Synthesis and Binding of Mannose-Specific Synthetic Carbohydrate Receptors.

Bravo, Marcelo Fernando; Palanichamy, Kalanidhi; Shlain, Milan; Schiro, Frank; Naeem, Yasir; Marianski, Mateusz; Braunschweig, Adam B

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 new C 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 5 biologically relevant C 1 -O-octyloxy glycans, α/β-glucoside ( α/β-Glc ), α/β-mannoside ( α/β-Man ), and β-galactoside ( β-Gal ), was studied by mass spectrometry, 1 H 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 that SCR017 (3-pyrrole), SCR021 (3-pyridine), and SCR022 (2-phenol) bind only to β-Glc . SCR019 (3-indole) binds only to β-Man. SCR020 (2-pyridine) binds β-Man and α-Man with a preference to the latter. SCR018 (2-indole) binds α-Man and β-Gal with 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, 2:1 glycan•SCR or 1:2 glycan•SCR , where the former are driven by positive allosteric cooperativity induced by glycan-glycan contacts.