Design and Synthesis of Glycomimetics as Selective Galectin Inhibitors

Sammanfattning: In last couple of decades the field of glycobiology has developed rapidly due to the increased understanding of glycans’ abilities to encode biological information, which may have impact on biological event and disease, such as for example tumour growth and inflammation. This development has been accompanied by an increasing focus on drug discovery revolving around a category of carbohydrate-based drugs termed glycomimetics. The proteins of interest in this thesis are the galectins, a family of proteins with affinity towards a-D-galactopyranoside-containing glycans. Galectins have been found to be involved in various diseases, such as cancer, inflammation, fibrosis, heart failure. Hence, the discovery of the small molecule inhibitors will not only provide key tools to study their biological functions and galectin-ligand interactions on a atomic level, but also provide lead compounds for discovery of galectin-targeting drugs.The overall aim of this thesis is divided into two parts, the first one is to develop organic synthetic methodology towards novel glycomimetic structures and to validate the new methodology by evaluating glycomimetic inhibitors fofor galectins and the second part is to develop galectin selective and high affinity inhibitors with novel glycomimetic structures targeting unexplored periferal galectin ligand subsites. The first part is presented in chapters 2-3, where I present in chapter 2 a new methodology to arylate amino sugars and in chapter 3 I used this method to develop N-aryl galactoside and guloside-based glycomimetics as domain selective inhibitors of human galectin-9 controlled by the galactose-gulose epimerization. This is the first report on domain selective inhibitors for any galectin. The impact of this discovery is that it opens a viable strategy for elucidating the particular roles of each domain of galectin-9 in different disease condition and as well in normal biological functions. Chapters 4 and 5 are dedicated to narrating the discovery of sulfonamide-derivatised galactoside as galectin-9N selective inhibitors and quinoline-derivatised galactosides as galectin-8N selective inhibitor, in which the sulfonamides and quinolines form specific and galectin-selective interactions with hitherto unexplored subsites periferal to the core galactopyranose subsite. These galectin-8N and 9N selective inhibitors are expected to be valuable in studies of biological functions of these galectins and as possible leads towards the discovery of galectin-8 or 9-targeting drugs.