Σύνθεση και μελέτη μη φυσικών δομών που αλληλεπιδρούν με το ριβοσωμικό RNA

Abstract

The bacterial ribosome represents the biological target for a variety of known antibiotics, aminoglycosides being the most characteristic example. The pharmaceutical properties of aminoglycosides are due to their ability to bind strongly to the bacterial A-site. This binding interferes with the mechanism of protein synthesis and eventually results in cell death. Nevertheless, despite their former universitality their effectiveness has been greatly diminished by the increasing appearance of resistant bacterial strains. In this thesis, aiming to a new generation of antibiotics based on the aminoglycoside structures, we have designed and synthesized a series of novel, spiro-bicyclic analogues. Selecting amongst the most promising analogues we proceeded to further derivatization by means of proper substitution. The resulting second generation products presented improved antibacterial properties. Furthermore we envisioned and tested a new protocol for indentifying the binding sites of small molecules within the RNA target. Being able to apply such a procedure to molecules with pharmaceutical significance would lead to better clarification of their mechanism of action and easier synthetic protocols of improved analogues.