Synthesis, Binding Properties, and Differences in Cell Uptake of G-Quadruplex Ligands Based on Carbohydrate Naphthalene Diimide Conjugates

G-quadruplexes (G4) are currently being explored as therapeutic targets in cancer and other pathologies. We have synthesized six carbohydrate naphthalene diimide conjugates (carb-NDIs) as G4 ligands to investigate their potential selectivity on G4 binding and on cell penetration. Carb-NDIs have shown certain selectivity for G4 structures against DNA duplexes but the different sugar moieties did not induce a preference for a specific G4 topology. Interestingly, when monosaccharides were attached through a short ethylene linker to the NDI scaffold their cellular uptake was 2-3 fold more efficient than when the sugar was directly attached through its anomeric position. Moreover, a correlation between the more efficient cell uptake of these carb- NDIs and their higher toxicity in cancerous cell lines has been observed. Carb-NDIs seem to be mainly translocated into the cancer cells through glucose transporters where GLUT4 plays a major role.