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Abstract

RNA plays key roles in essential biological processes, such as protein synthesis, transcriptional regulation, splicing and retroviral replication. The structural diversity of RNA molecules and the lack of known RNA repair mechanisms make these biopolymers a challenging, yet very important target for therapeutic intervention. In particular, the increasing problems of bacterial resistance to antibiotics make the search for novel RNA binders of crucial importance. Among known RNA binders, aminoglycosides were among the first to be recognized as effectors of RNA functions. Despite the established bactericidal properties of aminoglycoside antibiotics, their therapeutic use is limited, as internal administration of aminoglycoside antibiotics at high doses results in clinical side effects. The 1,3-hydroxylamine motifs and deoxystreptamine moiety, present in all aminoglycosides, are the elements of recognition of RNA. Binding properties of these compounds is believed to be a three-dimensional electrostatic complementarity rather than highly specific contacts between the aminoglycosides and an RNA receptor site. Macrolides are a second class of compounds that bind to the ribosome. A large variety of natural compounds displaying various biological activities are recorded through literature. Most of them, share a macrocyclic lactone ring. Macrolides and aminoglycosides, despite their high potency, remain structurally highly sophisticated. The exploration of new pathways toward molecules of lower structural complexity was performed. Starting from a non iterative method for the synthesis of 15 carbon polyolic chains, (2R,4S)-1,5-bis[(2RS,4SR)-6-(benzyloxy)methoxy]tetrahydro-2H-pyran-2-yl]pentane-2,4-diol, a new intermediate, was isolated and selectively functionalised. In addition, efficient tools for the selective protection of hydroxyl moieties on polyol chains were developed allowing the synthesis of a library of structurally diverse 1,3-hydroxylamine and deoxystreptamine containing compounds. Deoxystreptamine dimers were found to be better RNA binders than 2-deoxystreptamine itself, while linear aminopolyols were found to be good linker candidates for the synthesis of deoxystreptamine dimers. Dynamic combinatorial libraries with a bacterial RNA fragment as biological target were implemented for the identification of new potent RNA binders. Based on macrolactonisation reaction or ring closing metathesis, efficient synthetic routes were explored for the synthesis of polyhydroxylated macrolactones requiring the isolation of few synthetic intermediate and limited protecting groups' manipulations. Glycolipids analogs were also produced on bis amides formation or ring closing metathesis for the synthesis of macrocyclic rings containing a bis(hemiacetal) scaffold and diamino or diamido linkers.

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