Pyrrolic Tripodal Receptors Effectively Recognizing Monosaccharides. Affinity Assessment through a Generalized Binding Descriptor

Abstract

Pyrrolic and imino (3) or amino (4) H-bonding ligands were incorporated into a benzene-based tripodal scaffold to develop a new generation of receptors for molecular recognition of carbohydrates. Receptors 3 and 4 effectively bound a set of octylglycosides of biologically relevant monosaccharides, including glucose (Glc), galactose (Gal), mannose (Man), and N-acetyl-glucosamine (GlcNAc), showing micromolar affinities in CDCl3 and millimolar affinities in CD3CN by NMR titrations. Both receptors selectively recognized Glc among the investigated monosaccharides, with 3 generally less effective than 4 but showing selectivities for the all-equatorial beta-glycosides of Glc and GlcNAc among the largest reported for H-bonding synthetic receptors. Selectivities in CDCl3 spanned a range of nearly 250-fold for 3 and over 30-fold for 4. Affinities and selectivities were univocally assessed through the BC50 descriptor, for which a generalized treatment is described that extends the scope of the descriptor to include any two-reagent host-guest system featuring any number of binding constants. ITC titrations of betaGlc in acetonitrile evidenced, for both receptors, a strong enthalpic contribution to the binding interaction, suggesting multiple H bonding. Selectivity trends toward alphaGlc and betaGlc analogous to those obtained in solution were also observed in the gas phase for 3 and 4 by collision-induced dissociation experiments. From comparison with appropriate reference compounds, a substantial contribution to carbohydrate binding emerged for both the imino/amino and the pyrrolic H-bonding groups but not for the amidic group. This previously undocumented behavior, supported by crystallographic evidence, has been discussed in terms of geometric, functional, and coordinative complementarity between H-bonding groups and glycosidic hydroxyls and opens the way to a new designer strategy of H-bonding receptors for carbohydrates.

Boronic Acid‐Based Lectin Mimics (Boronolectins) That Can Recognize Cancer Biomarker, the Thomsen–Friedenrich Antigen

“…Such thinking is in line with earlier discoveries that CH-p interactions can be very important in carbohydrate recognition for the purpose of receptor design. [11] It is worth noting that the best receptor's affinity is comparable to or higher than that of some lectins, and compares favorably to the cage-like systems reported in the literature. [11] The preliminary data described in Hall's paper show the promise of using a peptidyl backbone to build boronic acid-/ benzoboroxole-based carbohydrate receptors for carbohydrate biomarkers of true biological significance.…”

Ion‐Pair Binding: Is Binding Both Binding Better?

“…Rather, what we need is to convert the set of association constants into a parameter describing the overall affinity. We have addressed this issue by using the median binding concentration (BC 50 ) parameter, [41] which we have shown to be a generalized binding descriptor [45] useful for comparing heterogeneous binding data and which we have recently extended to include the binding of salts. [46] The BC 50 parameter, which is defined as the total concentration of a reagent (e.g., a receptor or a ligand) necessary for binding 50 % of an observed species (e.g., a ligand or a receptor), is calculated from the measured formation constants [47] and is best expressed as a function of the fraction of bound reagent (i.e., the reagent for which we want to evaluate the affinity), which represents the saturation degree of the reagent itself.…”

“…This effect is due to the variable contribution to the BC 50 parameter made by complex species involving the counterion, which depend on the (variable) concentration of the latter imposed by the electroneutrality condition. [42] The intrinsic affinity parameter BC 0 50 therefore cannot be used for direct comparison as in two-reagent systems, [45] since these contributions vanish when the concentration of the counterion (along with the fraction of bound cation) is zero.…”

Chiral Diaminopyrrolic Receptors for Selective Recognition of Mannosides, Part 2: A 3D View of the Recognition Modes by X‐ray, NMR Spectroscopy, and Molecular Modeling

“…[3] These second-generation receptors improved substantially in terms of binding abilities and selectivities with respect to the aminopyrrolic tripodal receptors previously reported by us. [4] A closer insight into the origin of the improved performance of these receptors therefore appeared to be the natural development of our studies, thus, we aimed to elucidate the structural features of carbohydrate recognition and derive a 3D model of the complexes.…”