Synthesis of Indomorphan Pseudo-Natural Product Inhibitors of Glucose Transporters GLUT-1 and -3

Javier Ceballos, Melanie Schwalfenberg, George Karageorgis, Elena S. Reckzeh, Sonja Sievers, Claude Ostermann, Axel Pahl, Magnus Sellstedt, Jessica Nowacki, Marjorie A. Carnero Corrales, Julian Wilke, Luca Laraia, Kirsten Tschapalda, Malte Metz, Dominik A. Sehr, Silke Brand, Konstanze Winklhofer, Petra Janning, Slava Ziegler, Herbert Waldmann*

*Corresponding author for this work

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Abstract

Bioactive compound design based on natural product (NP) structure may be limited because of 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 afford structurally unprecedented “pseudo-natural products” (pseudo-NPs). The design, synthesis, and biological evaluation of a collection of indomorphan pseudo-NPs that combine biosynthetically unrelated indole- and morphan-alkaloid fragments are described. Indomorphane derivative Glupin was identified as a potent inhibitor of glucose uptake by selectively targeting and upregulating 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.

Original languageEnglish
JournalAngewandte Chemie - International Edition
Volume58
Issue number47
Pages (from-to)17016-17025
ISSN1433-7851
DOIs
Publication statusPublished - 2019

Keywords

  • antitumor agents
  • glucose transporters
  • inhibitors
  • natural products
  • pseudo-natural products

Cite this

Ceballos, J., Schwalfenberg, M., Karageorgis, G., Reckzeh, E. S., Sievers, S., Ostermann, C., Pahl, A., Sellstedt, M., Nowacki, J., Carnero Corrales, M. A., Wilke, J., Laraia, L., Tschapalda, K., Metz, M., Sehr, D. A., Brand, S., Winklhofer, K., Janning, P., Ziegler, S., & Waldmann, H. (2019). Synthesis of Indomorphan Pseudo-Natural Product Inhibitors of Glucose Transporters GLUT-1 and -3. Angewandte Chemie - International Edition, 58(47), 17016-17025. https://doi.org/10.1002/anie.201909518