Chemistry of carbohydrates and heterocycles subproject
subproject leader: Dr. László Juhász
I. Structure of the subproject
1. Carbohydrates WG
group leader: Prof. Dr. László Somsák
2. Oligosaccharides WG
group leader: Prof. Dr. Anikó Borbás
3. He terocycles WG
group leader: Prof. Dr. Tibor Kurtán
II. Scientific goals
1. Transformations of carbohydrate derivatives into lead compounds applicable for the treatment of metabolic, neurological, heart and cardiovascular disorders, cancer and microbial diseases
a. Glycoenzyme inhibitors as drug candidates
The inhibition of glycoenzymes relevant for various diseases may facilitate therapeutic interventions.
The pharmacological inhibition of glycogen phosphorylase (GP) may lead to a novel approach for the treatment of type 2 diabetes. Inhibitors of GP are also considered to have potential in treating cerebral and myocardial ischemias, other cardiovascular disorders and tumors.
The OGT and OGA enzymes play a role in the post-translational modification of proteins by attaching/detaching N-acetyl-D-glucosamine (O-GlcNAc) units to/from serine and threonine OH-groups of the polypeptide chain. The disregulation of this process is linked among others to cardiovascular disorders, type 2 diabetes, erectile disfunction, retinopathy, Alzheimer’s disease and the activation of some heat shock proteins.
New inhibitors of these enzymes will be designed by using structure-based inhibitor design utilizing crystallographic and/or NMR structure elucidation of the proteins and computer aided molecular docking. For the syntheses of these derivatives the development and study of new synthetic methodologies are also necessary (for example transformations of 1-C-substituted glycals and exo-glycals; cross-coupling reactions of the carbohydrate derivatives, synthesis of spirocyclic – and C-glycosyl derivatives).
b. Antiadhesion therapy by multivalent carbohydrates.
The early steps of bacterial and viral infections involve recognition and binding between cell-surface carbohydrates on the host cells and specific carbohydrate binding proteins (e.g. lectins, adhesins) of pathogens. Synthetic analogues of these oligosaccharides can be applied in antiadhesive therapy against infections caused by multidrug-resistant bacteria or by influenza virus strains resistant to neuraminidase inhibitors. Synthesis and antiviral evaluation of self-assembling multivalent sialic acid derivatives as potential inhibitors of influenza hemagglutinin will be carried out. Multivalent carbohydrates displaying various mono and disaccharide units will be prepared and tested against bacterial lectins to develop antibacterial agents or diagnostics.
c. Anticoagulant oligosaccharides
Synthesis of heparinoid oligosaccharides and their isosteric sulfonic acid derivatives will be performed and their anticoagulant and antimetastatic properties will be evaluated.
d Carbohydrates against parasites.
Some sulfur and selenium containing carbohydrate derivatives were shown to exert biological activities against Trypanosoma protozoa causing Chagas’ disease and African sleeping sickness. Novel derivatives will be synthetized to optimize the above effects and to study their binding to lectines and other proteins by isothermal titration calorimetry (ITC) and NMR methods.
2. Synthetic and stereochemical studies in the field of heterocycles and natural products with neuroprotective, antiproliferative, antidiabetic and antiobesity activities
a) Synthesis of heterocycles and study of their cross-coupling reactions.
Chiral benzannelated O-, N- and O,N-heterocycles are to be prepared for application against Alzheimer’s disease, for selective inhibition of protein phosphatase 1B (PTP1B, against type 2 diabetes and obesity), as well as for human in vitro antiproliferative studies. O-heterocycles substituted with alkenyl, aryl, heteroaryl, alkyl- and arylamino groups will be prepared with catalytic cross-coupling reactions for antiproliferative and antifungal studies.
b) Stereochemical studies of heterocyclic derivatives.
For the exploration of structure-activity relationships and the design of more active agents, the combination of chiroptical (OR, ECD, VCD) and computational chemistry methods will be applied for the tasks outlined below:
determination of the stereochemistry of pharmacologically active derivatives
determination of the absolute configuration of bioactive synthetic derivatives
comparison of the geometries of solution and solid-state conformers by means of solid-state ECD and VCD studies
III. Expected results
Based on the outcomes of the synthetic, structure elucidation and chemical biology studies, this project may result in new methodologies and basic knowledge for carbohydrate / oligosaccharide and heterocycle synthesis. Hopefully, new, more efficient lead compounds and drug candidates, with the potential to be further developed to useful therapeutic agents, will also be identified.
The results of the research will be incorporated into our educational programs.
IV. Infrastructure
Instruments to be purchased within the framework of the project:
ChirallR-2x MIR FT-VCD
With the acquisition of the instrument, the stereochemical/chiroptical laboratory is developed further to approach the international level of the field. The instrument supplements the presently available chiroptical instruments and quantum chemical computational potential of the University of Debrecen and enables the team to reach new scientific achievements in the field of stereochemical studies.
Jasco V-750 UV-VIS spectrometer
The UV-VIS spectrometer is one of the first tools for the structure elucidation of new compounds. Being an easy to use, cheap and fast tool, it offers an effective method for the design of further synthetic or spectroscopic investigations. The obtained results give possibilities to design better methods in chromatographic separations or to improve the preparation efficiency of a desired compound. The instrument can easily be applied to maintain the quality of the education.
Jasco P-2000 polarimeter
The determination of stereochemical properties is an indispensable part of characterization of organic compounds. The polarimeter is a useful tool for getting information about the configuration of compounds. It is a fast analytical method for monitoring the optical yield of a chemical reaction in the early state of research. Lots of data are available in the literature on the optical rotation of organic compounds, therefore, their comparison to the measured data offers an easy identification method.
Agilent 1260 Infinity ELSD_DAD
It is a combined HPLC system for analytical and preparative purposes with dual detection facility by using UV and ELSD detection in a parallel way. The system is capable to resolve 1 to 5 grams of compounds, it is unique in our Institute. The analytical mode of the system with the software gives the possibility for an automatic scale-up of analytical separations to preparative scales. The universal detection capabilities support the optimal separation for every research group of this project. The high throughput separation technique opens the way to obtain previously hardly available or expensive pure products. The column diversity gives the possibility to separate mixtures of enantiomeric compounds to optically pure isomers. This is the fastest way to obtain pure enantiomers from their mixture. This is also the best way to get desired amount of compounds with high purity for biological studies.
Preparative HPLC is a well-known method in daily use in the industry so the implementation of this method in the education facilitates to deliver more valuable knowledge for the students.
Asia 220 flow chemistry system
With the acquisition of the flowchem instrument the organic synthetic methodologies are developed to a higher level. The desired syntheses can be carried out faster and more efficiently, the transformations can be studied in microreactors or in larger scale by using tube reactors (solid and/or liquid phase), too. This equipment can be used in several fields of the preparative organic chemistry. We plan to study the applicability of this technique in the field of carbohydrate chemistry in details, which is one of the less studied area in the literature.