Novel synthetic inhibitors of selectin-mediated cell adhesion: synthesis of 1,6-bis[3-(3-carboxymethylphenyl)-4-(2-alpha-D- mannopyranosyloxy)phenyl]hexane (TBC1269)
| Autor: | Kathy L. McAbee, Scott Ian L, Timothy P. Kogan, Brian Dupre, Xin Hu, Kassir Jamal M, Peter Vanderslice, Richard A. F. Dixon, Huong Bui, Pamela J. Beck |
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| Rok vydání: | 1998 |
| Předmět: |
Models
Molecular Molecular model biology Chemistry Stereochemistry Cell adhesion molecule Biphenyl Compounds HL-60 Cells Ligand (biochemistry) Fusion protein Chemical synthesis Asthma Sialic acid chemistry.chemical_compound Mannosides Drug Discovery E-selectin biology.protein Cell Adhesion Selectins Molecular Medicine Humans Anti-Asthmatic Agents Mannose Selectin |
| Zdroj: | Journal of medicinal chemistry. 41(7) |
| ISSN: | 0022-2623 |
| Popis: | Reports of a high-affinity ligand for E-selectin, sialyl di-Lewis(x) (sLe(x)Le(x), 1), motivated us to incorporate modifications to previously reported biphenyl-based inhibitors that would provide additional interactions with the protein. These compounds were assayed for the ability to inhibit the binding of sialyl Lewis(x) (sLe(x), 2) bearing HL-60 cells to E-, P-, and L-selectin fusion proteins. We report that dimeric or trimeric compounds containing multiple components of simple nonoligosaccharide selectin antagonists inhibit sLe(x)-dependent binding with significantly enhanced potency over the monomeric compound. The enhanced potency is consistent with additional binding interactions within a single selectin lectin domain; however, multivalent interaction with multiple lectin domains as a possible alternative cannot be ruled out. Compound 15e (TBC1269) showed optimal in vitro activity from this class of antagonists and is currently under development for use in the treatment of asthma. |
| Databáze: | OpenAIRE |
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