Eligible for Fischer stipend

Multi-phytohormone analysis in different Ri plants
Supervisor: prof. Mgr. Ondřej Novák, PhD.

Study of plant morphogenesis at the (sub)cellular level
Supervisor: prof. Mgr. Ondřej Novák, PhD.

Natural products and their derivatives with anthelmintic aktivity
Supervisor: doc. RNDr. Jiří Pospíšil, Ph.D.

Synergistic and antagonistic effects of small organic compounds of natural origin on plant growth
Supervisor: doc. RNDr. Jiří Pospíšil, Ph.D.

Natural products: synthesis and study of their synergic interactions in living systems
Supervisor: doc. RNDr. Jiří Pospíšil, Ph.D.

Studium metabolismu methioninu a příbuzných sloučenin v rostlinách
Supervisor: Mgr. Michal Karady, PhD.

Uncovering subcellular pathways for phytohormone homeostasis in land plants
Supervisor: Federica Brunoni Ph.D.

Design and synthesis of novel heterocyclic compounds with potent antimicrobial activity
Supervisor: Doc. RNDr. Lucie Brulíková, Ph.D.
The increasing prevalence of microbial infections and the emergence of resistance to the currently available antimicrobial drugs requires the development of new chemical entities with an alternative mechanism of action to existing therapeutics directed toward unknown targets. The main goal of the thesis will be the design, synthesis and biological activity studies of novel antibacterial and antiparasitic agents. This work will cover the novel compounds design based on the molecular docking studies, their synthesis and optimisation of reaction sequences. Further, this project deals with biological testing. Moreover, these studies will be complemented with enzymatic assays. Final compounds will be further modified according to biological activity testing. Alternatively, a new pharmacophore will be investigated.

Axially Chiral Heterocyclic Compounds with Potential Application in the Area of Organocatalysis, Chiral Derivatization Agents, and Inhibition of Protein Kinases
Supervisor: doc. RNDr. Petr Cankař, Ph.D.
Axial chirality of organic compounds is often described for the ortho-substituted biaryl compounds, where is a single bond joining both aryls with restricted rotation. This bond lies on the chiral axis. In case, the energy barrier of restricted rotation is sufficiently high, it is possible to synthesize and isolate atropisomers for a variety of practical applications. Initially, the attention to atropisomerism was inadequate, since the first isolated atropisomers were not sufficiently stable for practical use. In the recent 20 years, there is a renaissance of the use of axial chirality for organic compounds; especially in organocatalysis and also medicinal chemistry in the last decade. The main reasons are novel opportunities in the spatial arrangement of molecules.
The goal of the Ph.D. thesis will be the synthesis and study of axially chiral heterocyclic compounds, which allow novel various spatial interactions by functional groups and heterocyclic systems for stereoselective organocatalysis or inhibition of protein kinases. Alternatively, another research area can be the use of axially chiral compounds as derivatizing agents for the analysis of stereoisomers and their mixtures.

Tunable non-covalent interaction-based catalysts for stereoselective reactions of iminium and oxonium intermediates
Supervisor: doc. RNDr. Jiří Pospíšil, Ph.D.
Anion-binding catalysis is a fast-growing but very challenging field of organic asymmetric synthesis. The principle of such transformation is fairly simple: the chiral catalyst scavenge/recognizes the anion (generally the chloride anion) and then exerts precise geometric control on the prochiral reaction site. However, the selectivity of the transformation does not rely on interactions with the variable substituents on the substrate. Criteria seem simple, but are not easy to fulfil, and so it is not surprising that only a few so-called 'privileged' molecular scaffolds can meet them. In our proposal, we introduce the novel molecular scaffold for asymmetric catalysis that has not been evaluated before, 1,3-diazetidin-2-one (DAZDO), as a new privileged molecular scaffold for asymmetric catalysis. To prove our concept, we developed DAZDO catalysts that are able to generate oxonium and iminium intermediates in situ and allow them to react with various C-nucleophiles with high stereoselection. Our concept and catalysts will be applied to the total synthesis of selected natural products. Aims of the project: (1) to develop a new generation of anion-binding organocatalysts based on the diazetidinone molecular skeleton (DAZDO); (2) to demonstrate the use of DAZDO catalysts in the context of natural product synthesis (stereoselective addition of C-nucleophiles to iminium and oxonium cyclic intermediates).

Tunable organocatalysts based on Lewis acid-enhanced non-covalent interactions
Supervisor: doc. RNDr. Jiří Pospíšil, Ph.D.
Hydrogen bond-donating (HBD) organocatalysts have recently gained a privileged place in the field of asymmetric synthesis. The activation of the substrates by HBD catalysts is based on multiple weak interactions, and therefore the concept of 'more, better' is applied. The common way to overcome such drawback is to develop catalysts that can form stronger HBD interactions or to multiply the number of them. However, recent advances in the description of substrate activation by catalyst, which introduced the Pauli repulsion-lowering concept, raised the possibility of a new method to overcome such a drawback. We introduce a novel molecular scaffold for asymmetric catalysis that has not been evaluated before and explore the use of the concept of Pauli repulsion-lowering activation. Our TCRP catalyst is built up around the thiourea HBD bidentate catalyst system, but further explores fine-tuning of the HBD abilities via the adjacent aryl groups and coordinated Lewis acid metal. TCRP catalysts are modular, allow fine-tuning of HBD abilities, and have a readily available source of chirality. We expect that the TCRP scaffold will become a new privileged scaffold in catalyst design. Goals of the project: (1) to develop organocatalysts based on non-covalent interactions enhanced by Lewis acid and the principle of Pauli repulsion-lowering (TCRP); (2) Demonstrate the use of TCRP catalysts in the context of organic synthesis (cycloaddition, epoxide opening, spirocyclization).

Synergy effects between polyketide natural products and peptides – total synthesis of polyketide natural products and their biological evaluation
Supervisor: doc. RNDr. Jiří Pospíšil, Ph.D.
The synergistic pharmacological effect of various drugs and/or natural products is a very important topic of pharmacology today. In many cases, clinicians observe synergistic effects when using a mixture of prescribed drugs with different modes of action and/or designed to treat various, often non-related illnesses. Such observations are in most cases based on empirical bases, and no relevant scientific follow-up is made to determine what happens in the human body. However, since recently, several natural drugs with expected/observed biological activity, eg, against bacteria or fungi, were used in the presence of certified drugs with known mode of action and the synergy effect was examined in detail. In this project, we are interested in two main goals: 1) total synthesis of selected natural products of polyketide origin; 2) to study the possible synergy effect between selected polyketides (either of natural or unnatural origin) and known polyaminoacid-based drugs (e.g. antibiotic drugs).

Synthesis and study of nitrogenous heterocycles as ligands for various biological targets
Supervisor: doc. RNDr. Miroslav Soural Ph.D.
Nitrogenous heterocycles represent a very important group of organic compounds. They form a common structural motif in a number of natural or synthetic, biologically active substances. Approximately 60% of drugs that have been approved for clinical use to date contain a nitrogen heterocycle in their structure. For this reason, nitrogenous heterocycles are an attractive chemotype in the field of medicinal chemistry. A number of heterocyclic derivatives have been prepared that exhibit a variety of biological effects, such as antibiotic, antibacterial, antifungal, antitumor, antiviral, analgesic, etc. If the biological target is known, a rational design of new analogues is possible to find analogues more advantageous pharmacological properties, e.g. higher activity, selectivity and metabolic stability. The aim of the dissertation is to search for new heterocyclic drugs based on standard procedures: 1) biological target selection and structural design of potential ligand (typically using scaffold hopping approach or molecular docking), 2) development and optimization of synthetic method to prepare target scaffold , 3) preparation of a series of substituted derivatives to study the structure-activity relationships, 4) primary testing and evaluation of SAR, 5) further rational structure modifications using the information obtained, leading to advanced derivatives and their pharmacological evaluation. The specific structural motives will be determined on the basis of the current results of the research group. At present, attention is paid mainly to cytotoxic compounds acting against tumor cells and derivatives oriented to biological targets located in the central nervous system. The biological evaluation is carried out in cooperation with the Department of Experimental Biology, the Institute of Molecular and Translational Medicine and the Jagiellonian University in Krakow.

Modification of pentacyclic triterpenoid molecules in the E and A ring region and study of their anticancer and neuroprotective activity.
Supervisor: doc. RNDr. Milan Urban, Ph.D.
Triterpenoids are natural compounds with a number of biological activities, at our research group we are mainly concerned with compounds with cytotoxic and related anticancer activity. The most active derivatives have IC50 values in the low micromolar to submicromolar range which, in the context of low toxicity, would predispose these molecules to become anticancer therapeutics. Lupane derivatives in particular are highly cytotoxic and have therefore received particular attention. A second area of interest is triterpenes with neuroprotective activity, which show significant protective effects in cellular models of Parkinson's and Alzheimer's disease.The main problem with active triterpenes is their high lipophilicity, low water solubility and associated lack of bioavailability when administered orally. For some neuroprotective compounds, the downside is their excessive cytotoxicity. One possibility to modify these undesirable properties is the preparation of prodrugs. Despite great efforts to find optimal prodrugs, the results of this research have so far been rather partial.
In the framework of this work, new compounds will be prepared mainly by a series of different oxidation reactions, halogenations, cross-couplings, cycloaddition reactions, etc. with the main aim to find molecules with better selective cytotoxic activity or neuroprotective activity than previously prepared derivatives.  For all new derivatives, the values of both biological activities will be measured and based on the results, suitable candidates will be selected for further development in one or the other activity category from which further derivatives will be synthesized with respect to pharmacological parameters, especially solubility, toxicity and bioavailability. For this purpose, previously developed procedures for the preparation of prodrugs will be used, but new alternatives will also be sought. It is anticipated that several series of derivatives will be prepared in the course of the work and will be fully characterised and tested for their biological activities. The results should show the effect of the different modifications and prodrug groups on activity and pharmacological properties, especially bioavailability and metabolism. The work should lead to the formulation of structure-activity relationships. All syntheses will go hand in hand with biological screening and feedback from this testing will guide the direction of syntheses towards optimised molecules suitable for anticancer drug development.