Chromopynones are pseudo natural product glucose uptake inhibitors targeting glucose transporters GLUT-1 and -3. Issue 11 (November 2018)

• Record Type: Journal Article
• Authors: Karageorgis, George; Reckzeh, Elena; Ceballos, Javier; Schwalfenberg, Melanie; Sievers, Sonja; Ostermann, Claude; Pahl, Axel; Ziegler, Slava; Waldmann, Herbert
• Is Part Of: Nature chemistry. Volume 10:Issue 11(2018)
• Page Start: 1103
• Page End: 1111
• Publication Date: 2018-11
• Subjects: Chemistry -- Periodicals; Chemistry, Physical and theoretical -- Periodicals; Bioorganic chemistry -- Periodicals; 540
• DOI: 10.1038/s41557-018-0132-6
• Languages: English
• ISSNs: 1755-4330

Abstract

Abstract 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. New natural-product-inspired molecules are often limited by their only partial coverage of biologically relevant chemical space. Combining fragments of natural products has now been shown to yield pseudo natural products, which — while still being inspired by natural products — populate previously unexplored areas of chemical space and have novel biological activities.