Most drugs on the market target proteins. Targeting nucleic acids instead can be a useful approach to developing new pharmaceutically active compounds. In particular, RNA can be an attractive target for small-molecule therapeutics. However, while many compounds can interact with RNA with very good affinities, the rational design of molecules that selectively interact with a specific RNA sequence remains challenging. Spirocyclic compounds that combine an aromatic unit with polyamine functions can show selectivity towards RNA sequences containing certain features in their secondary structures. However, the chemical space of spirocyclic RNA binders has remained somewhat underexplored so far.
Erica Benedetti, Laurent Micouin, Université Paris Cité, CNRS, Paris, France, and colleagues have developed efficient synthetic pathways for the preparation of new azaspirocycles that can serve as RNA binders. The team first prepared bicyclic hydrazine intermediates with benzyl substituents at one of their bridgehead carbon atoms and carbamate protecting groups (Z) on their nitrogen atoms (pictured above on the left). These intermediates were prepared from cyclopentadiene and the corresponding benzyl derivatives.
The hydrazine intermediates were converted to either indolino-piperidine spirocycles (pictured above in the bottom right) in six steps or isoquinoline-piperidine spirocycles (pictured above in the top right) in five steps. The desired spirocyclic cores were obtained via double reductive amination reactions, intramolecular cyclizations, and cleavages of the N–N bond.
The researchers investigated whether the synthesized azaspirocycles can serve as RNA binders. They found that some compounds show promising activity as inhibitors of interactions involving HIV trans-activation response (TAR) RNA and the trans-activator of transcription (Tat) protein, a potential target for disrupting the replication cycle of HIV-1. Overall, the work shows the promise of spirocyclic compounds in designing new small-molecule RNA-targeting agents.
- Design and Evaluation of Azaspirocycles as RNA binders,
Claire Fleurisson, Nessrine Graidia, Jihed Azzouz, Audrey Di Giorgio, Marc Gaysinski, Yann Foricher, Maria Duca, Erica Benedetti, Laurent Micouin,
Chem. Eur. J. 2024.
https://doi.org/10.1002/chem.202403518
