9 In the indomorphans, these fragments are merged to a bridged, bicyclic indolylethylamine-containing novel pseudo-natural product class (Figure 1).ĭesign of the indomorphan pseudo-NP class based on the natural product fragments derived from indole (in blue) and morphan (in red) alkaloids.īiological investigation of the compound collection revealed that the indomorphans define a truly novel, structurally unprecedented glucose uptake inhibitor chemotype. A piperidine fragment is attached in an edge-on connection to an indole moiety in numerous polycyclic indole alkaloids, 9 whereas a benzene ring is linked to a piperidine-containing fragment through a bridge in the scaffold of the morphinan alkaloids. Here we describe the design, synthesis, and biological investigation of indomorphan pseudo-natural products that contain characteristic structural fragments of the biosynthetically unrelated indole 7 and morphan 8 alkaloid classes, each of which is endowed with diverse and different bioactivities (Figure 1). They may have new biological targets and modes of action, such that their bioactivity will best be evaluated in unbiased target-agnostic cell-based assays covering a wide range of biological processes. 4 Pseudo-natural products are obtained by the de novo combination of natural product fragments 5 that generate unprecedented compound classes not accessible by known biosynthesis pathways, and, therefore, go beyond the chemical space explored by nature. These limitations may be overcome by the combination of BIOS with fragment-based design 3 to arrive at “pseudo-natural products”. 2 Limitations of BIOS derive from restricted coverage of natural product like chemical space and biological target space. This reasoning underlies, for example, biology-oriented synthesis (BIOS) 1 and ring-distortion and/or -modification approaches (“complexity to diversity” CtD). Strategies for the design and discovery of novel chemical matter endowed with bioactivity can draw from previous insight about the biological relevance of compound classes. 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. Glupin suppresses glycolysis, reduces the levels of glucose-derived metabolites, and attenuates the growth of various cancer cell lines. Indomorphane derivative Glupin was identified as a potent inhibitor of glucose uptake by selectively targeting and upregulating glucose transporters GLUT-1 and GLUT-3. The design, synthesis, and biological evaluation of a collection of indomorphan pseudo-NPs that combine biosynthetically unrelated indole- and morphan-alkaloid fragments are described. 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). 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.
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