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 new C2h 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 C1‐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, 1H 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.

Regiochemical Effects on the Carbohydrate Binding and Selectivity of Flexible Synthetic Carbohydrate Receptors with Indole and Quinoline Heterocyclic Groups

“…Based on the NMR titration data, we determined that the SCRs examined in this study formed exclusively 1 : 1 complexes with the glycans, except for SCR037 ⋅ β‐Glc, which formed the 1 : 2 SCR : glucoside complex, SCR037 ⋅ β‐Glc 2 . In SCR037 ⋅ β‐Glc 2 , a small positive allosteric cooperativity is demonstrated with K 2 > K 1 , [38a,c] and these data are further verified with the molecular modeling results. In addition, several of the SCRs formed dimers ( SCR030 , SCR032 , SCR034 ), with SCR034 having the highest K d , and, as a result, the dimerization was considered in the fitting model.…”

“…To prevent competition caused by H‐bonding with the chemical environment, the nonpolar organic solvent CD 2 Cl 2 was used in lieu of an aqueous solvent to strengthen association [21d,22a,31,32j,33–34,43] . We have also shown previously that some of these tetrapodal SCRs dimerize, [38a] and it is essential to determine the strength of this self‐association and account for this interaction to quantify accurately K a s between the carbohydrates and the SCRs. To do so, dilution experiments were performed on SCR030–SCR039 by examining peak shifting at a concentration range of 20 mM–200 μM to determine if dimerization occurs.…”

“…It should be noted that many peaks with Δδ>0.02 ppm could not be used to calculate K a values because they overlapped with other peaks in the spectra and could not be tracked accurately. To quantify the error in the NMR measurements, the titrations between SCR019 and β‐Man were performed in triplicate, and the error, reported as one standard deviation from the mean in K a , was 15 % [38a] . To demonstrate the data analysis, the NMR peak shift data for the association of SCR032 with α‐Man are shown (Figure 1B & Figure 1C).…”

“…The result of these studies is a library of SCRs with varying binding affinities and selectivities. Noteworthy among these was SCR018 , whose heterocycle is an indole linked to the core at the 2‐position that bound α‐Man [38a] strongly and specifically. α‐Man is a particularly important carbohydrate because of its prevalence on the surfaces of viruses [8–10] and cancer cells [2–4] .…”

Pattern recognition receptors in health and diseases

“…Mannose receptors (MRs) belong to membrane CLRs, which are single-chain transmembrane molecules. 157 – 159 The extracellular segment of MR consists of two parts: one is the proximal membrane end with eight consecutive CTLDs, which is responsible for the endocytosis and transport of the ligand; the other is the distal membrane end of the cysteine-rich lectin domain, which recognizes sulfation of carbohydrate conjugates. 160 The endogenous ligands of MR are lysosomal hydrolase and myeloperoxidase, as well as the mannan-rich structure expressed by pathogens.…”