Acyclic Tethers Mimicking Subunits of Polysaccharide Ligands: Selectin Antagonists

Abstract

We report on the design and synthesis of molecules having E- and P-selectins blocking activity both in vitro and in vivo. The GlcNAc component of the selectin ligand sialyl Lewis(X) was replaced by an acyclic tether that links two saccharide units. The minimization of intramolecular dipole-dipole interactions and the gauche effect would be at the origin of the conformational bias imposed by this acyclic tether. The stereoselective synthesis of these molecules, their biochemical and biological evaluations using surface plasmon resonance spectroscopy (SPR), and in vivo assays are described. Because the structure of our analogues differs from the most potent E-selectin antagonists reported, our acyclic analogues offer new opportunities for chemical diversity.

Pan-selectin inhibitors as potential therapeutics for COVID-19 treatment: in silico screening study

“…The experimentally confirmed inhibitors published in the articles by Calosso et al. (2014) ) and Gouge-Ibert et al.…”

“…Nonetheless, while IC 50 values allow for a straightforward comparison of the inhibitors within a single study, they cannot be used to compare inhibitors among the different studies due to the various experimental conditions. To deal with this issue, the logarithm of the ratio of IC 50 of a compound to IC 50 of sLe x was used ( Calosso et al. 2014 ) \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}\begin{equation*} \log \left(\mathrm{ratio}\right)=\log \left(\frac{IC_{50,{\mathrm{sLe}}^{\mathrm{X}}}}{IC_{50,\mathrm{cpd}}}\right).…”

“…To demonstrate the rigid receptor issue, docking of compounds 3 and 26 from the paper by Calosso et al. (2014) ) will be discussed in more detail.…”

Selectins—The Two Dr. Jekyll and Mr. Hyde Faces of Adhesion Molecules—A Review

“…Similarly, it was shown that sialic acid had little effect on the binding to E-selectin [48,343]. Thus, it was suggested to replace the GlcNAc residue with an acyclic tether with defined conformational bias [344], which led to the design and synthesis of selectin antagonists that exhibited the required activity both in vitro and in vivo [345]. Recently, several E-selectin inhibitors that have potential for anti-inflammatory drug development were designed with an approach that targets neighboring regions of the binding site [346].…”

Developing a Library of Mannose-Based Mono- and Disaccharides: A General Chemoenzymatic Approach to Monohydroxylated Building Blocks

“…Ethyl 2,3,4,6-tetra-O-acetyl-1-thio-α-d-mannopyranoside (4) Ethyl 2,3,4,6-tetra-O-acetyl-1-thio-α-d-mannopyranoside (4) was synthesized following a slightly modified protocol reported by Calosso M. et al [43].…”