Karageorgis, G orcid.org/0000-0001-5088-6047, Reckzeh, ES, Ceballos, J et al. (6 more authors) (2018) Chromopynones are pseudo natural product glucose uptake inhibitors targeting glucose transporters GLUT-1 and -3. Nature Chemistry, 10. pp. 1103-1111. ISSN 1755-4330
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.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | This is an author produced version of a paper published in Nature Chemistry. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
|
Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 26 Sep 2018 14:37 |
Last Modified: | 10 Mar 2019 01:38 |
Status: | Published |
Publisher: | Springer Nature |
Identification Number: | 10.1038/s41557-018-0132-6 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:136150 |