Design, synthesis, and evaluation of 1-phenylethanol and C2 threitol derivatives as non-pyranose galactose-mimicking inhibitors of Galectin-3

Abstract: Galectins are cytosolic protein family involved in several biological functions such as cell differentiation, cell migration and apoptosis amongst many others. Their presence is also substantial in diseases including acute inflammation, fibrosis, allergies, and cancer. This protein family consists of 15 members where the majority of them are found in humans and they are divided into three subgroups: prototype, chimera and tandem-repeat. Being the only member of the chimera group, Galectin-3 is an interesting protein to study since it has also been shown to for example promote tumor immune evasion. LacNAc is a fragment, consisting of galactose and glucose, which has been shown to bind to Galectin-3 effectively. By considering and retaining the essential bindings of LacNAc leading to interactions with the amino acid residues in the binding site, synthetic molecules can be developed. By synthesizing small and relatively nonpolar potential inhibitors of Galectin-3, it is predicted that they would be able to pass through the blood-brain barrier and suppress the protein’s function in cell differentiation of cancer cells positioned in the central nervous system. In this project, the derivatives of 1-phenylethanol and their respective enantiomers with S and R configuration, were studied with styrene compounds as starting materials. The reason behind it is to investigate whether a specific enantiomer will interact better with the active binding site of Galectin-3. Analyses of the compounds’ configuration were performed and it was concluded that the OH-group could have adapt its conformation to fit into the binding site. Thus, no significant difference was seen in the binding affinity of S and R-enantiomers. Meanwhile, it was also investigated if C2 threitol derivatives would enhance the affinity of other earlier studied threitol derivatives by interacting with Tryptophan 181. Starting from a D-galactose, a threitol compound can be obtained through a series of reactions where modifications can be further made on C2. In this case, it was concluded that converting the hydroxyl group of C2 to a ketone could have caused possible repulsion when interaction with Trp 181.