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

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.

Profiling and Identification of Biocatalyzed Transformation of Sulfoxaflor In Vivo

“…Biotic transformations can remove pesticides or organic chemicals from the environment, [15] but in some cases,t hey may also lead to potentially hazardous transformed compounds. [16] In the present study,the phase Iand II metabolites of sulfoxaflor by the liver metabolism pathway were detected. In consideration of higher intake and significantly higher superoxide dismutase (SOD) activity with minor injury, 125 mg kg À1 was chosen as an appropriate middle dose for accumulation of metabolites in the liver ( Figure S4A).…”

Design, Synthesis, and Biological Evaluation of Chemically and Biologically Diverse Pyrroquinoline Pseudo Natural Products

“…Thereby, they go beyond the chemical space explored in NP biosynthesis and may have new biological targets and modes of action. For instance, chromopynones [8] and indotropane [9] pseudo‐NPs are truly novel inhibitors of glucose uptake transporters GLUT1/3 and the pseudo‐NP myokinasib [10] defines an unprecedented ATP competitive/mixed type kinase inhibitor chemotype.…”

Guided by evolution: from biology oriented synthesis to pseudo natural products

“…For example, sp 3 -rich morphan fragments 41 were subjected to Fischer-indole synthesis to efficiently gain access to an indomorphan collection (42, Scheme 15). 66 Biological screening of this 63-membered library resulted in the discovery of glupin, another potent GLUT-1 and GLUT-3 inhibitor. In further studies, glupin was systematically truncated to validate the necessity of the recombination of these two fragments.…”