Développement de mimétiques du sialyl LewisX comportant une unité tartrate différenciée par l’incorporation d’un pharmacophore anionique
E- and P-selectins are important drug targets for treating inflammation related diseases. They play a key role in leukocyte recruitment at sites of injury, which is an important defense mechanism of the immune system. In response to inflammatory stimuli, the vascular cell walls express E- and P-selectins that bind to complementary transmembrane glycoprotein ligands ESL-1 and PSGL-1 located on the surface of leukocytes. These adhesion proteins interact with sialyl LewisX, a tetrasaccharide bound to ESL-1 and PSGL-1 to mediate the rolling and capture of leukocytes at sites of inflammation. Unfortunately, excessive infiltration or accumulation of leukocytes leads to several acute or chronic conditions such as stroke, rheumatoid arthritis and respiratory diseases. E- and P-selectins are also involved in cancer metastasis and in complications for sickle cell diseased patients. Therefore, there is a medical need for drugs that could prevent this excessive recruitment of leukocytes, such as novel sLeX analogues. Recent studies have provided insights into the bioactive conformation of sLeX binding to E- or P-selectins, revealing key pharmacophores. Previously, a first generation of tartrate-based mimetics synthesized and tested by our group have exhibited exciting results. Building upon these results, the objectives of my Master’s research presented in this thesis was to synthesize a second generation of sLeX mimetics functionalized at the acyclic tartrate tether with a side chain bearing an anionic pharmacophore could afford favorable interactions with a second binding site on the selectins. Preliminary results allowed us to isolate two analogues presenting better activity than our first generation of antagonists.
Sialyl LewisX Inflammation Tartrate Analogues Selectins Total synthesis Carbohydrates Mimetics