Projects / Programmes source: ARIS

New targets for old drugs – organoruthenium derivatives of hydroxyquinolines and beta-carbolines as potential anticancer agents

Research activity

Code Science Field Subfield
1.04.00  Natural sciences and mathematics  Chemistry   

Code Science Field
P003  Natural sciences and mathematics  Chemistry 

Code Science Field
1.04  Natural Sciences  Chemical sciences 
Synthesis and characterization, ruthenium, anticancer activity, cathepsins, leukaemia, DNA intercalation, phototherapy
Evaluation (rules)
source: COBISS
Researchers (1)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  30698  PhD Jakob Kljun  Chemistry  Head  2014 - 2016  170 
Organisations (1)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0103  University of Ljubljana, Faculty of Chemistry and Chemical Technology  Ljubljana  1626990  22,728 
The proposed project encompasses different fields of synthetic chemistry ranging from inorganic to organometallic and organic. The aim of the project is to prepare novel ruthenium complexes with 8-hydroxyquinoline and β-carboline ligand with potential anticancer activity. Four series of complexes are planned – complexes with nitroxoline and its 7-substituted derivatives, complexes with clioquinol and its halo analogs, complexes with chelating β-carbolines and photoactivable complexes with monodentate β-carbolines. The goal is to prepare samples of sufficient quantity and purity to perform a detailed physico-chemical characterization and biological evaluation. Synthesis and purification of novel compounds will involve modern experimental techniques such as microwave-assisted reactions, Schlenk techniques, high-performance liquid chromatography and column chromatography. Physico-chemical characterization will include all standard spectroscopic and analytical methods. However, single crystal X-ray crystallography and NMR spectroscopy be used to gain information about the structure and properties of the compounds in solid state, and non aqueous and aqueous solutions. Different approaches to the biological evaluation are planned for each series of compounds keeping in mind the chemical, physical, and biological properties of each group of ligands as the expected properties of the novel compounds. In collaboration with several research groups, we will evaluate/determine the toxicity towards selected cell lines, mechanism of cell death, inhibitory potency of enzymes from the cathepsin family, interactions with other potential macromolecular targets and the possibility of use of the novel compounds in phototherapy.
Significance for science
Biological studies involving metal-containing species are a hot topic in current research and many high-impact journals recently dedicated issues to this topic. The fast development of analytical and spectroscopic techniques (which either exploit the specific physical properties of metals or have reached sufficient accuracy or resolution) allows us to study the mechanisms of action of metal complexes. These very often act as prodrugs – in aqueous solution or in contact with the target biomolecule – they undergo a chemical transformation which generates the active chemical species. Moreover, metal ions have been found to partake at a certain stage of a number of chemical processes. It is thus, on the one hand, of utmost importance to study metal complexes of biologically active compounds. In the case of compounds proposed in this study, 8-hydroxyquinolines, their biological activity is directly connected to the metal-binding properties of the organic moiety. On the other hand, it is possible to study the effects of metal-conjugation through chemical modification of a biologically active molecule and the assessment of the validity of such strategy. Ruthenium complexes have repeatedly proven to be very effective in in vitro and in vivo studies as potential anticancer agents. However, the mechanisms of action still remain unclear and the action through multiple targets is currently proposed. In order to predict (or at least soundly propose) the relationship between structure and activity more structural data must be obtained and coupled with screenings of biological activity (enzyme inhibition, DNA interactions, in vitro toxicity,…) as well as detailed biological evaluations on carefully selected and effective compounds. The proposed study offered both, through the experience of the fellow as synthetic and structural chemist (all crystal structure data of novel compounds will be submitted to the Cambridge structural database and thus available to the scientific community after publication) as well as the multitude of proposed collaborations with long-time partners of the host researcher.
Significance for the country
Even though this project is classified as 'Basic Postdoc project' the economic exploitation of the outcome will be thoroughly considered. As part of the synthetic experimental work, novel ruthenium precursors are envisioned as international suppliers of chemicals currently do not offer a wide range of products at easily affordable prices. Demand for such products is rising as ruthenium complexes are widely studied and used as catalysts in organic chemistry in reactions involving C-H bond activation and olefin metathesis (Nobel prize in Chemistry in 2005). Should a suitable synthetic process for a precursor(s) be developed, the founding of a spin-off company, which would deal with the production and distribution of such chemical(s) is considered. The central European region is the world's leading region in both bioinorganic chemistry and ruthenium chemistry which also comprises the fields of catalysis – olefin metathesis and C-H bond activation – and dyes for dye-sensitized solar cells. There are long-time collaborations between many of the most prominent teams of I. Turel (Ljubljana, Slovenia), B. K. Keppler (University of Vienna, Austria), P. J. Dyson (EPFL, Lausanne, Switzerland), Roger Alberto (ETH, Zurich, Switzerland) and E. Alessio (University of Trieste, Italy) as well as other emerging groups. The award of the fellowship to the candidate continues and strengthens the collaboration between some of those teams as well as reinforce the European position in the field of bioinorganic medicinal chemistry. The project deals with topics of high current interest in inorganic, organometallic, structural, and medicinal chemistry and such research is expected to be the topic of extensive research in the future decades. Moreover, the involvement of the fellow in the study process has allowed him, through close contact with undergraduate, graduate, as well as postgraduate students, to encourage their mobility though various mobility schemes supported by the EU (Erasmus, COST, etc.) within the Central European region, focusing on existing international collaborations of the host research group. However, the postdoc candidate and the host scientist have been able to establish new collaborations arising from the scientific outcome of this project. Part of the knowledge (structural data of novel compounds) were be submitted to the Cambridge Structural Database, a world-wide used database which gathers structural data of small-molecule organic, metal-organic, organometallic and inorganic chemical compounds. This database is used by researchers worldwide for computational studies involving the prediction of chemical properties, the design of novel drug candidates, etc.
Most important scientific results Annual report 2015, final report
Most important socioeconomically and culturally relevant results Annual report 2015, final report
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