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

Nat Chem. 2018 Nov;10(11):1103-1111. doi: 10.1038/s41557-018-0132-6. Epub 2018 Sep 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Products / chemistry
  • Biological Products / pharmacology*
  • Cell Proliferation / drug effects
  • Glucose / metabolism
  • Glucose Transporter Type 1 / drug effects*
  • Glucose Transporter Type 3 / drug effects*
  • Humans
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Proof of Concept Study
  • Structure-Activity Relationship


  • Biological Products
  • Glucose Transporter Type 1
  • Glucose Transporter Type 3
  • SLC2A1 protein, human
  • SLC2A3 protein, human
  • Glucose