Article | Published:

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

Nature Chemistryvolume 10pages11031111 (2018) | Download Citation


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    van Hattum, H. & Waldmann, H. Biology-oriented synthesis: harnessing the power of evolution. J. Am. Chem. Soc. 136, 11853–11859 (2014).

  2. 2.

    Wetzel, S., Bon, R. S., Kumar, K. & Waldmann, H. Biology-oriented synthesis. Angew. Chem. Int. Ed. 50, 10800–10826 (2011).

  3. 3.

    Huigens, R. W. et al. A ring distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products. Nat. Chem. 5, 195–202 (2013).

  4. 4.

    Pye, C. R., Bertin, M. J., Lokey, R. S., Gerwick, W. H. & Linington, R. G. Retrospective analysis of natural products provides insights for future discovery trends. Proc. Natl Acad. Sci. USA 114, 5601–5606 (2017).

  5. 5.

    Brakhage, A. A. & Schroeckh, V. Fungal secondary metabolites—strategies to activate silent gene clusters. Fungal Genet. Biol. 48, 15–22 (2011).

  6. 6.

    Khaldi, N. et al. SMURF: genomic mapping of fungal secondary metabolite clusters. Fungal Genet. Biol. 47, 736–741 (2010).

  7. 7.

    Scherlach, K. & Hertweck, C. Triggering cryptic natural product biosynthesis in microorganisms. Org. Biomol. Chem. 7, 1753–1760 (2009).

  8. 8.

    Klein, J. et al. Yeast synthetic biology platform generates novel chemical structures as scaffolds for drug discovery. ACS Synth. Biol. 3, 314–323 (2014).

  9. 9.

    Crane, E. A. & Gademann, K. Capturing biological activity in natural product fragments by chemical synthesis. Angew. Chem. Int. Ed. 55, 3882–3902 (2016).

  10. 10.

    Murray, C. W. & Rees, D. C. The rise of fragment-based drug discovery. Nat. Chem. 1, 187–192 (2009).

  11. 11.

    Roughley, S. D. & Hubbard, R. E. How well can fragments explore accessed chemical space? A case study from heat shock protein 90. J. Med. Chem. 54, 3989–4005 (2011).

  12. 12.

    Over, B. et al. Natural-product-derived fragments for fragment-based ligand discovery. Nat. Chem. 5, 21–28 (2013).

  13. 13.

    Pascolutti, M. et al. Capturing nature's diversity. PLoS One 10, e0120942 (2015).

  14. 14.

    Prescher, H. et al. Construction of a 3D-shaped, natural product like fragment library by fragmentation and diversification of natural products. Bioorg. Med. Chem. 25, 921–925 (2017).

  15. 15.

    Shen, H. C. Asymmetric synthesis of chiral chromans. Tetrahedron 65, 3931–3952 (2009).

  16. 16.

    Babczinski, P., Sandmann, G., Schmidt, R. R., Shiokawa, K. & Yasui, K. Substituted tetrahydropyrimidinones: a new herbicidal class of compounds inducing chlorosis by inhibition of phytoene desaturation. Pest. Biochem. Physiol. 52, 33–44 (1995).

  17. 17.

    Reyes, F. et al. Aplicyanins A–F, new cytotoxic bromoindole derivatives from the marine tunicate Aplidium cyaneum. Tetrahedron 64, 5119–5123 (2008).

  18. 18.

    von Nussbaum, F., Brands, M., Hinzen, B., Weigand, S. & Häbich, D. Antibacterial natural products in medicinal chemistry—exodus or revival? Angew. Chem. Int. Ed. 45, 5072–5129 (2006).

  19. 19.

    Feher, M. & Schmidt, J. M. Property distributions: differences between drugs, natural products, and molecules from combinatorial chemistry. J. Chem. Inform. Comput. Sci. 43, 218–227 (2003).

  20. 20.

    Lee, M.-L. & Schneider, G. Scaffold architecture and pharmacophoric properties of natural products and trade drugs: application in the design of natural product-based combinatorial libraries. J. Comb. Chem. 3, 284–289 (2001).

  21. 21.

    Matache, M. et al. Synthesis of fused dihydro-pyrimido[4,3-d]coumarins using Biginelli multicomponent reaction as key step. Tetrahedron 65, 5949–5957 (2009).

  22. 22.

    Ryabukhin, S. V., Plaskon, A. S., Ostapchuk, E. N., Volochnyuk, D. M. & Tolmachev, A. A. N-substituted ureas and thioureas in Biginelli reaction promoted by chlorotrimethylsilane: convenient synthesis of N1-alkyl-, N1-aryl-, and N1,N3-dialkyl-3,4-dihydropyrimidin-2 (1H)-(thi)ones. Synthesis 2007, 417–427 (2007).

  23. 23.

    Ertl, P., Roggo, S. & Schuffenhauer, A. Natural product-likeness score and its application for prioritization of compound libraries. J. Chem. Inform. Model. 48, 68–74 (2008).

  24. 24.

    Bento, A. P. et al. The ChEMBL bioactivity database: an update. Nucleic Acids Res. 42, D1083–D1090 (2014).

  25. 25.

    Law, V. et al. DrugBank 4.0: shedding new light on drug metabolism. Nucleic Acids Res. 42, D1091–D1097 (2014).

  26. 26.

    Grabowski, K., Baringhaus, K.-H. & Schneider, G. Scaffold diversity of natural products: inspiration for combinatorial library design. Nat. Prod. Rep. 25, 892–904 (2008).

  27. 27.

    Sauer, W. H. B. & Schwarz, M. K. Molecular shape diversity of combinatorial libraries: a prerequisite for broad bioactivity. J. Chem. Inf. Comput. Sci. 43, 987–1003 (2003).

  28. 28.

    Colomer, I. et al. A divergent synthetic approach to diverse molecular scaffolds: assessment of lead-likeness using LLAMA, an open-access computational tool. Chem. Commun. 52, 7209–7212 (2016).

  29. 29.

    Reker, D. et al. Revealing the macromolecular targets of complex natural products. Nat. Chem. 6, 1072–1078 (2014).

  30. 30.

    Bray, M.-A. et al. Cell painting, a high-content image-based assay for morphological profiling using multiplexed fluorescent dyes. Nat. Protoc. 11, 1757 (2016).

  31. 31.

    Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

  32. 32.

    Godoy, A. et al. Differential subcellular distribution of glucose transporters GLUT1-6 and GLUT-9 in human cancer: ultrastructural localization of GLUT1 and GLUT5 in breast tumor tissues. J. Cell. Physiol. 207, 614–627 (2006).

  33. 33.

    Medina, R. et al. Differential regulation of glucose transporter expression by estrogen and progesterone in Ishikawa endometrial cancer cells. J. Endocrinol. 182, 467–478 (2004).

  34. 34.

    Barron, C. C., Bilan, P. J., Tsakiridis, T. & Tsiani, E. Facilitative glucose transporters: implications for cancer detection, prognosis and treatment. Metabolism 65, 124–139 (2016).

  35. 35.

    Meneses, A. M. et al. Regulation of GLUT3 and glucose uptake by the cAMP signalling pathway in the breast cancer cell line ZR-75. J. Cell. Physiol. 214, 110–116 (2008).

  36. 36.

    Siebeneicher, H. et al. Identification and optimization of the first highly selective GLUT1 inhibitor BAY-876. ChemMedChem 11, 2261–2271 (2016).

  37. 37.

    Wang, D. et al. Development of a novel class of glucose transporter inhibitors. J. Med. Chem. 55, 3827–3836 (2012).

  38. 38.

    Yamamoto, N., Sato, T., Kawasaki, K., Murosaki, S. & Yamamoto, Y. A nonradioisotope, enzymatic assay for 2-deoxyglucose uptake in L6 skeletal muscle cells cultured in a 96-well microplate. Anal. Biochem. 351, 139–145 (2006).

  39. 39.

    Li, N. et al. Highly enantioselective organocatalytic Biginelli and Biginelli-like condensations: reversal of the stereochemistry by tuning the 3,3′-disubstituents of phosphoric acids. J. Am. Chem. Soc. 131, 15301–15310 (2009).

  40. 40.

    Macheda, M. L., Rogers, S. & Best, J. D. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J. Cell. Physiol. 202, 654–662 (2005).

  41. 41.

    Szablewski, L. Expression of glucose transporters in cancers. Biochim. Biophys Acta Rev. Cancer 1835, 164–169 (2013).

  42. 42.

    Barretina, J. et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603–607 (2012).

  43. 43.

    Zhan, T., Digel, M., Küch, E.-M., Stremmel, W. & Füllekrug, J. Silybin and dehydrosilybin decrease glucose uptake by inhibiting GLUT proteins. J. Cell. Biochem. 112, 849–859 (2011).

  44. 44.

    Hao, Y. et al. Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer. Nat. Commun. 7, 11971 (2016).

  45. 45.

    Isayev, O. et al. Inhibition of glucose turnover by 3-bromopyruvate counteracts pancreatic cancer stem cell features and sensitizes cells to gemcitabine. Oncotarget 5, 5177–5189 (2014).

  46. 46.

    Goto, Y., Ito, Y., Kato, Y., Tsunoda, S. & Suga, H. One-pot synthesis of azoline-containing peptides in a cell-free translation system integrated with a posttranslational cyclodehydratase. Chem. Biol. 21, 766–774 (2014).

  47. 47.

    Ozaki, T. et al. Dissection of goadsporin biosynthesis by in vitro reconstitution leading to designer analogues expressed in vivo. Nat. Commun. 8, 14207 (2017).

  48. 48.

    Asai, T. et al. Use of a biosynthetic intermediate to explore the chemical diversity of pseudo-natural fungal polyketides. Nat. Chem. 7, 737–743 (2015).

  49. 49.

    Kikuchi, H. et al. Monoterpene indole alkaloid-like compounds based on diversity-enhanced extracts of iridoid-containing plants and their immune checkpoint inhibitory activity. Org. Lett. 18, 5948–5951 (2016).

  50. 50.

    Lovering, F., Bikker, J. & Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009).

  51. 51.

    Nicholls, A. et al. Molecular shape and medicinal chemistry: a perspective. J. Med. Chem. 53, 3862–3886 (2010).

  52. 52.

    Krzeslak, A. et al. Expression of GLUT1 and GLUT3 glucose transporters in endometrial and breast cancers. Pathol. Oncol. Res. 18, 721–728 (2012).

Download references


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


  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


  1. Search for George Karageorgis in:

  2. Search for Elena S. Reckzeh in:

  3. Search for Javier Ceballos in:

  4. Search for Melanie Schwalfenberg in:

  5. Search for Sonja Sievers in:

  6. Search for Claude Ostermann in:

  7. Search for Axel Pahl in:

  8. Search for Slava Ziegler in:

  9. Search for Herbert Waldmann in:


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.

Supplementary information

  1. Supplementary Information

    Supplementary Tables and Figures, Methods, References, Spectra and HPLC traces

  2. Reporting Summary

About this article

Publication history