čas: 23.4.2021 00:09:49
Obnovit | RAW
Department of Chemistry of Natural Compounds
List of available PhD theses
Approaches to the Total Synthesis of Fumiquinazoline-Based Pyrazinoquinazoline Alkaloids and Analogs
In this project, short and bioinspired synthetic approaches to complex fumiquinazoline-based pyrazinoquinazoline alkaloids will be developed. The total syntheses will be modular and aimed at investigating their biological profiles in collaboration. Small focussed libraries of analogs are envisaged to complement the total syntheses of the natural products.
Approaches to the Total Synthesis of Glyantrypine-Based Pyrazinoquinazoline Alkaloids and Analogs
In this project, short and bioinspired synthetic approaches to complex glyantrypine-based pyrazinoquinazoline alkaloids will be developed. The total syntheses will be modular and aimed at investigating their unknown biological profiles in collaboration. Small focussed libraries of analogs are envisaged to complement the total syntheses of the natural products.
Comprehensive approach to structural analysis of novel polycyclic diterpenes from termites
Termites are the group of insects with the richest repertoire of defensive chemicals. They are especially famous for the production of roughly one hundred different polycyclic diterpenes with variable topologies of double bonds combined with different oxygenated moieties attached to bi-, tri- and tetracyclic diterpene skeletons. In spite of the extensive quest for new termite diterpenes during the past decades, large part of their structural richness remains undiscovered. The proposed PhD. project focuses on chemical diversity of polycyclic diterpenes in the so-called Subulitermes group of species from South America, in which we recently unveiled an unexpected repertoire of diterpenes structures. The project will address the diterpene diversity as a tool for chemical taxonomy on the one hand, and an opportunity to fully identify structures of new and complex natural compounds on the other hand. The first goal will be to characterize individual species based on combination of characteristic chemical profiles with mitochondrial DNA sequences, to identify new species, to discriminate cryptic species, and ultimately to build phylogenetic hypotheses on their relationships. The knowledge on the overall diterpene diversity will serve as a basis for the second goal of the project, which will combine traditional analytical workflow with modern approaches and computational tools to fully characterize the molecular structures in a maximum of detected diterpenes.
Crystalline sponge method
Our lab combines cutting-edge experimental (e.g., LC-MS, metabolomics, RNA-seq) and computational (e.g., bioinformatics, molecular networking, machine learning) approaches to develop rapid, generally applicable workflows for the discovery and utilization of bioactive molecules derived from plants. We are looking for talented and motivated chemist with a strong experience in small molecule X-ray crystallography. The successful candidate for this position will be developing protocols for the “crystalline sponge” structure elucidation method and applying them to various plant natural products, particularly terpenes.
Design and synthesis of inhibitors of purine nucleoside phosphorylases – SAR study
We have recently prepared a novel type of acyclic nucleoside phosphonates as potent inhibitors of human purine nucleoside phosphorylase (hPNP). Such compounds may have potential to treat various T-cell leukemias. In order to select suitable candidates for preclinical evaluation, the goal is design and synthesis of a larger amount of derivatives and evaluation of their biological properties. The synthesis of potential PNP inhibitors will be developed and optimized.
Design and synthesis of novel photoswitches derived from heteroarylazobenzenes and bis-azobenzenes
We have recently reported synthesis of variously substituted 5-phenylazopyrimidines (see references for more information). Their physicochemical properties were studied using in situ irradiation NMR spectroscopy and optical spectroscopy. The goal of the current project will be synthesis of novel molecular photoswitches based on a combination of bis-azobenzenes and pyrimidines (and other heterocycles), namely bis(pyrimidinyldiazenyl)benzenes. Their synthesis will be developed/optimized and their physicochemical properties will be studied.
Design and synthesis of novel prodrugs of acyclic nucleoside phosphonates
Acyclic nucleoside phosphonates (ANPs) represent an important class of antiviral agents. The phosphonate group is deprotonated at physiological pH and, thus, ANPs are polar molecules unable to effectively penetrate into cells. Prodrugs of ANPs help to overcome this obstacle. The goal of the project will be design and synthesis of novel prodrugs of ANPs and study of their properties.
Development of new chemical tools to study cell-cell interactions
Cell-cell interactions play an important role in a myriad of biological processes. These interactions enable cells to communicate, respond to changes in the environment and are involved in many pathologies including cancer. Despite their importance, our ability to study the molecular details and nature of these interactions is still very limited. In this project, we will employ chemical glycoengineering in combination with biocompatible chemical crosslinking reactions to capture, identify and study biomolecules involved in these interactions. This project aims to elucidate the complexity of cell-cell interactions and shed light on individual proteins involved in the process. The ideal candidate should have interest in organic chemistry, chemical biology and related fields.
Identification of new psychoplastogenic compounds through structure-activity relationship studies as potential neurochemical tools for investigating human cognition
Objectives of this research project are to discover and synthetize novel chemical compounds with potential psychoplastogenic properties to be used as tools for neuroimaging studies elucidating their underlying neurobiological mechanisms. Using structure-activity relationship investigations of already known and described psychoactive compounds primarily of the tryptamine and phenethylamine classes, this project aims to design and develop synthetic routes for their new analogues and to identify suitable substances for pharmacological and neurobiological investigations. Their biological activity will be tested within international collaboration for their interaction with monoamine receptors and transporters, cytotoxicity, and effects on growth of neuronal cells (by monitoring the BDNF factor). Selected compounds will be subjected to preclinical studies in animal models, especially with the use of behavioral tests and imaging methods such as EEG, fMRI and in the case of isotopically labeled substances also with PET.
Modified DNAzymes and DNA origami
We will design and synthesize modified deoxyribonucleoside triphosphates bearing functional groups or ligands for complexation of metals. They will be used for enzymatic synthesis of modified oligonucleotides which will be applied in selection and construction of functional DNAzymes or DNA origami.
New deazapurine nucleosides and nucleotides as potential antivirals or cytostatics
We will design and synthesize new modified deazapurine nucleosides, nucleotides and prodrugs as inhibitors of polymerases or other enzymes of nucleotide metabolism, or as ligands (agonists or antagonists) of nucleotide receptors. Selected active compounds will be further optimized in order to identify preclinical candidates for development of potential antiviral or antitumour agents.
New heterocyclic inhibitors of selected protein kinases
We will design and synthesize modified heterocyclic compounds as inhibitors of selected protein kinases that are relevant targets for potential therapeutics of tumours or neurodegenerative diseases. A combination of rational design, synthesis of combinatorial libraries and optimization of hits will be used.
Novel glycomimetics as inhibitors of galectins
Carbohydrates are structurally diverse group of natural products which play an important role in numerous biological processes, including immune regulation, infection, and cancer metastasis. Unfortunately, native carbohydrates suffer from inherently weak binding affinities and poor pharmacokinetic properties. To enhance their potential as drug candidates, glycomimetics have been developed. They are more drug-like compounds, which mimic the structure and function of native carbohydrates. However, the advancement in carbohydrate research is relatively slow due to the problems associated with the complexity of carbohydrates structures and the lack of general synthetic methods. This problem could be solved using photoinduced chemistry under catalytic conditions. The use of photocatalysis is heading towards “greener” chemistry, where enhanced synthetic efficiency through the reduction of unnecessary waste is attained. The goal of the PhD project will be the development of synthetic methodologies for the preparation of various biologically prospective glycomimetics with affinity towards galectins (Gal-1, Gal-3, Gal-7), which are involved in many physiological functions, such as inflammation, immune responses, cell migration, autophagy, and signaling.
Study of natural biologically active substances transport through membrane systems
This research work will deal with studies of biological membranes (skin, cornea, blood-brain barrier) in terms of their permeability to a number of natural biologically active substances with neuropsychopharmacological potential. Emphasis will be placed on the development and preparation of formulations containing CBD, THC derivatives and neuroactive steroids with suitable transport carriers across the skin, cornea and blood-brain barrier. The quantity of permeated substances and the changes in membranes caused by the passage of active substances and their carriers will be monitored. Commercial Franc diffusion cells will be used for the in vitro model of transdermal transport. The wok will also include the development of a new diffusion cell for transcorneal transport. The permeation of substances across the blood-brain barrier will be monitored by their pharmacological studies in the animal model with Wistar rats. An advanced separation technique coupled with mass spectroscopy will be used for the pharmacological study. Vibrational spectroscopy techniques will serve as advanced tools for the investigation of structural changes and the distribution of substances in membranes. The research will be carried out in cooperation with the International Eya Bank of Prague and the National Institute of Mental Health.
Study of the photocatalytic degradation of organic polutants from wastewater
The work is focused on the utilization of liquid chromatography coupled to mass spectrometry to measure kinetics of photocatalytic degradation of selected biologically active pollutants in wastewater. Analytical methods elaborated in frame of the project will be further utilized for the identification of ultratrace quantities of degradation products. In silico prediction will be used to determine the degradation products and correlated with experimental data. The biological activity and possible toxicity of the products resulting from the photocatalytic degradation will be assessed in collaboration with the Institute of Experimental Medicine AV ČR.
Synthesis and application of ligands for P2X7 receptor imaging
The development and application of organelle-targeted bioorthogonal cleavage reactions
Chemical reactions that can be performed under physiological conditions offer unique possibility to manipulate and study biological processes. Our group has a long-term interest in these, so-called, bioorthogonal reactions. They are mainly known as efficient chemical transformations leading to formation of covalent bonds. It has been only recently when the concept was extended to something what is known as bioorthogonal cleavage reactions. The power of this type of reactions is only slowly becoming recognized. In this project, we aim to develop and employ the release reactions, which will enable de-caging of small molecules within specific cellular compartments. We believe that such systems will offer not only a unique possibility to deliver and activate functional molecules within particular subcellular location, but in a broader sense, to shed light on the function of individual cellular organelles. This project combines organic chemistry with modern chemical biology experiments.