Quinoline carbohydrate derivatives as galectin-8 inhibitors - From galactose to galactal

Abstract

Galectins are an old fifteen-member protein family. Every galectin has one or two highly conserved carbohydrate recognition domains (CRDs) through which it binds their mutual ligand galactose. They are involved in various pathways such as signaling, autophagy and immune response. However, they also contribute to pathological functions including fibrosis, metastasis, cardiovascular diseases and diabetes. Among this protein family, galectin-8 is known to promote tumor progression and lymphangiogenesis. For this reason, synthesis of novel galectin-8 inhibitors with drug lead abilities is needed as it might help cure those diseases.

As shown by an earlier study, 3-O quinoline methyl -D-galactopyranoside derivatives were discovered to have promising galectin-8N inhibitor potential. To investigate it further, analogues of the most promising compound - methyl 3-O-((7-carboxy)quinolin-2-yl)-methyl)--D-galactopyranoside - were synthesized during this project by functionalizing the carboxylic acid on position 7 of the quinoline. The inhibition capacities of the amide and urea derivatives against galectin-8N measured by fluorescence polarization assay indicated that the affinity dropped compared to the compound of reference. However, the benzylamide derivative displayed a higher selectivity for galectin-8N than the original molecule.

Subsequently, the galactopyranoside was substituted by D-galactal. The inhibition capacities of the galactal-derived quinoline compounds were measured and compared with their corresponding methyl -D-galactopyranoside analogues. It resulted that D-galactal has a better natural affinity and selectivity for galectin-8N than methyl -D-galactopyranoside. However, due to the presence of impurities in the samples, the binding data from the galactal compounds could only be considered as indication and not hard data. Non the less, the benzylamine galactal derivative showed promising affinity and an acute selectivity for galectin-8N. Therefore, it became the new compound of interest.

The crystal structure of methyl 3-O-((7-carboxy)quinolin-2-yl)-methoxy)--D-galactopyranoside was determined with a resolution of 1.56 Å and indicated that the carboxylate on position 7 of the quinoline favored the interaction with the binding-site by forming water-bridged hydrogen bonds with the amino acids Arg52 and Gln54. The crystal structure of 3-O-((7-carboxy)quinolin-2-yl)-methyl)-D-galactal was also determined by X-ray crystallography but the data refinement wasn’t finalized in time to be included in this thesis. Getting the crystal structure of the benzylamine galactal derivative would give interesting insights on the binding properties.

Popular Abstract

“Biology is the most powerful technology ever created. DNA is software, proteins are hardware, cells are factories.”
- Arvind Gupta

What are proteins and why are they so important? A protein is a folded chain of building blocks called amino acids. All building blocks have the same structure except for one subpart that vary from one amino acid to another. In total, they are twenty different amino acids. Most proteins are approximately 400 amino acids long but their size varies greatly depending on their function. Thus there are a lot of possible amino acids combinations which means there are a lot of different proteins.

Proteins are responsible for almost everything that happens in the body, from transporting molecules from one place to another to speeding chemical reactions up through building structures or releasing signals. Therefore, they are fundamental. However, due to their implication in every mechanism and the complexity of our system, they can cause various diseases when ill-regulated. Therefore, a great amount of work is put in research to find ways to block proteins.

In order to activate a protein, a small molecule - called ligand - has to attach itself on a particular part of the surface of the protein - called binding pocket -. Each protein’s binding pocket is specific which is why different proteins respond to different ligands. One way of blocking a protein is to introduce a new small molecule resembling the ligand - called inhibitor - that will bind strongly to the protein without activating it. If the protein’s binding site is occupied by the inhibitor, the ligand can’t be attached and the protein won’t be expressed. Thus inhibitors are good drugs as they are highly selective for their particular proteins which is a must since only the protein involved in the targeted disease has to be shut down.

The research in our group is focused on galectins, a small family of proteins. Galectins are widely spread in the body and take part in many central biological functions such as sending signals and regulating the interactions between cells. However, they are sometimes involved in biological disorders such as cardiac diseases, fibrosis and tumor spreading. Thus they are important drug targets.

There are fifteen different types of galectins. All of them bind a sugar called galactose. The aim of this project was to develop new inhibitors for galectin-8 which is a protein known to be involved in organ graft rejection and diverse types of cancer. An earlier research showed that adding a specific chemical group, called quinoline, to the left side of the natural ligand made it a relatively good inhibitor. Based on these results, the synthesis strategy of this project was to modify the chemical group on the left-hand side of the quinoline to try to improve the affinity even further. During the project, it was discovered that replacing the galactose by another sugar named galactal improved both the affinity and selectivity of the compounds for galectin-8. These promising results will help develop the next generation of galectin-8 inhibitors.

In conclusion, new galectin-8N inhibitors were synthesized with insightful results. However, further optimization is needed to make even better inhibitors.

• author: Baussière, Floriane
• supervisor: Mujtaba Hassan
• organization: Department of Chemistry
• course: KEMR31 20191
• year: 2019
• type: H2 - Master's Degree (Two Years)
• subject: Chemistry
• keywords: organic chemistry, organisk kemi
• language: English
• id: 8991128
• date added to LUP: 2019-08-19 13:51:29
• date last changed: 2019-08-19 13:51:29