Journal article
Synthesis of Indomorphan Pseudo-Natural Product Inhibitors of Glucose Transporters GLUT-1 and -3
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.
Language: | English |
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Publisher: | John Wiley and Sons Inc. |
Year: | 2019 |
Pages: | 17016-17025 |
ISSN: | 15213773 and 14337851 |
Types: | Journal article |
DOI: | 10.1002/anie.201909518 |
ORCIDs: | 0000-0002-9606-7247 and Laraia, Luca |
SDG 3 - Good Health and Well-being antitumor agents glucose transporters inhibitors natural products pseudo-natural products
Biological Products Biological Transport Cell Cycle Cell Proliferation Glucose Glucose Transporter Type 1 Glucose Transporter Type 3 Glucose transporters: Glycolysis Humans Inhibitors Morphinans Natural products Neoplasms Pseudo-natural products SLC2A1 protein, human SLC2A3 protein, human Tumor Cells, Cultured cancer