Chemistry and chemical biology of carbohydrates and heterocycles | Kémiai Tudományok Doktori Iskola

Doctoral program (K5) of the Doctoral School of Chemistry at the University of Debrecen

Leader of the program: Somsák László full professor

Main areas of reserch

• Synthesis of carbohydrate containing compounds of natural origin and their core scaffolds.
• Design and synthesis of glycomimetics and enzyme inhibitors.
• Study of mechanisms of action of glycoenzymes.
• Investigation of carbohydrate–protein interactions by up-to-date instrumental methods.
• Synthesis, selective transformations and structural elucidation of potentially pharmacologically active natural O-heterocycles (e. g. flavonoids, chromonoids, coumarins), their sulfur-containing analogues and O,N-heterocycles.

Background

More than half of the known organic compounds are derivatives of heterocycles, the heteroatom being nitrogen, sulfur, and oxygen in most of them. Heterocyclic compounds form the basic scaffold of numerous pharmacologically important families of compounds of natural origin e. g. flavonoids, alkaloids, antibiotics, and they play fundamental roles in biochemical processes of living organisms. The majority of active ingredients of natural and synthetic drugs as well as agrochemicals contain at least one heterocycle whose preparation in an efficient and stereoselective manner is a major challenge for synthetic organic chemistry. 

Carbohydrates (glycans) – the most widespread compounds with the biggest mass on Earth – also appear as heterocycles. The study of carbohydrates, due to the high number of functional groups and stereogenic centres as well as their biological properties, is a more or less separate domain of organic and biochemistry, however, because of mutual interactions with other fields of science (e. g. analytics, biomedicine, materials science) the formation of a complex approach called glycoscience can be seen nowadays. 

Glycobiology, studying the biological roles, biosynthesis and biotransformations of carbohydrates, has demonstrated the key roles of sugar derivatives and their conjugates (e. g. glycoproteins and glycolipids) in a range of fundamental biological, first of all recognition processes. The fast development of this field and that of glycoscience in its broadest sense is continuing and takes new impetuses from the perfection of analytical, separation, and structural elucidation methods. Similarly to other „omics” fields, the systematic study of the whole assembly of carbohydrates (glycans) of a cell or even an organism (the glycom) has been the subject of „glycomics”. 

Biological roles of heterocycles and carbohydrates are most frequently realized by their interactions with macromolecules e. g. proteins recognizing or/and transforming (small) molecules or inducing immune responses (receptors/lectines, (glyco)enzymes, antibodies, respectively). Investigation of such interactions is also the subject of chemical biology. In these studies a function of a biological system is „perturbed” by small molecules in vitro or in vivo and the observed „responses” may give informations on essential properties of the system. Such knowledge can be utilised among others in drug design. 

Based on the aforementioned background, important research fields can be derived for synthetic carbohydrate and heterocyclic chemistry: preparation of natural products (e. g. oligosaccharides, glycoproteins, glycolipids, alkaloids, antibiotics) and/or their essential constituents (e. g. N- and O-glycosylated amino acids, -peptides, heterocyclic scaffolds); synthesis of mimetics (compounds analogous to natural products in their structure and/or biological effect e. g. C-glycosyl derivatives, neoglycoconjugates, glycodendrimers, vaccines, bioisosteric compounds); design and synthesis of inhibitors offering the possibilities of intervention in natural processes. 

Education and research offered in this doctoral program

Research topics

• Elaboration of protecting groups for carbohydrates, their application for the synthesis of biologically active oligosaccharides.
• Utilization of cyclodextrines for the preparation of linear glycoside derivatives.
• Synthesis of N-glycans and N-glycopeptides.
• Transformation of the anomeric centre of carbohydrates by radical-, carbanion-, and carbene-mediated reactions.
• Design and synthesis of glycomimetics (e. g. sugar sulfonic acids, compounds with non-classical glycosidic bonds, C-glycosyl derivatives, neoglycoproteins, carbohydrate–amino acid hybrides), inhibitors of glycoenzymes (e. g. glycoside hydrolases, neuraminidases, glycosyl transferases, glycogen phosphorylases).
• Binding site mapping of glycoenzymes, investigation of their active sites and mechanism of action.
• Enzyme-catalyzed syntheses.
• Study of carbohydrate–protein interactions by MS, ITC and NMR methods.
• Stereoselective syntheses and transformations of benzo-condensed chiral heterocycles (e. g. chroman, isochroman, 1,4-benzodioxan, benzoxazepin), study of the above reactions by combinations of chiroptical spectroscopy, X-ray diffractometry and NMR methods).
• Investigation of domino reactions towards multicyclic, condensed and bridged heterocycles.
• Applications of special ring-closing reactions (e. g. oxa-Pictet-Spengler, intramolecular oxa-Michael, hetero Diels-Alder) for the syntheses of heterocycles.
• Investigation of metal-catalyzed and metal-free cross-coupling reactions for the formation of C-C and C-N bonds (e. g. Suzuki-Miyaura-, Heck-Mizoroki, Sonogashira-, Buchwald-Hartwig- and Ullman-couplings) for the preparation of natural products, hybrids of O-heterocycles and amino acids, peptides, carbohydrates, study of stereochemical properties of the products of the above reactions.
• Investigations into chemo- and regioselectivity issues of substrates with multiple leaving groups.
• Cross-couplings of O-heterocycles based on C-H activation.
• Synthesis of biologically active heterocycles (e. g. SSAO inhibitors, HSP co-inducers).

The particular research topics for PhD studies may vary year by year. These are generally characterized by complex investigations of chemical, biochemical, and chemical biological aspects of the topics and applications of a broad arsenal of analytical and structural elucidation methods. 

PhD courses