Medicinal chemistry of analogues of nucleobases and nucleosides

Novel methodologies developed in our group are directly applied in the synthesis of modified nucleobases, nucleosides and nucleotides for biological activity screening. At first, series of new derivatives with a high degree of diversity of structural types are prepared and tested. In the next stage, fine tuning of structures of active lead compounds is performed. The series of new modified derivatives are being systematically screened on in vitro biological activity. Cytostatic activity against a broad panel of leukemia and tumour cell-lines is tested at IOCB, at the Palacky University Olomouc and in Gilead Sciences, Inc. (Foster City, CA, U.S.A.). Antiviral activity (HIV, HBV, HCV, RSV, Dengue etc.) is studied in Gilead Sciences, Inc. (Foster City, CA, U.S.A.) and at the Novartis Institute for Tropical Diseases (Signapore). Inhibition of several key enzymes of nucleotide metabolism is also systematically tested. In the most active compounds, the metabolism and mechanism of action is studied in collaboration with biochemists, pharmacologists and oncologists.

6-Aryl- and 6-hetarylpurine ribonucleosides were found to possess significant cytostatic activity and anti-HCV activity in submicromolar concentrations. More recently, two important novel classes of potent cytostatics with activities in nanomolar concentrations were discovered: 6-hetaryl-7-deazapurine ribonucleosides and 7-hetaryl-7-deazaadenosines. The most promising examples of these two classes of compounds are now studied in precilinical in vivo tests at the Palacky University Olomouc.