Synthesis of Sulfated Glycomimetics with Micromolar Affinity for Midkine

A series of sulfated oligosaccharides (one tetra- and ten disaccharides) have been synthesized to study their interactions with midkine, a heparin-binding growth factor involved in cancer and inflammation. These compounds were prepared as glycosaminoglycan (GAG) mimetics and displayed hydrophobic groups at specific positions to enhance midkine binding. For the synthesis of the tetrasaccharide, a fluoro-assisted strategy was adopted. The use of an <i>N</i>-phenyltrifluoroacetimidate donor, instead of the analogous trichloroacetimidate, proved to be crucial in obtaining the desired tetramer with good yield. On the other hand, the synthesized disaccharides differed in the number of sulfates present and in the substituent at position 2 of the glucosamine unit. Fluorescence polarization competition experiments provided relative binding affinities for each glycomimetic expressed as IC₅₀ values. Our results indicated that all the mimetics interacted with midkine in the micromolar range, highlighting the affinity of the 4,6-di-<i>O</i>-sulfated disaccharides with aromatic rings on the 2-amide group (IC₅₀'s from 3.4 ± 0.8 to 4.3 ± 1.1 μM). Overall, this study offers valuable data for the design and synthesis of high-affinity midkine ligands with potential biological applications.