Chromopynones are pseudo natural product glucose uptake inhibitors targeting glucose transporters GLUT-1 and -3

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.

Small‐Molecule Inhibition of Glucose Transporters GLUT‐1–4

“…as a potent GLUT‐1/‐3 isoform‐selective inhibitor. Chromopynone‐1 was developed from a chromane–tetrahydropyrimidone hit class that was identified in a cell‐based screen monitoring the uptake of 2DG by enzyme‐coupled resazurin detection in HCT116 cells . It inhibits glucose uptake (IC 50 =414 n m ) in a GLUT‐1‐/‐3‐selective manner as determined with partial rescue of 2DG uptake inhibition in CHO cells that transiently overexpress hGLUT‐1 to ‐4 (Tables and ).…”

“…[26] Chromopynone-1 ( Figure 2) was identified by Waldmann et al as ap otent GLUT-1/-3 isoform-selective inhibitor.C hro-mopynone-1 was developed from ac hromane-tetrahydropyrimidoneh it class that was identified in ac ell-baseds creen monitoring the uptake of 2DG by enzyme-coupled resazurin detection in HCT116 cells. [27] It inhibits glucose uptake (IC 50 = 414 nm)i naGLUT-1-/-3-selective manner as determinedw ith partial rescue of 2DG uptake inhibition in CHO cells that transiently overexpress hGLUT-1 to -4 (Tables 1a nd 2). Growth of HCT116 cells was inhibited by chromopynone-1 with aG I 50 value of > 25 mm (25 mm glucose) and 3.8 mm (5 mm glucose) and of MIA PaCa-2 cells with aG I 50 value of 2.8 mm (25 mm glucose)a nd 0.6 mm (5 mm glucose)a sd etermined by live-cell imaging ( Table 2).…”

Design, Synthesis, and Phenotypic Profiling of Pyrano‐Furo‐Pyridone Pseudo Natural Products

“…[6,29] Given the unprecedented structure of the pseudo NPs, their bioactivities may be unexpected and may differ widely from the activities displayed by the guiding NPs.T herefore, similar to the biological evaluation of newly discovered NPs, they should be investigated in multiple individual bioassays covering aw ide spectrum of biology.A lternatively,p seudo NPs may be more readily and conclusively characterized by target-agnostic phenotyping approaches based on high-content technologies [9] because such phenotypic profiling may efficiently cover larger areas of biological space in one experimental approach. [6,29] Given the unprecedented structure of the pseudo NPs, their bioactivities may be unexpected and may differ widely from the activities displayed by the guiding NPs.T herefore, similar to the biological evaluation of newly discovered NPs, they should be investigated in multiple individual bioassays covering aw ide spectrum of biology.A lternatively,p seudo NPs may be more readily and conclusively characterized by target-agnostic phenotyping approaches based on high-content technologies [9] because such phenotypic profiling may efficiently cover larger areas of biological space in one experimental approach.…”

“…[6,31] Subsequent investigation in cell-based assays excluded autophagy and Hedgehog signaling as well as glucose uptake inhibition as potential modes of action. [6,31] Subsequent investigation in cell-based assays excluded autophagy and Hedgehog signaling as well as glucose uptake inhibition as potential modes of action.…”

“…Forthe design of such compound classes,biological relevance is ak ey property to consider.O ne way to guarantee this relevance is to draw inspiration from the structural properties of the biologically pre-validated molecular repository generated in evolution. [5] We recently proposed and provided proof for the concept of uniting the principles of BIOS with the logic of fragmentbased compound discovery [6] to overcome these limitations. [4] However,t he BIOS approach is biased in the exploration of chemical and biological space since it focuses primarily on the structures of the guiding NPs and their molecular target(s).…”