UC San Diego
A modular approach to the synthesis of small molecules targeting RNA
- Author(s): Carnevali, Maia
- et al.
This study is focused on the synthesis of small RNA- binding molecules that are potential inhibitors of hepatitis C virus protein synthesis and of thymidylate synthase expression. The molecules synthesized are chosen for their "RNA friendly" properties, i.e. hydrogen bonding donor and acceptor properties, pi-stacking ability, rigid, non-planar structure and positively charged amino groups. The two sets of molecules synthesized have a "modular" structure, providing versatility, diversity and the ability to perform parallel synthesis. The first set is a novel class of molecules that contain a cis-3,5- diaminopiperidine (DAP) moiety as a structural mimetic of the 2-deoxystreptamine (2-DOS) pharmacophore of the RNA- binding, natural aminoglycoside antibiotics. Parallel synthesis has been used to obtain focused libraries around scaffolds containing the DAP ring linked to amino acids. The amino acid building blocks allowed for further diversification with various carboxylic acids. Compounds from the libraries have been tested for binding and biological activity against hepatitis C virus RNA. We have also synthesized a library of hydrazone compounds obtained from the reaction of an aromatic hydrazide with an isatin or indole aldehyde. Compounds from the libraries have been tested for binding and biological activity against hepatitis C virus RNA and thymidylate synthase mRNA and structure activity relationship were explored