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

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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Fig. 1: Design of chromopynone pseudo NPs.
Fig. 2: Synthesis of chromopynones.
Fig. 3: Chromopynones occupy a different portion of chemical space from selected BIOS collections and NPs, and may be endowed with advantageous physiochemical properties.
Fig. 4: Modulation of 2-DG uptake of different cell lines by (−)-(R,R)-chromopynone-1.
Fig. 5: Modulation of proliferation of different cell lines by (−)-(R,R)-chromopynone-1.

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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.

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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.

Corresponding author

Correspondence to Herbert Waldmann.

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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.

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

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Karageorgis, G., Reckzeh, E.S., Ceballos, J. et al. Chromopynones are pseudo natural product glucose uptake inhibitors targeting glucose transporters GLUT-1 and -3. Nature Chem 10, 1103–1111 (2018). https://doi.org/10.1038/s41557-018-0132-6

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