Synthetic Route towards macrocyclic Galectin-3 Inhibitors

Abstract

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.

Popular Abstract

Galectins are a specific class of proteins that occur in the cells of our bodies. They can bind to carbohydrates such as the sugar galactose. Galactose is a so-called monosaccharide that makes up half of the disaccharide lactose, which is part of milk. Galectin-proteins participate in numerous cell-processes, for example the regulation of cell death and responses of the immune system. Furthermore, they are linked to diseases such as heart disease or cancer. This makes them an interesting research subject for the development of medical drugs.
By chemically modifying sugars such as galactose we can enhance their binding on galectins and eventually block these proteins. This blocking of dedicated proteins in the body is a principle of many drugs. It ideally results in a positive therapeutic effect with only few side effects. To find such modified sugar-molecules that bind well to the galectins it is necessary to understand in detail how these sugars and proteins interact. This can be done by conducting so called interaction-studies, that show us in detail which parts of the proteins and sugar molecules interact with each other. Experiments like these also give us information how spontaneous or “voluntary” these interactions are.
Macrocycles are organic ring-shaped molecules, that contain 12 or more ring atoms. Some drugs that are used broadly today, for instance certain antibiotics are macrocyclic compounds. Many of them are orally available, so they can be administered to patients in the form of pills. This is a generally beneficial feature of a drug or drug candidate. Their large and flexible ring-structure gives macrocycles special chemical and biophysical properties. This allows them to bind to shallow protein surfaces or binding pockets. The protein pocket where galectins bind and recognize sugars is such a flat and shallow groove. A macrocycle could therefore be suitable to fit into the binding pocket of the galectin-proteins.
This project work is a contribution to a chemical synthesis of a galactose-based macrocycle that could be used for further binding studies on galectins in the future. A precursor of this macrocycle was newly synthesized during the project. It was discovered, that it binds well to one of the members of the galectin protein family.

• author: Schulze, Markus
• supervisor: Ulf Nilsson
• organization: Department of Chemistry
• course: KEMP30 20201
• year: 2020
• type: L3 - Miscellaneous, Projetcs etc.
• subject: Chemistry
• keywords: Medicinal Chemistry, Galectins, Macrocycles, Organic Synthesis, Medicinsk kemi
• language: English
• id: 9032484
• date added to LUP: 2020-12-11 14:12:57
• date last changed: 2020-12-11 14:12:57