Synthesis and Evaluation of Oligomeric Thioether-Linked Carbacyclic β-(1→3)-Glucan Mimetics

Extrapolating from lessons learnt with previous low-molecular-weight β-(1→3)-glucan mimetics, we designed a series of minimal 2,4-dideoxy-thioether-linked carbacyclic β-(1→3)-glucan mimetics and synthesized di-, tri-, and tetramers in an enantiomerically pure form by an iterative sequence based on a simple building block readily available from commercial ( S)-(-)-3-cyclohexenecarboxylic acid. These substances were screened for their ability to inhibit anti-CR3-fluorescein isothiocyanate (FITC) staining of human neutrophils and anti-Dectin-1-FITC staining of mouse macrophages as well as for their ability to stimulate phagocytosis and pinocytosis. In each assay, the synthetic compounds displayed comparable activity to the corresponding native β-(1→3)-glucans, laminaritriose, and tetraose, suggesting that the exploitation of hydrophobic patches in the lectin-binding domains of CR3 and Dectin-1 is a promising strategy for the development of small-molecule analogues of β-(1→3)-glucans.