Dept. of Organic Chemistry
Address: Marulićev trg 20, HR-10000 Zagreb
Phone: +385 1 4597 241
Head: Prof. Irena Škorić, Ph.D.
- NEW HETEROCYCLES AS ANTITUMOR AND ANTIVIRAL («SMART») DRUGS: Synthesis of new, specially selected heterocyclic systems: benzimidazoles, benzthiazoles. benzimidazoquinolines, benzimidazoquinazolines, oxa (thia)-diazacycolpenta[c]fluorenes, benzazoles, pyrimidobenzimidazoles, oxazolo- and thiazolo-pyrimidinium salts and naphthofuran compounds, all bearing pharmacophoric groups (primary cyano and protonated amino and amidino groups), as potential antitumor and antivirus («smart») drugs. Development of new synthetic and photosynthetic methods, specially introducing the photosynthetic methods in water so called «green photochemistry».- Development of microwave synthetic methods.-Introducing the molecular modeling and QSAR methods in drug design and synthesis.- Research of binding (complexing) new synthesized compounds with DNA and determining the new complexes with spectroscopic and and other analitical methods (fluorescence, UV, specrtoscopy, NMR spectroscopy, cyrcular dicroism CD. Flow linear dicroism LD, electrophoresis, x-ray structural analysis).- Complexing of new heterocyclic compounds with methal cations important in living organisms. –Development of chemical compounds for «photodinamic therapy» of cancer which includes the nonactiv and (nontoxic)chemical compound «in situ» of cancer desease and their transformation into antitumor active compound, by using less agresive electronic irradiation (UV or visible light).-Presumption of the mechanism of action of new prepared compounds as intercalators, groove binders, enzime topoisomerase I and II supressors.- By using all acceptable scientific methods and knowledge, we would approach the possibilities to synthesize «smart» drugs in anticancer therapy. (Grace Karminski-Zamola)
- DEVELOPMENT OF NEW PRODRUGS AND DRUGS AGAINST VIRUSES AND CANCER: Widely spread viral infections and cancer represent a health problem of world wide dimension. The main problems in antiviral and cancer chemotherapy are drug resistance and side effects on normal tissues. Therefore, the principal aim of our research is to synthesize the novel compounds that could be used as effective and selective agents against pathogen viruses and human malignant tumors. To achieve this goal the following studies are performed: (i) the synthesis of novel compounds: A. unsaturated acyclic nucleoside analogues; B. bicyclic pyrimidine derivatives of L-ascorbic acid; C. purine and pyrimidine derivatives of unnatural cyclopropane amino acids; D. 1,2,4-triazole-3-carboxamide derivatives of L-ascorbic acid; (ii) the novel compounds are evaluated against pathogen viruses, in particular, human immunodeficiency virus (HIV), human papilloma virus (HPV), herpes simplex virus types 1 an 2 (HSV-1 and 2) and hepatitis C virus (HCV), and human malignant tumor cell lines (e.g. pancreatic carcinoma (MiaPaCa-2), cervical carcinoma (HeLa), non-small cell lung cancer cell lines (NCI-H727)); (iii) the leading compounds with inhibitory activities (EC50) less than 0.1 μg/mL are selected for their in vivo evaluation on appropriate animal models. The research proposal is continuation of our previous studies in which we found the leading compounds of the pyrimidine and purine derivatives of L-ascorbic acid (showing potent and selective inhibitory activities against viruses HPV and HIV, and malignant human tumor cell lines MiaPaCa-2 and HeLa). Our studies are specifically focused on structure optimization of those leading compounds in order to obtain more effective and less toxic antiviral and antitumoral agents. The specific aim of the research is to increase the efficacy of antiviral activity of the nucleoside mimetica leads by their transformation into amino acid phosphoroamidate prodrugs. The proposed studies are highly interdisciplinary and are carried out in collaboration with the Institute for Medical Research, Leuven, Belgium, Laboratory of Functional Genomics of the Department for Molecular Medicine, Institute Ruđer Bošković, Zagreb and National Institute for Chemistry, Ljubljana, Slovenia. (Mladen Mintas)
- DEVELOPMENT OF NEW TRACER MOLECULES FOR POSITRON EMISSION TOMOGRAPHY (PET): Synthesis of specifically fluorinated acyclic pyrimidine and purine derivatives as nucleoside mimetics: (i) C-5 and C-6 disubstituted pyrimidine derivatives, (ii) C-5 alkyl derivatives of N-(hydroxyethoxymethyl)- and N-(1,3-dihydroxyisopentyl)pirimidine, (iii) C-6 acyclic thymine derivatives and (iv) fluorinated derivatives of acyclovir and penciclovir and their application for noninvasive imaging of the viral thymidine kinase enzyme (TK) activity. Development of new 18F-radiolabeled molecules with potential application in visualizing tumor proliferation by positron emission tomography (PET). The research has been performed in collaboration with Center for Radiopharmaceutical Science, ETH and PSI, Zürich, Switzerland. (Silvana Raić-Malić)
- HETEROPOLYCYCLES, SCAFFOLDS TO BIOACTIVE COMPOUNDS. SYNTHESIS AND PHOTOCHEMISTRY: The project involves syntheses and photochemical behaviour of new heterocyclic systems. The emphasis is on the photochemical metodology of the synthesis and the study of the reaction mechanisms by means of which these compounds undergo photochemical intra- or intermolecular cycloaddition reactions to heteropolycyclic compounds. What is being studied is the aromatic conjugated unsaturated polyene system with heterocyclic rings that transform themselves under the influence of light to complicated heteropolycyclic structures, which are often hard to be obtain in a traditional synthetic approach. The heterocyclic derivatives that are studied include furan, pyrrole, thiophene, oxazole or sydnone rings and the influence of the heteroatom on the photoreaction course is investigated. Structure determination of all obtained new compounds is performed by spectroscopic methods using modern techniques. All studied structures are very interesting substrates for biological screening on the presumed pharmacological effect. (Marija Šindler)