Synthetic Route towards macrocyclic Galectin-3 Inhibitors

Galectins are a 15-member family of β-D-galactose binding proteins that are interesting targets in drug development, since they are linked to various inflammatory diseases, fibrosis and cancer. Efforts to find galactose derived high-affinity inhibitors that are selective towards members of the galectin-family have increased in the last decade. On top of that Galectin-3 has been shown to be a suitable model protein for thermodynamic affinity studies. Galactosides carrying C1 naphthamidomethyl and C3 phenyltriazolyl moieties have reportedly shown high affinity and selectivity towards galectin-3. Based on this knowledge we want to develop a new class of macrocyclic inhibitors featuring these structural elements. Apart from that, the influence of macrocyclization on binding thermodynamics is aimed to be a future subject of study, particularly in the context of conformational entropy. This project work is a contribution to the synthesis of a macrocyclic inhibitor. By means of a fluorescence polarization assay it was discovered that a precursor of the target macrocycle shows an increased affinity to galectin-3, compared to previously reported C1 naphthamidomethyl carrying inhibitors. (Less)