Synthesis of Indomorphan Pseudo-Natural Product Inhibitors of Glucose Transporters GLUT-1 and -3.
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Ceballos J, Schwalfenberg M, Karageorgis G, Reckzeh ES, Sievers S, Ostermann C, Pahl A, Sellstedt M, Nowacki J, Carnero Corrales MA, Wilke J, Laraia L, Tschapalda K, Metz M, Sehr DA, Brand S, Winklhofer K, Janning P, Ziegler S, Waldmann H
Angew. Chem. Int. Ed. Engl. 58 (47) 17016-17025 [2019-11-18; online 2019-10-07]
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.
Swedish Metabolomics Centre (SMC) [Service]
PubMed 31469221
DOI 10.1002/anie.201909518
Crossref 10.1002/anie.201909518