RNA has a multitude of functions including regulating gene expression, catalyzing chemical reactions, and post transcriptional modification. Sequence selective identification of non-coding RNA has been accomplished with the use of peptide nucleic acid (PNA) through Hoogsteen hydrogen bonding to double stranded RNA to form a triple helix. However, sequence selectivity has been limited to polypurine strands containing two sites for Hoogsteen hydrogen bonding. Only one site for pyrimidines results in weaker binding. Our work aims to prepare synthetic nucleobases that afford better binding and sequence selectivity by extending across the U-A base pair forming three hydrogen bonds. Ab initio computations suggest that a design with a modified uracil connected at C5 to a benzamide will afford strong binding affinity. Herein we report the development of the synthesis of T3 and initial binding studies that show strong affinity for the U-A base pair. Optimization of the synthesis includes the coupling of the isoorotic acid to the aminobenzamide moiety through acyl substitution using coupling reagents such as HATU and the introduction of microwave conditions for pyrimidine alkylation. Additionally, various analogs of T3 with different functionalization (hydrogen bond donors) on the aromatic ring will be reported.

Synthesis of a modified amide-based extended heterocyclic nucleobase capable of hydrogen bonding to the U-A base pair in double stranded RNA

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.