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Selective transformations of complex molecules are enabled by aptameric protective groups

Abstract

Emerging trends in drug discovery are prompting a renewed interest in natural products as a source of chemical diversity and lead structures. However, owing to the structural complexity of many natural compounds, the synthesis of derivatives is not easily realized. Here, we demonstrate a conceptually new approach using oligonucleotides as aptameric protective groups. These block several functionalities by non-covalent interactions in a complex molecule and enable the highly chemo- and regioselective derivatization (>99%) of natural antibiotics in a single synthetic step with excellent conversions of up to 83%. This technique reveals an important structure–activity relationship in neamine-based antibiotics and should help both to accelerate the discovery of new biologically active structures and to avoid potentially costly and cumbersome synthetic routes.

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Figure 1: Structures of aminoglycosides, protection mode and sequences of APGs.
Figure 2: Comparison of acetylation of neomycin B (1) in presence and absence of APG apt1.
Figure 3: Chemo- and regioselective transformation of amino groups of aminoglycosides 1 and 2, and structural confirmation of their derivatives 5 and 8a.

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Acknowledgements

This research was supported by the European Union (European Research Council Starting Grant and Electronic Chemical Cell), the Netherlands Organization for Scientific Research (NWO-Vici, NWO-Echo) and the Zernike Institute for Advanced Materials. A.B. thanks P.v.d. Meulen for help in recording the NMR spectra, as well as M. Pudelko and M. Bastian for useful discussions and suggestions.

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A.B. performed the synthesis and characterization of all the compounds within this project and participated in the design of the study. A.M. tested the antimicrobial activity of the antibiotics and their derivatives. A.H. conceived and designed the study and co-wrote the manuscript with A.B.

Corresponding author

Correspondence to Andreas Herrmann.

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The authors declare no competing financial interests.

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Bastian, A., Marcozzi, A. & Herrmann, A. Selective transformations of complex molecules are enabled by aptameric protective groups. Nature Chem 4, 789–793 (2012). https://doi.org/10.1038/nchem.1402

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