Prodrug activation by 4,4’-bipyridine-mediated aromatic nitro reduction

Qing Wang, Yikang Song, Shuowei Yuan, Yaoji Zhu, Wenjing Wang and Ling Chu ()
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Qing Wang: Tsinghua University
Yikang Song: Tsinghua University
Shuowei Yuan: Tsinghua University
Yaoji Zhu: Tsinghua University
Wenjing Wang: Tsinghua University
Ling Chu: School of Pharmaceutical Sciences MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology Tsinghua University

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract Unleashing prodrugs through nitro-reduction is a promising strategy in cancer treatment. In this study, we present a unique bioorthogonal reaction for aromatic nitro reduction, mediated by 4,4‘-bipyridine. The reaction is a rare example of organocatalyst-mediated bioorthogonal reaction. This bioorthogonal reaction demonstrates broad substrate scope and proceeds at low micromolar concentrations under biocompatible conditions. Our mechanistic study reveals that water is essential for the reaction to proceed at biorelevant substrate concentrations. We illustrate the utility of our reaction for controlled prodrug activation in mammalian cells, bacteria, and mouse models. Furthermore, a nitro-reduction-annulation cascade is developed for the synthesis of indole derivatives in living cells.

Date: 2024
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DOI: 10.1038/s41467-024-52604-y

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