The synthesis of C-analogues of thiodigalactoside (TDG) as novel enzymatically stable galectin-1 inhibitors

Session: 
S8.2 Lectins II
Code: 
OL8.2.4
Location (hall): 
Mannose
Start/end time: 
Thursday, July 4, 2019 - 12:30 to 12:45
Kamil
Parkan

Kamil Parkan1, Marcela  Pávová2, Petr Pachl2, Radek Pohl2

1University of Chemistry and Technology, Prague 6 – Dejvice, Czech Republic, 2Institute of Organic Chemistry and Biochemistry, AS CR, Prague 6 – Dejvice, Czech Republic

targets for anticancer and anti-inflammatory drugs development. They are defined by their affinity for β-D-galactopyranoside moieties and their possession of a conserved carbohydrate-recognition domain (CRD). Since lactose and thiodigalactoside (TDG) are known scaffold in preparation of galectin-1 and galectin-3 inhibitors, our goal was therefore preparation of their carba-analogs as enzymatically stable glycomimetics.[1]

Our approach for the synthesis of C-analogues of TDG 1 employs Pd-catalyzed sp2-sp3 cross-coupling reaction of 9-BBN derivative 2 with corresponding 1-iodoglycals 3. The cross-coupling products 4 with one endocyclic double bond allow access to various C-glycosides 1 using various stereoselective transformations. We have found that CDG (β-D-Galp-C-(1→1)-β-D-Galp) occupies in free unbound state predominantly one conformation, which is very similar to the conformation of TDG, and therefore perfectly arranged to fit into the binding site of galectin-1. However, the determination of binding affinity of CDG (Kd = 416 mM) to galectin-1 by ITC showed repeatedly Kd worse than for lactose (Kd = 327 mM). Moreover, TDG binds to galectin-1 about 6 times stronger than lactose (Kd = 57 mM). This difference in binding affinities of CDG and TDG might be therefore attributed to the special geometric arrangement in the proximity of sulfide bridge. We have tested prepared glycomimetics in our optimized viral entry assay using LuSIV cells infected with HIV-1 and in red blood cells hemagglutination assay. Both assays show that CDG has a comparable effect as TDG. These biochemical and biological findings, together with molecular modeling, will serve as a basis for further synthesizing novel glycomimetics with improved efficiency, stability and bioavailability.

Left: X-ray of LecA bound to a divalent ligand and exemplary structure and binding parameters.  Right: Example of trivalent HA inhibitor.

References: 
  1. Hsieh, T.-J.; Lin, H.-Y.;  Tu, Z.;  Lin, T.-C.; Wu, S.-C.;  Tseng, Y.-Y.;  Liu, F.-T.; Hsu, S.-T. D.; Lin, C.-H., Sci. Rep. 2016, 6, 29457.

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