Ceballos, J, Schwalfenberg, M, Karageorgis, G orcid.org/0000-0001-5088-6047 et al. (17 more authors) (2019) Synthesis of Indomorphan Pseudo Natural Product Inhibitors of Glucose Transporters GLUT‐1 and ‐3. Angewandte Chemie International Edition, 58 (47). pp. 17016-17025. ISSN 1433-7851
Abstract
Bioactive compound design based on natural product (NP) structure may be limited due to partial coverage of NP‐like chemical space and biological target space. These limitations can be overcome by combining NP‐centered strategies with fragment‐based compound design through combination of NP‐derived fragments to structurally unprecedented “pseudo natural products” (pseudo‐NPs). We describe the design, synthesis and biological evaluation of a collection of indomorphan pseudo‐NPs that combine biosynthetically unrelated indole‐ and morphan‐alkaloid fragments. Biological investigation in a cell‐based screen for modulators of glucose uptake identified the indomorphane derivative Glupin as potent inhibitor of glucose uptake. Glupin selectively targets and upregulates both, glucose transporters GLUT‐1 and GLUT‐3. Glupin suppresses glycolysis, reduces the levels of glucose‐derived metabolites and attenuates the growth of various cancer cell lines. Our findings underscore the importance of dual GLUT‐1 and GLUT‐3 inhibition to efficiently suppress tumor cell growth and the cellular rescue mechanism, which counteracts glucose scarcity.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) (https://creativecommons.org/licenses/by/4.0/) |
Keywords: | cancer; Natural products; Glucose transporters: Inhibitors; Pseudo-natural products |
Dates: |
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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: | 07 Oct 2019 10:05 |
Last Modified: | 19 Nov 2019 15:36 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1002/anie.201909518 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:151777 |