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.
Subject(s)
Biological Products/pharmacology , Cell Proliferation , Glucose Transporter Type 1/antagonists & inhibitors , Glucose Transporter Type 3/antagonists & inhibitors , Glucose/metabolism , Morphinans/chemical synthesis , Neoplasms/drug therapy , Biological Transport , Cell Cycle , Glycolysis , Humans , Tumor Cells, CulturedABSTRACT
Cancer cells sustain growth by altering their metabolism to accelerated aerobic glycolysis accompanied by increased glucose demand and employ glutamine as additional nutrient source. This metabolic adaptation induces upregulation of glucose transporters GLUT-1 and -3, and simultaneous targeting of both transporters and of glutamine metabolism may offer a promising approach to inhibit cancer cell growth. We describe the discovery of the very potent glucose uptake inhibitor Glutor, which targets glucose transporters GLUT-1, -2, and -3, attenuates glycolytic flux and potently and selectively suppresses growth of a variety of cancer cell lines. Co-treatment of colon cancer cells with Glutor and glutaminase inhibitor CB-839 very potently and synergistically inhibits cancer cell growth. Such a dual inhibition promises to be particularly effective because it targets the metabolic plasticity as well as metabolic rescue mechanisms in cancer cells.
Subject(s)
Glucose Transport Proteins, Facilitative/antagonists & inhibitors , Glucose Transport Proteins, Facilitative/metabolism , Glutaminase/metabolism , Benzeneacetamides/pharmacology , Cell Cycle , Cell Line, Tumor , Cell Proliferation/drug effects , Citric Acid Cycle , Female , Glucose/metabolism , Glucose Transporter Type 1/antagonists & inhibitors , Glucose Transporter Type 1/metabolism , Glucose Transporter Type 3/antagonists & inhibitors , Glucose Transporter Type 3/metabolism , Glutaminase/antagonists & inhibitors , Glutamine/metabolism , Glycolysis/drug effects , Humans , Male , Neoplasms/metabolism , Thiadiazoles/pharmacologyABSTRACT
The principles guiding the design and synthesis of bioactive compounds based on natural product (NP) structure, such as biology-oriented synthesis (BIOS), are limited by their partial coverage of the NP-like chemical space of existing NPs and retainment of bioactivity in the corresponding compound collections. Here we propose and validate a concept to overcome these limitations by de novo combination of NP-derived fragments to structurally unprecedented 'pseudo natural products'. Pseudo NPs inherit characteristic elements of NP structure yet enable the efficient exploration of areas of chemical space not covered by NP-derived chemotypes, and may possess novel bioactivities. We provide a proof of principle by designing, synthesizing and investigating the biological properties of chromopynone pseudo NPs that combine biosynthetically unrelated chromane- and tetrahydropyrimidinone NP fragments. We show that chromopynones define a glucose uptake inhibitor chemotype that selectively targets glucose transporters GLUT-1 and -3, inhibits cancer cell growth and promises to inspire new drug discovery programmes aimed at tumour metabolism.
Subject(s)
Biological Products/pharmacology , Glucose Transporter Type 1/drug effects , Glucose Transporter Type 3/drug effects , Biological Products/chemistry , Cell Proliferation/drug effects , Glucose/metabolism , Humans , Neoplasms/metabolism , Neoplasms/pathology , Proof of Concept Study , Structure-Activity RelationshipABSTRACT
Due to their enhanced metabolic needs many cancers need a sufficient supply of glucose, and novel inhibitors of glucose import are in high demand. Cytochalasin B (CB) is a potent natural glucose import inhibitor which also impairs the actin cytoskeleton leading to undesired toxicity. With a view to identifying selective glucose import inhibitors we have developed an enantioselective trienamine catalyzed synthesis of a CB-inspired compound collection. Biological analysis revealed that indeed actin impairment can be distinguished from glucose import inhibition and led to the identification of the first selective glucose import inhibitor based on the basic structural architecture of cytochalasin B.