Synthesis and binding of mannose-specific synthetic carbohydrate receptors

Abstract

Synthetic carbohydrate receptors (SCRs) that selectively recognize cell-surface glycans could be used for detection, drug delivery, or as therapeutics. Here we report the synthesis of seven newC(2h)symmetric tetrapodal SCRs. The structures of these SCRs possess a conserved biaryl core, and they vary in the four heterocyclic binding groups that are linked to the biaryl core via secondary amines. Supramolecular association between these SCRs and five biologically relevant C-1-O-octyloxy glycans, alpha/beta-glucoside (alpha/beta-Glc), alpha/beta-mannoside (alpha/beta-Man), and beta-galactoside (beta-Gal), was studied by mass spectrometry,H-1 NMR titrations, and molecular modeling. These studies revealed that selectivity can be achieved in these tetrapodal SCRs by varying the heterocyclic binding group. We found thatSCR017(3-pyrrole),SCR021(3-pyridine), andSCR022(2-phenol) bind only to beta-Glc. SCR019(3-indole) binds only to beta-Man. SCR020(2-pyridine) binds beta-Manand alpha-Manwith a preference to the latter.SCR018(2-indole) binds alpha-Manand beta-Galwith a preference to the former. The glycan guests bound within their SCR hosts in one of three supramolecular geometries: center-parallel, center-perpendicular, and off-center. Many host-guest combinations formed higher stoichiometry complexes, 2:1glycan.SCRor 1:2glycan.SCR, where the former are driven by positive allosteric cooperativity induced by glycan-glycan contacts.