Projects / Programmes
Chemistry and structure of biologically active compounds
January 1, 2009
- December 31, 2014
| Code |
Science |
Field |
Subfield |
| 1.04.00 |
Natural sciences and mathematics |
Chemistry |
|
| 1.05.00 |
Natural sciences and mathematics |
Biochemistry and molecular biology |
|
| Code |
Science |
Field |
| P390 |
Natural sciences and mathematics |
Organic chemistry |
| Code |
Science |
Field |
| 1.04 |
Natural Sciences |
Chemical sciences |
chiral molecules, asymmetric synthesis, chiral catalysts, NMR spectroscopy, structure, conformation, oligonucleotides, G-quadruplex, RNA interference
Researchers (23)
Organisations (2)
Abstract
The research program represents a synergy of activities and plans of two research groups- synthetic and structural, and includes synthesis of biologically active compounds and new synthetic approaches for their preparation as well as exploration of their structure. One part of research consists of studying of catalytic transformations, synthesis of new ligands and their metal complexes (catalysts). Our main interest is in the development of catalysts for two industrially important synthetic transformations: asymmetric reductions and C-C bond formation. Such transformations are commonly used in the synthesis of biologically active compounds and can also be used in the synthesis of modified oligonucleosides. NMR spectroscopy will be a useful tool in structure elucidation of catalysts and intermediates as well as in the studies of reaction mechanisms with purpose to improve synthetic techniques. Second part of research activities involves chemical identification and conformational studies as well as 3D structure determination. Knowledge of 3D structure can contribute to our understanding of the roles of nucleic acids such as guanine-quadruplexes and short synthetic RNA molecules which have been shown to silence particular gene through RNA interference. 3D structure and insight into intermolecular interactions with atomic resolution are very useful for prediction, interpretation, modification and design of their functions.
Significance for science
Up till now, very little is known about structural features of G-quadruplexes, which are made of guanine and cytosine residues only, as well as hybrid DNA:RNA quadruplexes. New data on pre-folded structures and new quadruplex structural features is important for the design of new organic molecules that could specifically stabilize certain G-quadruplex structure or its preorganized form and thus help in fight against various forms of cancer, many viral diseases and frontotemporal dementia and amyotrophic lateral sclerosis. We will also contribute to the development of experimental methods for oligonucleotide structure elucidation. A strong correlation between RNA G-quadruplex structures and their biological activity is expected to be developed. Results of our studies uncover biological relevance of RNA G-quadruplexes and help in the design stage of new selective ligands for G-quadruplex stabilization and development of potential anti-cancer drugs. Expected results of our research will help to broaden and deepen knowledge of structures and folding of DNA, RNA and proteins involved in several important biological processes as well as their mutual interactions and interactions with small molecules and cations. Understanding of processes in living organisms is based on knowledge of the relationship between structure and function, which recently also includes knowledge of the dynamic properties of molecules. Here, we accentuate the power of NMR in providing information on conformatial exchange and dynamic processes across a large span of time-scales. So far, very little is known about the structural motifs of G-quadruplex structures, which are taken up by guanine-rich regions in the promoter regions of oncogenes. Such knowledge is important for the understanding of the regulation of gene expression and in the design of new organic molecules, which can specifically stabilize a particular G-quadruplex structure. Novel ligands will help in the fight against various forms of cancer and many viral diseases. Novel media for determination of RDC coupling constants are expected to extend possibilities for a partial alignment of small organic molecules and contribute to determination of stereochemistry is systems with chiral centers. So far, anisotropic media created by assembly of G-quartet based systems and G-quadruplexes forming liquid crystalline media have been exploited poorly. New methods will facilitate studies of complex biological mixtures, such as metabolites or peptidoglycans. We were developing new efficient catalysts for better, simpler and economically more efficient processes, where less by-products and waste materials are produced. Study of reaction mechanisms of catalysis will contribute to better understanding of catalytic processes and will improve properties of catalysts. Development of efficient chiral ligands and catalysts to be used in asymmetric synthetic transformations is of the top interest for academic and industrial laboratories all over the world. Onset and prolongation of amyloid neuronal diseases (Parkinson's disease, Alzheimer's disease, Transmissible spongiform encephalopathy, etc.) still represent an unsolved problem. In further studies we hope to contribute to understanding of prion protein conversion into amyloid deposits and transfer knowledge to other models of amyloid diseases. Knowledge about the identity and composition of bioactive substances in the tissues of medicinal plants will enable their further studies towards finding their natural resources. At the same time, identification of compounds gives a starting point for further research on their effectiveness and possible use. In the case of use of hops in brewing, the obtained information will help to understand hops role in the persistence and stability of beer, as is already known that it is a component, which plays a decisive role.
Significance for the country
Research within the program group P1-242 represents an important part of the activities of the Slovenian NMR Centre, which as a core partner of the EN-FIST Centre of Excellence connects academic users and industrial partners. New NMR methods will be available to the widest range of users. NMR spectroscopy is being extensively used to solve both structural and conformational problems of smaller molecules, including organic compounds, active pharmaceutical ingredients and macromolecules such as proteins, nucleic acids and carbohydrates. We expect to contribute to the dissemination and expansion of knowledge in the field of modern NMR spectroscopy to the broader Slovenian scientific community. We wish to emphasize our long-standing collaboration with pharmaceutical and chemical companies in Slovenia, particularly Krka, Lek, Helios, Bia Separations, Melamin and FerroČrtalič. The search for correlations between the structure and function is highly relevant for pharmaceutical industry. We expect that our results will contribute to the understanding of various structural features of DNA, RNA and hybrid DNA:RNA quadruplex structures as well as their pre-folded forms. These systems could be used as targets for development of new drugs as well as in the design of nanomachines based on dynamic folding of oligonucleotides. Novel NMR methods for partial allignment and RDC meassurements could be used in pharmaceutical and chemical industry in determination of relative stereochemistry. Structural, conformational and stereochemical features of molecules of natural origin and potential active pharmaceutical ingredients could be studied by means of NMR spectroscopy. By identifying structural anomalies of prion protein, we hope to better understand the initial stages of transmissible spongiform encephalopathy and prion disease in particular. The acquired knowledge will enable us to screen for compounds that could prevent further stages of the disease. Our goal is to transfer knowledge into pharmaceutical industry that is highly developed in Slovenia. The results of our studies will be very important for the future determination of NMR solution-state RNA G-quadruplex structures. Furthermore, studies of binding interfaces will help to explain possible roles of RNA G-quadruplexes and will be attractive for pharmaceutical companies since we will focus on RNA G-quadruplexes located in the 5’-UTRs of certain mRNAs involved also in cancer. We are the only group in Slovenia working in the field of asymmetric catalysis. Aiming at the construction of new practical catalysts, their application would result in reduction of catalyst loadings still operating in a timely fashion, therefore improving the economics of industrial processes for the synthesis of enantiopure organic compounds. The interest of pharmaceutical industry for such robust catalytic processes to reliably supply the bulk active pharmaceutical ingredients (APIs) is increasing and we are actively collaborating with the local pharmaceutical companies, and developing collaborations with European academic groups. Also, we are introducing asymmetric catalysis to students of chemistry since it is only briefly presented to them during undergraduate studies. Knowledge about the possible effectiveness of medicinal plants provides a starting point for the diversification of agricultural production in Slovenia in the field of cultivation of these plants. A strong interest in agriculture and related processing industries is reflected in search of new possibilities for the production and processing while achieving higher added value. At the same time, such programs create new green jobs and with the displacement of monocultures enrich natural landscape. Optimization of processes in brewing and their deeper understanding provide potential technological improvements and achieving higher competing demands in the brewing industry in Slovenia and on export markets.
Most important scientific results
Annual report
2009,
2010,
2011,
2012,
2013,
final report,
complete report on dLib.si
Most important socioeconomically and culturally relevant results
Annual report
2009,
2010,
2011,
2012,
2013,
final report,
complete report on dLib.si
