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bioRxiv · 10.64898/2026.03.28.714988

Multicopper oxidase mediated single-carbon insertion for skeletal remodeling

Jiang, B.·Chen, B.·Gao, H.·Huang, J.·Liu, X.·Ma, M.·Wang, Y. A.
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Abstract

Modern drug discovery demands efficient strategies for generating structurally diverse compound libraries. Skeletal editing--a transformative paradigm enabling precise atom-level modifications within molecular frameworks, offers a sustainable alternative to traditional synthetic routes. While carbene insertion-mediated approaches have dominated single-carbon insertion strategies, current methodologies are limited by their reliance on hazardous, unstable carbene precursors and harsh reaction conditions. Herein, we report a multicopper oxidase (MCO)-catalyzed skeletal editing that enables the direct, one-step transformation of phenolic and indole derivatives into functionalized tropones and quinoline analogues through exogenous single-carbon insertion. This platform employs stable and safe nitroalkanes as carbon sources and O2 as the sole terminal oxidant. It accommodates a broad substrate scope and yields products with superior antibacterial activity against to multidrug-resistant strains relative to their parent compounds. This work introduces the first biocatalytic platform for exogenous single-carbon insertion skeletal editing. This sustainable and scalable strategy overcomes key limitations of synthetic approaches, offering efficient skeletal remolding and rapid expansion of bioactive compound libraries. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/714988v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@1f1d09borg.highwire.dtl.DTLVardef@b67c65org.highwire.dtl.DTLVardef@a0cd4dorg.highwire.dtl.DTLVardef@106afe5_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Jiang, B., Chen, B., Gao, H., Huang, J., Liu, X., Ma, M., Wang, Y. A.. 2026-03-31. Multicopper oxidase mediated single-carbon insertion for skeletal remodeling. https://doi.org/10.64898/2026.03.28.714988

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