Design and Evaluation of Azaspirocycles as RNA binders

Abstract

This study presents efficient synthetic pathways for preparing novel azaspirocycles. These methodologies involve functionalizing key bicyclic hydrazines with a substituent on one of their bridgehead carbon atoms. The desired spirocyclic cores were successfully obtained through double reductive amination reactions, intramolecular cyclizations, and cleavages of the N−N bond. The isolated molecules possess unique three-dimensional structures, suggesting potential applications in medicinal chemistry and drug discovery. With the growing interest in targeting nucleic acids as a complementary approach to protein-targeting strategies for developing novel active compounds, we investigated the potential of the synthesized azaspirocycles as RNA binders. As a proof of concept, we highlight the promising activity of some compounds as strong binders of HIV-1 TAR RNA and inhibitors of Tat/TAR interactions.