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Chromopynones are pseudo natural product glucose uptake inhibitors targeting glucose transporters GLUT-1 and -3

Nature Chemistryvolume 10pages11031111 (2018) | Download Citation

Abstract

The principles guiding the design and synthesis of bioactive compounds based on natural product (NP) structure, such as biology-oriented synthesis (BIOS), are limited by their partial coverage of the NP-like chemical space of existing NPs and retainment of bioactivity in the corresponding compound collections. Here we propose and validate a concept to overcome these limitations by de novo combination of NP-derived fragments to structurally unprecedented ‘pseudo natural products’. Pseudo NPs inherit characteristic elements of NP structure yet enable the efficient exploration of areas of chemical space not covered by NP-derived chemotypes, and may possess novel bioactivities. We provide a proof of principle by designing, synthesizing and investigating the biological properties of chromopynone pseudo NPs that combine biosynthetically unrelated chromane- and tetrahydropyrimidinone NP fragments. We show that chromopynones define a glucose uptake inhibitor chemotype that selectively targets glucose transporters GLUT-1 and -3, inhibits cancer cell growth and promises to inspire new drug discovery programmes aimed at tumour metabolism.

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Acknowledgements

The authors acknowledge the Max-Planck Gesellschaft for financial support. G.K. acknowledges the Alexander von Humboldt Stiftung for a post-doctoral fellowship. E.S.R., M.S. and J.C. acknowledge the International Max-Planck Research School for a doctoral scholarship.

Author information

Affiliations

  1. Max-Planck-Institut für Molekulare Physiologie, Abt. Chemische Biologie, Dortmund, Germany

    • George Karageorgis
    • , Elena S. Reckzeh
    • , Javier Ceballos
    • , Melanie Schwalfenberg
    • , Sonja Sievers
    • , Claude Ostermann
    • , Axel Pahl
    • , Slava Ziegler
    •  & Herbert Waldmann
  2. Technische Universität Dortmund, Fakultät Chemie, Lehrbereich Chemische Biologie, Dortmund, Germany

    • Elena S. Reckzeh
    • , Javier Ceballos
    • , Melanie Schwalfenberg
    •  & Herbert Waldmann
  3. Compound Management and Screening Center, Dortmund, Germany

    • Sonja Sievers
    • , Claude Ostermann
    •  & Axel Pahl

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Contributions

H.W., S.Z. and G.K. conceived and design the project. G.K. and J.C. performed the chemical synthesis. G.K., E.S.R., M.S. and S.S. performed the biological experiments. G.K., C.O. and A.P. performed the chemoinformatic analyses. H.W., S.Z., G.K., E.S.R. and A.P. analysed the results. All authors discussed the results and commented on the manuscript. H.W., S.Z., A.P. and G.K. prepared the manuscript.

Competing interests

H.W. is an academic sponsor of a drug discovery project at Lead Discovery GmbH, aimed at the development of GLUT inhibitors. A patent application for the chrompynones naming naming H.W., G.K., E.S.R., J.C., M.S. and S.Z. as inventors has been filed. S.S., A.P. and C.O. declare no competing financial interests.

Data availability

The materials and data reported in this study are available upon request from H.W.

Corresponding author

Correspondence to Herbert Waldmann.

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DOI

https://doi.org/10.1038/s41557-018-0132-6