Development of Glucose Transporter (GLUT) Inhibitors

Abstract

The discovery of novel compound classes endowed with biological activity is at the heart of chemical biology and medicinal chemistry research. This enables novel biological insights and inspires new approaches to the treatment of diseases. Cancer cells frequently exhibit altered glycolysis and glucose metabolism and an increased glucose demand. Thus, targeting glucose uptake and metabolism may open up novel opportunities for the discovery of compounds that differentiate between normal and malignant cells. This review discusses the different chemical approaches to the development of novel inhibitors of glucose uptake through facilitative glucose transporters (GLUTs), and focusses on the most advanced and potent inhibitor classes known to date. GLUT inhibitors may find application not only in the treatment of cancer, but also of other proliferative diseases that exhibit glucose addiction.

Keywords: Antitumor agents; Cancer; GLUT inhibitors; Natural products; Virtual screening.

Figure 1

The Warburg effect. The preferred pathway for glucose metabolism in differentiated cells (a) and proliferative tissue (b). GLUT=facilitative glucose transporters; TCA=tricarboxylic acid cycle; OXPHOS=oxidative phosphorylation. Adapted from Reckzeh et al.8

Figure 2

Phylogenetic GLUT similarity and functional role. a) Amino acid sequence similarities between GLUT isoforms 1–14 as obtained by CLUSTAL multiple alignment. Adapted from Scheepers et al.10 b) Main expression side, function and preferred substrate of GLUT class I–III.11 Glc = glucose, 2‐DG = 2‐deoxy‐D‐glucose, GlcN = glucosamine, Fru = fructose, Tre = trehalose, HMIT = Proton myo‐inositol cotransporter.

Figure 3

Overview of different assay principles to identify GLUT inhibitors. Glucose or 2‐DG is taken up by the cell via GLUTs and directly quantified using isotope labeling or indirectly quantified by means of enzyme‐coupled reduction of resazurin to resorufin or by quantification of the glycolytic ATP production via simultaneous treatment with inhibitors of oxidative phosphorylation (e.g. rotenone or oligomycin). Virtual screening may be performed using the crystal structure or homology models of GLUTs. GLUT = facilitative glucose transporters; TCA = tricarboxylic acid cycle; OXPHOS=oxidative phosphorylation.

Figure 4

Natural products with GLUT‐inhibiting activity and natural product‐inspired GLUT inhibitors.

Figure 5

Examples for BIOS32 and pseudo natural product design17, [33c] starting from an indole.

Scheme 1

Synthesis of chromopynone‐1 and derivatives. (i) urea (1 equiv.), aldehyde (1 equiv.), 1,3‐dicarbonyl compound (1.5 equiv.), TMSCl (6 equiv.), DMF, r.t., 18 h; (ii) NaHCO₃, MeOH/H₂O, 40 °C, 16 h; (iii) LiOH (15 equiv.), THF/H₂O, 40 °C, 18 h; (iv) 1 m HCl, pH 1–2, 80 °C, 6 h. Synthetic scheme adapted from Karageorgis et al.17

Figure 6

Structures of selected non‐natural GLUT inhibitors.

Scheme 2

Synthetic procedure to obtain Glutor and derivatives. i) 1‐Chloroacetone, K₂CO₃, 18‐crown‐6, 1,4‐dioxane, reflux, 12–72 h; ii) 1–2 % NaOH, H₂O, 70 °C, 1 h; iii) MeOH, r.t.‐40 °C, 5–24 h.