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Design, synthesis and evaluation of novel inhibitors of class II PI4Ks and RIPK2/3 kinases
Misehe, Mbilo ; Nencka, Radim (advisor) ; Soural, Miroslav (referee) ; Baszczyňski, Ondřej (referee)
Synthetic kinase inhibitors are chemical tools to investigate cellular roles of kinase enzymes and, potentially, find new treatments for various diseases that are connected with their dysregulated expressions and activities. This thesis focuses on two projects that were devoted to design, synthesize and evaluate novel compounds as kinase inhibitors. In a first project, employing structure-based docking methods, novel 7-aryl- or 7-heteroaryl-substituted 4-aminoquinazoline-6-carboxamide compounds were developed as inhibitors of class II phosphatidylinositol 4-kinases (PI4K2A/2B). A simple synthetic approach enabled the preparation and the functionalization of the 4-aminoquinazoline scaffold in six steps. Enzymatic evaluation for activity and selectivity against PI4Ks (i.e., PI4K2A and class III PI4Ks) highlighted several compounds with low micromolar potency and good selectivity against PI4K2A. Moreover, the binding mode of the new compounds in the conserved ATP-binding sites of class II PI4Ks was corroborated by X-ray crystallography. This suggests the applied rationale of the design can be a strategical option to obtain more potent and selective PI4K class II inhibitors, to conduct additional investigations on these kinases. In a second project, novel 4,6- and 4,6,7-substituted quinazoline...
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Synthesis of Alkaloid-like Compounds with Quaternary Carbon Centers
Jansa, Petr ; Matoušová, Eliška (advisor) ; Baszczyňski, Ondřej (referee) ; Nováková, Veronika (referee)
Synthesis inspired by natural products has a long tradition in drug development. Because the structure of bioactive natural compounds is often very complex, preparation of their derivatives requires the development of specific synthetic procedures. This thesis focuses on derivatives of certain alkaloids from the Amaryllidaceae plant family as examples of such compounds. The thesis explores the possibilities of preparing polycyclic compounds that contain the structural motif present in tazettine, crinine, or mesembrine-type alkaloids. This motif includes a quaternary all-carbon center, for which a method involving a tandem cyclization/Suzuki coupling reaction and a halocarbocyclization was developed and optimized in this work. The scope of these reactions was studied, and variously substituted products containing oxygen and nitrogen cycles were prepared. Furthermore, methods for the synthesis of N-alkylated derivatives, dehydrohalogenation to form a double bond, or various mainly oxidative modifications of the cycle adjacent to the aromatic ring were developed. After developing a method for the preparation of enantiomerically enriched starting material, an asymmetric version of the entire synthesis was successfully performed. Finally, biological properties of selected compounds were studied. Some...
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Synthesis of NIR Reductive Probes to Monitor Hypoxia During Fungal Infection
Kárníková, Tereza ; Baszczyňski, Ondřej (advisor) ; Míšek, Jiří (referee)
Invasive fungal infections represent a significant problem, resulting in approximately 1.5 million deaths worldwide annually. Among the most common invasive fungal infections are aspergillosis and candidiasis. Both opportunistic infections have a high mortality rate (50% and 27%, respectively). The diagnosis of these infections is often complex, leading to delayed detection and an increased risk of complications. Recently, near-infrared (NIR) hypoxia probes have been investigated for the diagnosis and monitoring of fungal infections. These probes enable non-invasive measurement of tissue oxygen concentration and can contribute to early diagnosis of fungal infections. Hypoxia can also be a relevant target for the delivery of antifungal agents. For this reason, a series of hypoxia-selective probes has been developed. These probes contain N-methyl-2-nitroimidazole and a fluorophore that absorbs in the near-infrared spectrum. We anticipate that probes will function as follows: the reducible breakdown of N- methyl-2-nitroimidazole in a hypoxic environment will activate the probe, leading to the release of the fluorophore, which absorbs in the near-infrared spectrum. Confocal microscopy will be used to observe whether the fluorophore is selectively released in the hypoxic environment or at the site of...
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N-heterocyclic carbene catalysis in enantioselective cycloadditions
Krejčířová, Kateřina ; Veselý, Jan (advisor) ; Baszczyňski, Ondřej (referee)
This diploma thesis deals with selected enantioselective cycloaddition reactions catalyzed by N-heterocyclic carbenes. First, we focused on studying the [4+3] cycloaddition reaction. Non-commercial ketimines were prepared as starting materials for the model reaction. Subsequently, the reaction between ketimines and salicylaldehyde was studied, where, despite all efforts, preparing the desired product was impossible. Furthermore, the [3+3] cyclization reaction was studied. Aminopyrazole and substituted α-bromenals were prepared for these purposes. However, while optimizing this reaction, the same concept was published. Finally, our attention was focused on the [3+2] cycloaddition reaction between α-bromenals and hydrazides derived from oxalic acid esters. Here, the reaction conditions were optimized, and the substrate scope was subsequently studied.
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Synthesis of fluorinated nucleosides
Nguyen, Van Hai ; Hocek, Michal (advisor) ; Baszczyňski, Ondřej (referee)
The key intermediate 6-amino-7-iodo-7-deazapurine 3'-deoxy-3'-fluororibonucleoside was synthesized using multistep sequence of several reactions, which started from the commercially available D-xylose and 6-chloro-7-deazapurine. The synthetic strategy was based on fluorination of sugar and glycosylation with corresponding nucleobase afterwards. The fluorination of 5-protected-1,2-isopropylidine xylose with different protecting groups at position 5 always led to elimination. It was later discovered that isopropylidine forces the conformation, which is unfavorable for substitution. During the extensive optimization it was also found out that DAST appears to be an optimal fluorinating agent. Fluorination was performed on 2,3-unprotected xylose, which was subsequently used for glycosylation. After several unsuccessful attempts on "protection group free" glycosylation, Vorbrüggen glycosylation was successful and gave desired 3'-fluoro nucleoside in good yield. However, benzoyl group had to be introduced into position 2'. The protected nucleoside was then aminated and simultaneously deproctected with solution of aqueous NH3 and 1,4-dioxane. The obtained key intermediate was used for synthesis of a small series of desired 6-amino-7-hetaryl nucleoside using Pd-catalyzed Suzuki reaction under aqueous...
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Synthesis of self-immolative linkers suitable for bioconjugation
Taraj, Lukáš ; Baszczyňski, Ondřej (advisor) ; Jindřich, Jindřich (referee)
Self-immolative (SI) linkers are chemical constructs that undergo controlled self- fragmentation based on an appropriate stimulus, e.g., activation by light or a chemical agent. SI linkers are used in the targeted delivery of drugs, in the construction of probes for biochemistry, or in various polymers. The aim of the thesis will be the synthesis of new phosphorus-based SI linkers, which will contain a reactive chemical function for conjugation with thiols. Such a function will be, for example, a vinyl phosphonate or alkynyl phosphonate group. The aim of the work will be to examine the synthesis, self-immolation, stability, and the possibility of conjugability of such linkers with thiols, e.g., cysteine, glutathione, etc. The content of the student's work will be the synthesis of SI linkers, analysis of the obtained data, planning and monitoring of chemical experiments, and writing the diploma thesis. Keywords: self-immolative, bioconjugation, phosphorus, drug delivery
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Synthesis and characterization of binding ligands for the study of targeted lysosomal protein degradation
Sidej, Natan ; Konvalinka, Jan (advisor) ; Baszczyňski, Ondřej (referee)
Targeted protein degradation is a novel concept of chemical biology that has been formulated about 20 years ago. Its central postulate is based on the fact that instead of suppressing protein activity with low-molecular inhibitors, we can instead use molecular tools to hijack the host organism's own degradation pathways and force it to degrade chosen proteins by itself. This diploma thesis revolves around the preparation of biocompatible polymeric conjugates called "iBodies" that will be used to induce targeted lysosomal degradation of two model enzymes - Fibroblast activation protein α, and Glutamate carboxypeptidase II. First, a total of four low-molecular ligands were prepared and fully characterized by standard methods of organic synthesis. The first two are mannose-6-phosphonate derivatives that serve as the inducers of protein degradation via the cellular endosomal-lysosomal degradation pathway. The remaining two are known potent inhibitors of the chosen model enzymes that will serve as their targeting-ligands. The prepared compounds were then used to prepare a total of eight poly-N-(2-hydroxypropyl)methacrylamide conjugates called iBodies, after which the polymeric conjugates were fully characterized by standard means of macromolecular chemistry. Afterwards, the obtained conjugates will be...
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Methionine synthase as a potential therapeutic target
Kellovská, Kristýna ; Baszczyňski, Ondřej (advisor) ; Snášel, Jan (referee)
This thesis focuses on the enzyme methionine synthase (MS), which catalyzes methylation of homocysteine to produce methionine. Two main families of these enzymes are recognized in nature - cobalamin-dependent and cobalamin-independent. These two enzymes share no sequence homology, and they also use different catalytic mechanisms, substrates and cofactors. Cobalamin-dependent MS is found in humans, whereas cobalamin-independent MS is typical for plants and fungi. In humans, the enzyme provides a connection between folate and methionine cycle - two metabolic pathways which are crucial for example for DNA synthesis and S-adenosylmethionine-dependent biological methylations. Recently, the enzyme has been recognized as a potentially promising target for the development of chemotherapeutics and antifungal drugs, mainly based on its essentiality for the proliferation of cancer cells and both viability and virulence of pathogenic fungal species.
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Development of New Approachs to Selaginpulvilins
Beytlerová, Nela ; Kotora, Martin (advisor) ; Baszczyňski, Ondřej (referee)
The objective of this diploma thesis was application of catalytic [2+2+2]cyclotrimerization of alkynes induced by transition metals complexes in synthesis of selaginpulvilins O and S -natural products with the fluorene scaffold. Selaginpulvilins are bioactive natural compounds present in the Asian plants from Selaginella genus. Their isolation and structure determination was reported for the first time by Yin et al. in 2014.1 The plants are used in traditional Chinese medicine for treatment of asthma and chronic pneumonia disease. The integral part of the project was a study to assess efficacy of various transition metal catalysts and catalytic systems, solvents, reaction temperatures and reaction time on the course of the cyclotrimerization reaction. Synthesis of a suitable precursor for the cyclotrimerization step was achieved from commercially available 2-bromo-5- hydroxybenzaldehyde (153) as that starting compound. The total formal synthesis of selaginpulvilins O and S were completed by conversion of cyclotrimerization product. Key words: [2+2+2]cyclotrimerization; selaginpulvilin O; selaginpulvilin S; fluorene core; transition metal catalysis
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Derivatives of N-acetylglucosamine-1-phosphate as potential inhibitors of UDP-GlcNAc pyrophosphorylase
Černá, Lucie ; Baszczyňski, Ondřej (advisor) ; Veselý, Jan (referee)
This bachelor thesis deals with the preparation of phosphonate derivatives of N-acetyl- ᴅ-glucosamine-1-phosphate (GlcNAc-1-P), the substrate for UDP-GlcNAc pyrophospho- rylase (UAP1) enzyme, which is responsible for the chitin synthesis in fungal cell walls. Structural analogs of GlcNAc-1-P could potentially inhibit UAP1 and; therefore, their synthesis may enable the development of new antifungal drugs. This work is mainly focused on the synthesis of diethyl (2-acetamido-1,2-dideoxy-β-ᴅ-glucopyranosyl)phosphonate which was selected as a key model compound. The goal was to find the most suitable synthetic route leading to the synthesis of phosphonate and phosphinate GlcNAc-1-P analogues. Two synthetic methods were studied: 1) Michael addition of H-phosphonates to 2-nitroglucals; and 2) nucleophilic substitution of activated GlcNAc substrates (trichloroacetimidate and bromide) by phosphorus nucleophiles. Keywords: GlcNAc-1-P, UDP-GlcNAc pyrophosphorylase, antifungal, inhibitor
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