these substances unique photophysical features. These substances have many industrial applications. One of these applications is the use of phthalocyanines as photosensitizers in photodynamic therapy, for treating both oncological and non-oncological diseases. When photosensitizer is activated by radiation at a specific wavelength (in the visible light range), it enters its excited state. It dissipates the absorbed energy by transferring it to an oxygen molecule, creating thus reactive molecule of singlet oxygen, that causes tissue damage. The subject of this thesis is synthesis of asymmetric derivatives of phthalocyanines with amphiphilic character, which, due to their structure, could be incorporated into cell membranes and subsequently used as photosensitizers. The first step of this synthesis was preparation of the precursor...
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Synthesis of substituted aminoadamantyl compounds
Janišová, Denisa ; Zimčík, Petr (advisor) ; Zitko, Jan (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Deparment: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Denisa Janišová Supervisor: prof. PharmDr. Petr Zimčík, Ph.D. Advisor: Mgr. Lucia Rychvalská Title of Thesis: Synthesis of substituted aminoadamantyl compounds This work deals with the topic of photodynamic therapy using phthalocyanines as photosensitizers. The theoretical part summarizes the basic knowledge and findings about photodynamic therapy, its principle, application and used photosensitizers. Phthalocyanines (Pcs), their structure and possible variations, their synthesis and aggregation are also described.The last part is dedicated to cucurbiturils,which form stronghost-guest complexes with small molecules,in our case with aminodamantanes.These complexes mayincrease the monomerization and solubility of phthalocyanines in water. In the experimental part of the work, attention was focused on the synthesis of 1-aminoadamantane substituted by thiol group on two-carbon linker. However, synthesis of this compound was not successful anddespite number ofalternativeapproaches we were not able to prepare it. The reactions ran better in case of extension ofthe linker to three carbons and 3-((adamant-1-yl)amino)propan-1-thiol was succesfully synthesized by...
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Synthesis of novel inhibitors of human topoisomerase based on highly substituted phenyl scaffold
Domanský, Miroslav ; Zitko, Jan (advisor) ; Zimčík, Petr (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Supervisor: Assoc. Prof. PharmD. Jan Zitko, PhD. Consultant: Mgr. Marek Kerda Author: Miroslav Domanský Title of diploma thesis: Synthesis of novel inhibitors of human Topoisomerase based on highly substituted phenyl scaffold. Despite progress in anticancer therapy, cancer is still one of the leading causes of death in the world. Patients treated with current anticancer therapy suffer from many side effects. This is caused by the low selectivity of the current drugs. The development of chemotherapeutics aims to prepare more selective and therefore better tolerated anticancer drugs. Topoisomerases are nuclear enzymes occurring in every cell. They have an essential role - to preserve DNA and repair it. Topoisomerase isoform IIα is an isoform that controls and edits the conformation of DNA during cell replication. Its expression is highly elevated in proliferating cells. That makes it a good target for anticancer drugs. The design of synthesized molecules is based on previously reported ATP-competitive inhibitors of human topoisomerase IIα. Alterations of 3,4-dichloro-5-methyl-N-phenyl-1H- pyrrole-2-carboxamide have been synthesized based on Computational-Aided Drug Design. The in silico study is based on the previous discovery of the...
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Synthesis of novel 5,6-disubstituted derivatives of uracil as potential drugs
Vu, Lien Phuong ; Kučerová, Marta (advisor) ; Zimčík, Petr (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Candidate: Vu Lien Phuong Supervisors: PharmDr. Marta Kučerová, Ph.D. Tanja Bruun, M.Sc. (Pharm.) Prof. Jari Yli-Kauhaluoma Title of diploma thesis: Synthesis of novel 5,6-disubstituted derivatives of uracil as potential drugs In this thesis, uracil was used as the core structure given its many biological activities that were reported such as antitumor, antiviral, antibiotic, hypoglycemic, diuretic and many others. The work was focused on the preparation of new 5,6- disubstituted uracil derivatives as potential biologically active agents. 2,4,6-Trichloropyrimidine was used for the preparation of 6-chlorouracil that was condensed with phenols or anilines to give the respective 6-phenoxyuracils and 6- phenylaminouracils. These intermediates were then modified in position 5 to give the final products. For this very challenging last step, various alkylating and acylating agents were used, e.g. Vilsmeier reagent, alkylchlorides, chloroacetyl chloride, ethyl chlorooxoacetate and ethyl bromoacetate. In the end, ethyl bromoacetate gave the most promising results affording four novel 5,6-disubstituted uracil derivatives. During the experimental work it was found that pH of water used...
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Investigation of the compounds influencing the melting temperature of oligonucleotide probes
Kostelanský, Filip ; Zimčík, Petr (advisor) ; Hocek, Michal (referee) ; Krátký, Martin (referee)
Charles University, Faculty of Pharmacy in Hradec Kralove Department: Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Author: Mgr. Filip Kostelanský Supervisor: prof. PharmDr. Petr Zimčík, Ph.D. Doctoral Thesis: Investigation of the compounds influencing the melting temperature of oligonucleotide probes Real-time PCR is widely used method in various research fields like biomedicine, microbiology, veterinary medicine, etc. Quantification of gene expression, allelic discrimination and alteration detection are new and interesting application possibilities. Mismatch discrimination is not optimal when longer probes are used. Melting temperature difference between fully complementary duplex and mismatched duplex is negligible in the case of longer probes. The short oligodeoxynucleotide (ODN) probes, on the other hand, are suitable for good discrimination of single nucleotide variants. However, these probes suffer from low melting temperatures. Adding minor groove binders (MGB), or other substances, which can strongly interact with DNA such as intercalating dyes or polyamines, can increase the melting temperature of short probes duplexes. In this work, several series of acridine-4-carboxamide intercalators were synthesized. MGB (Hoechst 33258) and polyamine (spermine) were modified and...
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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...
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