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.
Highlights
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
Calculation of the natural product score (NP-score) distribution[12] of this pseudo-NP class, and comparison with the scores calculated for the NP set in ChEMBL,[13] as well as for the set of marketed and experimental drugs listed in DrugBank,[14] revealed that indomorphans exhibit a narrow distribution in a part of the NP-score graph that is not heavily populated by NPs but rather by synthetically accessible biologically relevant molecules (Figure S2 a)
Our results demonstrate that the combination of natural product (NP) fragments in unprecedented arrangements may yield biologically relevant pseudo-NP collections with both novel NP-inspired structure and novel bioactivity
Summary
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 This reasoning underlies, for example, biology-oriented synthesis (BIOS)[1] and ring-distortion and/or -modification approaches (“complexity to diversity”; CtD).[2] Limitations of BIOS derive from restricted coverage of natural product like chemical space and biological target space. These limitations may be overcome by the combination of BIOS with fragment-based design[3] to arrive at “pseudo-natural products”.[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, go beyond the chemical space explored by nature.
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