1 research outputs found
Synthesis of Indomorphan Pseudo Natural Product Inhibitors of Glucose Transporters GLUTâ1 and â3
Bioactive compound design based on natural product (NP) structure may be limited due to partial coverage of NPâlike chemical space and biological target space. These limitations can be overcome by combining NPâcentered strategies with fragmentâbased compound design through combination of NPâderived fragments to structurally unprecedented âpseudo natural productsâ (pseudoâNPs). We describe the design, synthesis and biological evaluation of a collection of indomorphan pseudoâNPs that combine biosynthetically unrelated indoleâ and morphanâalkaloid fragments. Biological investigation in a cellâbased 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 GLUTâ1 and GLUTâ3. Glupin suppresses glycolysis, reduces the levels of glucoseâderived metabolites and attenuates the growth of various cancer cell lines. Our findings underscore the importance of dual GLUTâ1 and GLUTâ3 inhibition to efficiently suppress tumor cell growth and the cellular rescue mechanism, which counteracts glucose scarcity