carba-Nucleopeptides (cNPs): A Biopharmaceutical Modality Formed through Aqueous Rhodamine B Photoredox Catalysis.

Jacob R Immel, Steven Bloom

Angewandte Chemie (International ed. in English) 2022 Jul 11

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Exchanging the ribose backbone of an oligonucleotide for a peptide can enhance its physiologic stability and nucleic acid binding affinity. Ordinarily, the eneamino nitrogen atom of a nucleobase is fused to the side chain of a polypeptide through a new C-N bond. The discovery of C-C linked nucleobases in the human transcriptome reveals new opportunities for engineering nucleopeptides that replace the traditional C-N bond with a non-classical C-C bond, liberating a captive nitrogen atom and promoting new hydrogen bonding and π-stacking interactions. We report the first late-stage synthesis of C-C linked carba-nucleopeptides (cNPs) using aqueous Rhodamine B photoredox catalysis. We prepare brand-new cNPs in batch, in parallel, and in flow using three long-wavelength photochemical setups. We detail the mechanism of our reaction by experimental and computational studies and highlight the essential role of diisopropylethylamine as a bifurcated two-electron reductant. © 2022 Wiley-VCH GmbH.

Citation

Jacob R Immel, Steven Bloom. carba-Nucleopeptides (cNPs): A Biopharmaceutical Modality Formed through Aqueous Rhodamine B Photoredox Catalysis. Angewandte Chemie (International ed. in English). 2022 Jul 11;61(28):e202205606